Diabetes Mellitus

Dr Fedlu J. Oumer
MD, Internist
February, 2026
 Diabetes Mellitus
• Group of common metabolic disorders
• Unified by hyperglycemia phenotype
• Caused by complex interaction of genetics + environment
• Contributing factors:
• ↓ Insulin secretion
• ↓ Glucose utilization
• ↑ Glucose production
• Leads to metabolic dysregulation → secondary changes in
multiple organ systems
• Tremendous burden on individuals & healthcare system
• In the U.S., DM is the leading cause of:
• End-stage renal disease (ESRD)
• Nontraumatic lower-extremity amputations
• Adult blindness
• Major risk factor for cardiovascular disease → primary cause
of morbidity & mortality
 Classification of Diabetes Mellitus
• Four major etiologic classification of DM:
1. T1DM
2. T2DM
3. GDM
4. Other Types of Diabetes
• Type 1 Diabetes Mellitus
• Autoimmune destruction of beta cells → insulin deficiency
• Recently defined 3 stages:
• Autoantibodies against pancreatic beta cell antigens
• Worsening dysglycemia
• Clinical diabetes
• Type 2 Diabetes Mellitus
• Heterogeneous group of disorders
• Features:
• Insulin resistance
• Impaired insulin secretion
• ↑ Hepatic glucose production
• Preceded by prediabetes:
• Impaired fasting glucose (IFG)
• Impaired glucose tolerance (IGT)
Classification of DM…
• Other Types of Diabetes
• A. Genetic Defects of Beta Cell Function (e.g., monogenic,
MODY):
• HNF4α, Glucokinase, HNF1α
• IPF-1, HNF1β, NeuroD1
• Other regulators: KLF11, PAX4, BLK, GATA4/6, GLUT2, GLIS3
• Mitochondrial DNA mutations
• Monogenic diabetes (MODY):
• Autosomal dominant inheritance
• Early onset (<25 years; sometimes neonatal)
• Impaired insulin secretion
• Insulin receptor mutations:
• Rare disorders with severe insulin resistance
• B. Neonatal Diabetes (<6 months)
• Mutations: ATP-sensitive K⁺ channel, RFX6, insulin
• C. Transient Neonatal Diabetes
Classification of DM…
• Other Types of Diabetes…
• D. Diseases of Exocrine Pancreas
• Pancreatitis, pancreaticectomy, neoplasia
• Cystic fibrosis, hemochromatosis, fibrocalculous pancreatopathy
• Carboxyl ester lipase mutations
• E. Genetic Defects in Insulin Action
• Type A insulin resistance
• Leprechaunism, Rabson-Mendenhall syndrome
• Lipodystrophy syndromes
• F. Endocrinopathies
• Acromegaly, Cushing’s syndrome
• Glucagonoma, pheochromocytoma
• Hyperthyroidism, somatostatinoma, aldosteronoma
 Classification of DM…
• Other Types of Diabetes…
• G. Drug- or Chemical-Induced
• Glucocorticoids, calcineurin/mTOR inhibitors
• Pentamidine, nicotinic acid, statins
• HIV therapies, diazoxide, β-agonists, thiazides
• PCSK9 inhibitors, hydantoins, asparaginase
• α-interferon, antipsychotics, epinephrine, vacor
• H. Infections
• Congenital rubella, CMV, coxsackievirus
• I. Uncommon Immune-Mediated Forms
• Stiff-person syndrome
• Anti-insulin receptor antibodies
• Immune checkpoint inhibitor therapy
• J. Genetic Syndromes Associated with Diabetes
• Wolfram, Down’s, Klinefelter’s, Turner’s
• Friedreich’s ataxia, Huntington’s chorea
• Laurence-Moon-Biedl, dystonic syndromes, porphyria
• Prader-Willi syndrome
Classification of DM…
• Gestational Diabetes Mellitus (GDM)
• Glucose intolerance developing in 2nd or 3rd trimester
• Caused by insulin resistance due to metabolic & hormonal changes of
pregnancy
• Diabetes diagnosed in 1st trimester = preexisting (pregestational) DM,
not GDM
• IDF (2021): ~16% of pregnancies worldwide affected by GDM or
preexisting DM
• Clinical Course
• Most women revert to normal glucose tolerance postpartum
• High risk of future DM: 35–60% within 10–20 years
• Offspring: ↑ risk of metabolic syndrome & type 2 DM later in life
• Recommendations
• ADA: Lifelong screening for women with history of GDM
• Frequency: At least every 3 years
Classification of DM…
• Atypical Diabetes
• Forms of diabetes with features of both type 1 & type 2 DM
• Distinct from monogenic forms (MODY) → not linked to single-gene
defects
• Examples
• Type 2 DM phenotype before puberty
• Type 2 DM phenotype in very lean individuals
• Type 1 DM phenotype without autoantibodies
• Ketosis-prone diabetes:
• Presents with ketoacidosis
• Does not require long-term exogenous insulin
• More common in individuals of African American or Asian
heritage
• Mechanisms underlying atypical forms are actively studied
 Epidemiology & Global Considerations of DM
• Global Trends
• 1985: ~30 million cases
• 2021: 537 million cases (10.5% prevalence)
• Projections (IDF):
• 2030: 643 million (11.3%)
• 2045: 783 million (12.2%)
• Drivers of Rising Prevalence
• Rapid increase in type 2 DM
• Contributing factors:
• Dietary changes & obesity
• Reduced physical activity (industrialization)
• Aging populations
 Epidemiology & Global Considerations…
• Countries with Highest Burden (2021)
• China: 140.9 million
• India: 74.2 million
• Pakistan: 33.0 million
• United States: 32.2 million
• Indonesia: 19.5 million
• Brazil: 15.7 million
• Mexico: 14.1 million
• United States Data (2021)
• Prevalence: 11.6% of population
• Prediabetes: ~38% of adults
• Undiagnosed DM: 22.8% of adults
• Age-specific prevalence:
• 18–44 yrs: 3.0%
• 45–64 yrs: 14.5%
• ≥65 yrs: 24.4%
• Global Undiagnosed Burden
• ~50% of individuals in middle- & low-income countries remain
undiagnosed
Epidemiology & Global Considerations…
• Type 1 Diabetes
• Highest incidence:
• Scandinavia, Middle East
• Lowest incidence:
• Pacific Rim
• Intermediate incidence:
• Northern Europe, United States
• Risk linked to HLA alleles, but incidence rising in non-European
groups
• Countries with greatest number of type 1 DM (<19 yrs):
• India
• United States
• Brazil
• China
• Adult-onset type 1 DM increasingly recognized, prevalence
unclear
Epidemiology & Global Considerations…
• Type 2 Diabetes
• Highest prevalence:
• Pacific Islands
• Middle East
• Intermediate prevalence:
• India, United States
• Influenced by genetic, behavioral, environmental factors
• Ethnic variation within countries:
• U.S. prevalence (age >20 yrs, 2019–2021):
• Non-Hispanic whites: 10.3%
• Asians: 9.2%
• Hispanics: 10.3%
• Non-Hispanic blacks: 12.5%
• Native American/Alaskan natives: 16%
• Earlier onset in most non-Hispanic groups
• Asian populations:
• ↑ prevalence at lower BMI
• Younger age
• ↑ visceral adiposity
• ↓ insulin secretion
Epidemiology & Global Considerations…
• Global Burden & Mortality
• ~75% of individuals with DM live in low- or middle-income
countries
• Mortality:
• 2021: 6.7 million deaths worldwide
• 12.2% of global adult mortality (20–79 yrs)
• ~1/3 of deaths occur in individuals <60 yrs
• Economic impact: ~$1 trillion in global healthcare expenditures
(2021)
Worldwide prevalence of diabetes mellitus.
Spectrum of Glucose Homeostasis & DM Diagnosis
• Glucose homeostasis is a spectrum:
• Normal glucose tolerance → Impaired glucose tolerance →
Diabetes
• Applies to Type 1 DM, Type 2 DM, specific types, gestational
DM
• Categories are not abrupt, can be bidirectional:
• Example: Type 2 DM may revert to impaired glucose tolerance
with weight loss
• Gestational DM may revert to normal or impaired tolerance
postpartum
Spectrum of Glucose Homeostasis & DM Diagnosis…
• Diagnostic Criteria (Right Portion of Spectrum)
1. HbA1c ≥ 6.5%
• Must be measured in NGSP-certified labs (aligned with DCCT reference
assay)
2. Fasting Plasma Glucose (FPG) ≥ 126 mg/dL
• Fasting = no caloric intake ≥ 8 hours
3. 2-hour Plasma Glucose (PG) ≥ 200 mg/dL
• After 75 g oral glucose load (OGTT)
4. Random Plasma Glucose ≥ 200 mg/dL
• With symptoms of hyperglycemia
• Notes
• In absence of unequivocal hyperglycemia, confirm with repeat testing
• Values do not apply to gestational DM
• 1-hour glucose may aid risk prediction in cystic fibrosis or pancreatic
disease
Spectrum of glucose homeostasis and diagnosis of diabetes mellitus
2-h PG
FPG (Fasting Random
(Plasma
Category HbA1c Plasma Plasma
Glucose
Glucose) Glucose
after OGTT)
<5.6%
<5.6 mmol/L <7.8 mmol/L
• Normal Glucose Tolerance (<41 –
(100 mg/dL) (140 mg/dL)
mmol/mol)
5.6–6.9 7.8–11.0
• Prediabetes
5.7–6.4% (42– mmol/L mmol/L
(IFG / IGT) –
47 mmol/mol) (100–125 (140–199
mg/dL) mg/dL)
• Hypergl
ycemia ≥ 11.1
≥ 11.1
• Diabetes mmol/L
≥ 6.5% (≥48 ≥ 7.0 mmol/L mmol/L
Mellitus (≥200
mmol/mol) (≥126 mg/dL) (≥200
mg/dL) +
mg/dL)
symptoms
• Glycemic spectrum in DM
• Not insulin requiring
• Insulin required for control
• Insulin required for survival
 Diagnosis of Diabetes Mellitus
• Categories of Glucose Homeostasis
• Normal glucose tolerance
• Impaired glucose tolerance (Prediabetes)
• Diabetes Mellitus (DM)
• Diagnostic Criteria
• Normal
1. HbA1c < 5.7%
2. FPG < 5.6 mmol/L (<100 mg/dL)
3. 2-h PG < 7.9 mmol/L (<140 mg/dL) after OGTT
• Diabetes Mellitus
1. HbA1c ≥ 6.5% (≥48 mmol/mol)
2. FPG ≥ 7.0 mmol/L (≥126 mg/dL)
3. 2-h PG ≥ 11.1 mmol/L (≥200 mg/dL) after OGTT
4. Random PG ≥ 11.1 mmol/L (≥200 mg/dL) + classic symptoms (polyuria,
polydipsia, weight loss)
• Key Principle
• DM defined as the level of glycemia at which diabetes-specific
complications (e.g., retinopathy) occur, not just deviation from
population mean.
Diagnosis of Diabetes Mellitus…
• Impaired Glucose Homeostasis (Prediabetes)
• ADA
1. HbA1c: 5.7–6.4%
2. Impaired Fasting Glucose (IFG):
• FPG 5.6–6.9 mmol/L (100–125 mg/dL)
3. Impaired Glucose Tolerance (IGT):
• 2-h PG 7.8–11.0 mmol/L (140–199 mg/dL) after OGTT
• WHO Criteria
• IFG defined as FPG > 6.1 mmol/L (110 mg/dL)
• Clinical Significance
• Different mechanisms, but all groups:
• ↑ Risk of progression to Type 2 DM
• ↑ Risk of cardiovascular disease
• Risk increases continuously, not discretely, with rising HbA1c, FPG, or
PG
• Risk Estimates
• HbA1c 6.0–6.5% → 25.5% 5-year risk of Type 2 DM
Diagnosis of Diabetes Mellitus…
• Practical Considerations
• Preferred tests:
• HbA1c & FPG (most reliable, convenient)
• OGTT:
• Limited use (pregnancy, cystic fibrosis-related DM)
• Continuous glucose monitoring (CGM): Emerging role in early
Type 1 DM diagnosis
• Repeat testing recommended unless acute hyperglycemia
present
• Diagnosis can be withdrawn if glucose tolerance reverts to
normal
Screening for Diabetes Mellitus
• Many individuals with DM are asymptomatic & unaware
• Type 2 DM may be present for up to a decade before diagnosis
• Some patients already have diabetes-specific complications at
diagnosis
• Early treatment can alter natural history & reduce complications
• Identifying prediabetes enables prevention strategies
• ADA Recommendations
• All individuals >35 years:
• Screen every 3 years
• Earlier screening:
• If overweight +
• ≥1 risk factor
• Special populations:
• Cystic fibrosis–related DM:
• Start at age 10,
• use OGTT
• Post-transplantation DM:
• Use OGTT
• Additional Considerations
• Rising incidence in children & adolescents, especially minority groups
• Screening in youth increasingly recommended
Criteria for Screening for Type 2 DM in Adults
Criterion Details
• BMI ≥25 kg/m² (≥23 kg/m² in Asian Americans) AND one of:
• Family history (parent/sibling with type 2 DM)
• Race/ethnicity: African American, Latino, Native American, Asian
American, Pacific Islander
• Hypertension ≥130/80 mmHg
• HDL <35 mg/dL (0.90 mmol/L) and/or triglycerides >250 mg/dL (2.82
• 1. Overweight/Obese +
mmol/L)
≥1 Risk Factor
• Polycystic ovary syndrome
• Acanthosis nigricans
• History of cardiovascular disease
• Physical inactivity
• Other insulin resistance conditions (severe obesity, acanthosis
nigricans)
• 2. Prediabetes • IFG, IGT, or HbA1c 5.7–6.4% → screen annually
• 3. Women with GDM • Screen at least every 3 years
• 4. General Population • Initiate testing at age ≥35 years, repeat every 3 years
• 5. Medications • HIV therapy, second-generation antipsychotics, glucocorticoids
• 6. History of Pancreatitis • Screen within 3–6 months post-episode
• 7. Cystic Fibrosis • Begin at age 10 years; OGTT recommended
• 8. Organ Transplantation • Screen post-transplant; OGTT recommended
Regulation of Glucose Homeostasis
• Overall Regulation
• Balance between:
1. Energy intake (food)
2. Hepatic glucose production (gluconeogenesis, glycogenolysis)
3. Peripheral tissue uptake & utilization
• Insulin
• primary regulator
• Other regulators:
• Glucagon
• Neural input
• Metabolic signals
• Adipokines
• Myokines
• Bone-derived factors…
Regulation of Glucose Homeostasis…
• Overall Regulation…
• Fasting State
• Low insulin + modest glucagon rise →
• ↑ hepatic gluconeogenesis & glycogenolysis
• ↓ glucose uptake in muscle & fat
• ↑ mobilization of amino acids & free fatty acids (lipolysis)
• Postprandial State
• ↑ Insulin, ↓ Glucagon →
• Optimized glucose disposal
• Insulin promotes:
• Carbohydrate & fat storage
• Protein synthesis
• Skeletal muscle = major site of postprandial glucose utilization
• Brain uses glucose insulin-independently
Regulation of glucose homeostasis. The organs shown contribute to glucose
utilization, production, or storage
Regulation of Glucose Homeostasis…
• Insulin Biosynthesis
• Site of Production
• Beta cells of pancreatic islets
• Steps of Biosynthesis
• Preproinsulin
• Single-chain, 86–amino acid precursor
• Contains signal peptide
• Proinsulin
• Signal peptide removed
• Structurally related to IGF-I & IGF-II (weak binding to insulin receptor)
• Mature Insulin + C-peptide
• Cleavage of 31–residue fragment → C-peptide
• A-chain (21 aa) + B-chain (30 aa) linked by disulfide bonds
• Stored & co-secreted with C-peptide in secretory granules
Regulation of Glucose Homeostasis…
• Insulin Biosynthesis…
• Clinical Significance
• C-peptide:
• Cleared more slowly than insulin
• Useful marker of endogenous insulin secretion
• Differentiates endogenous vs exogenous insulin in hypoglycemia
evaluation
• Proinsulin levels:
• Elevated in type 1 & type 2 DM → marker of beta cell dysfunction
• Co-secreted Peptides
• Islet amyloid polypeptide (IAPP / Amylin)
• 37–amino acid peptide
• Major component of amyloid fibrils in type 2 DM islets
• Analogue used therapeutically in type 1 & type 2 DM
Regulation of Glucose Homeostasis…
• Insulin Secretion
• Key Regulators
• Primary regulator:
• Glucose
• Other influences:
• Amino acids
• Ketones
• Nutrients
• Gastrointestinal peptides (e.g., GLP-1, GIP)
• Neurotransmitters
• Glucose Threshold
• Insulin synthesis stimulated when glucose > 3.9 mmol/L (70 mg/dL)
• Mechanism: enhances protein translation & processing
• Biphasic Insulin Secretion
• First phase:
• Rapid release of pre-stored insulin
• Second phase:
• Prolonged, sustained secretion
• Clinical note:
• Impaired first-phase response →
• Early abnormality in Type 1 & Type 2 diabetes
Regulation of Glucose Homeostasis…
• Insulin Secretion…
• Glucose Entry & Metabolism
• Transport via facilitative glucose transporter
• Glucokinase phosphorylation = rate-limiting step
• Glycolysis → ATP generation
• ATP inhibits ATP-sensitive K⁺ channel
• K⁺ Channel & Depolarization
• K⁺ channel components:
• Sulfonylurea receptor (drug binding site)
• Kir6.2 inward rectifier
• Inhibition
• Membrane depolarization
• Opens voltage-dependent Ca²⁺ channels →
• Ca²⁺ influx → insulin release
• Alternative Model
• Glycolysis & pyruvate kinase activity
• Localized glucose metabolism modulates K⁺ channel activity
• Independent of oxidative phosphorylation
Regulation of Glucose Homeostasis…
• Insulin Secretion…
• Amplifying Pathways
• Internal cues:
• Ca²⁺ release from ER & intracellular stores
• External cues:
• Incretins (GLP-1, GIP) →
• ↑ cAMP → insulin secretion
• Only active when glucose > fasting level
• Incretin Effects
• Effects
• Stimulate insulin secretion
• Suppress glucagon secretion
• Therapeutic use:
• GLP-1 analogues & DPP-4 inhibitors in Type 2 DM
• Sources:
• Classical: GI tract L-cells after food ingestion
• Emerging evidence: intra-islet GLP-1 from alpha cells
Mechanisms of glucose-stimulated insulin secretion and abnormalities in diabetes. Glucose and other nutrients
regulate insulin secretion by the pancreatic beta cell. Glucose is transported by a glucose transporter (GLUT1 and/or
GLUT2 in humans, GLUT2 in rodents); subsequent glucose metabolism by the beta cell alters ion channel activity,
leading to insulin secretion. The SUR receptor is the binding site for some drugs that act as insulin secretagogues.
Mutations in the events or proteins underlined are a cause of monogenic forms of diabetes.
Regulation of Glucose Homeostasis…
• Insulin Action
• Portal Circulation
• Insulin secreted into portal venous system
• Suppresses hepatic glucose production
• Increases hepatic glucose uptake
• First-pass clearance by liver (~50%)
• Creates portal-to-peripheral gradient ~2:1
• Clinical implication: exogenous insulin lacks this gradient
• Peripheral Circulation
• Uncleared insulin enters systemic circulation
• Targets:
• Skeletal muscle
• Adipose tissue
• Binds to insulin receptor
Regulation of Glucose Homeostasis…
• Insulin Action…
• Insulin Receptor Activation
• Binding → intrinsic tyrosine kinase activity
• Autophosphorylation of receptor
• Recruitment of insulin receptor substrates (IRS)
• IRS + adaptor proteins → signaling cascade
• PI3-Kinase Pathway
• IRS activates PI3-kinase
• Stimulates GLUT4 translocation to cell surface
• Crucial for glucose uptake in muscle & fat
• Other Signaling Pathways
• Glycogen synthesis
• Protein synthesis
• Lipogenesis
• Gene regulation in insulin-responsive cells
• Mitogenic effects (growth, proliferation)
Pathogenesis of T1DM
• Result of genetic, environmental, and immunologic interactions
• Leads to immune-mediated destruction of pancreatic β-cells
• Consequence:
• Absolute insulin deficiency
• Clinical Presentation
• Often dramatic & acute symptoms
• Marked hyperglycemia
• 25–50% present with diabetic ketoacidosis (DKA)
• Can occur at any age
• Classically:
• Prepuberty & adolescence
• Up to 40% onset >30 years
• Adult-onset cases often misdiagnosed as Type 2 DM
• Autoimmunity
• Most patients show islet-directed autoimmunity
• Detected by autoantibodies against islet cell antigens
• ≥2 autoantibodies = Stage 1 Type 1 DM
• Autoantibodies appear after triggering event (infection/environmental)
Pathogenesis of T1DM…
• Natural History of β-cell Decline
• Stage 1:
• Autoantibodies present, normal glucose
• Stage 2:
• Progressive β-cell dysfunction, impaired insulin response
• Stage 3:
• Clinical diabetes with metabolic decompensation
• Timeline:
• Early: loss of first-phase insulin response (years before onset)
• Gradual decline in insulin secretion
• Accelerated decline ~1–2 years before diagnosis
• Susceptibility & triggers of autoimmunity
• Genetic predisposition (HLA associations, family history)
• Environmental factors: infections, toxins (not definitively
proven)
• Immune dysregulation → autoreactive T-cells attack β-cells
Pathogenesis of T1DM…
• Time Course & Honeymoon Phase in T1DM
• Variable Progression
• Time from triggering event → Stage 3 DM varies widely
• Some progress rapidly to clinical diabetes
• Others evolve slowly over years
• Autopsy studies: variable β-cell loss at presentation
• Residual β-cell Function
• At diagnosis: residual functional β-cells remain
• Insufficient in number & quality to maintain glucose tolerance
• Transition to frank hyperglycemia often linked to:
• Infections
• Puberty (↑ insulin requirements)
Pathogenesis of T1DM…
• Honeymoon Phase
• After initial diagnosis: temporary remission
• Glycemic control with modest insulin doses
• Rarely, insulin not needed briefly
• Represents endogenous insulin production from residual β-
cells
• Transient → eventually disappears → complete insulin
deficiency
• Long-Term β-cell Persistence
• Even in long-standing Type 1 DM:
• Small amounts of insulin produced (C-peptide detectable)
• Autopsy studies: β-cells persist decades after diagnosis
• Clinical implication: potential for β-cell preservation therapies
Temporal model for development of type 1 DM. Individuals with a genetic predisposition are exposed to a
trigger that initiates an autoimmune process, resulting in the development of islet autoantibodies and a
gradual decline in beta cell function and mass. Stage 1 disease is characterized by the development of two or
more islet cell autoantibodies but the maintenance of normoglycemia. Stage 2 disease is defined by continued
autoimmunity and the development of dysglycemia. Stage 3 is defined by the development of hyperglycemia
that exceeds the diagnostic criteria for the diagnosis of diabetes. The downward slope of the beta cell function
varies among individuals and may not be continuous. A “honeymoon” phase may be seen in the first 1 or 2
years after the onset of diabetes and is associated with reduced insulin requirements.
Pathogenesis of T1DM…
• Genetic Considerations in T1DM
• Genetic Contribution
• Susceptibility involves multiple genes
• Concordance in identical twins: 30–70%
• Indicates role of additional modifying factors (environmental,
immunologic)
• Major Susceptibility Gene
• Located in HLA region (chromosome 6)
• Accounts for ~50% of genetic risk
• Encodes MHC class II molecules →
• Antigen presentation to helper T cells
• Antigen presentation depends on amino acid composition of binding sites
• Can have predisposing & protective haplotypes
• Predisposing haplotypes:
• DRB1∗0301-DQB1∗0201 (DR3-DQ2)
• Protective haplotypes:
• DRB1∗1501
Pathogenesis of T1DM…
• Genetic Considerations in T1DM…
• Non-HLA Genetic Loci
• 60 loci identified via GWAS
• Examples:
• Insulin gene promoter polymorphisms
• CTLA-4 gene
• IL-2 receptor
• PTPN22
• Polygenic risk scores improve prediction in population-based screening
• Changing Genetic Landscape
• Recent cohorts show:
• ↓ representation of highest-risk HLA alleles
• ↑ penetrance in lower-risk genotypes
• Suggests environmental factors play increasing role in pathogenesis
• Familial Risk
• Risk in relatives:
• Parent with Type 1 DM → 1–9%
• Sibling with Type 1 DM → 6–7% (depends on shared haplotypes)
• Majority (>80%) of individuals with Type 1 DM have no family history
Pathogenesis of T1DM…
• Pathophysiology of TDM…
• Insulitis
• Pancreatic islets show lymphocytic infiltration (insulitis)
• Frequency is heterogeneous within and between individuals
• Autoimmune Abnormalities
• Identified in both innate & adaptive immunity:
1. Islet cell autoantibodies (ICAs)
2. Activated lymphocytes in islets & peripancreatic lymph nodes
3. T lymphocytes proliferating with islet protein stimulation
4. Cytokine release within insulitis
• Islet Cell Autoantibodies (ICAs)
• Directed at:
• Insulin
• Glutamic acid decarboxylase (GAD)
• Islet antigen 2 (IA-2)
• Zinc transporter 8 (ZnT8)
• Present in >85% of new-onset Type 1 DM cases
• Useful for:
• Classifying DM type
• Identifying at-risk individuals (esp. in research cohorts)
Pathogenesis of T1DM…
• Pathophysiology of TDM…
• Predictive Value of ICAs
• Children with high genetic risk:
• ≥2 ICAs in first 3 years → ~70% risk at 10 years
• >80% risk at 15 years
• Led to revised staging system:
• Multiple autoantibodies = Stage 1 Type 1 DM
• Mechanisms of Beta Cell Destruction
• ICAs = biomarkers only, not direct mediators
• Beta cell death primarily via:
• CD8+ T cell–mediated cytotoxicity
• Beta cell “neoantigens” + ↑ MHC class I expression
• Cytokine toxicity:
• TNF-α
• Interferon-γ
• IL-1
• Reactive oxygen species from infiltrating immune cells
Pathogenesis of T1DM…
• Pathophysiology of TDM…
• Autoimmune Suppression Efforts
• Goal: slow beta cell destruction
• Reflected by slower decline in C-peptide levels
• Interventions at diagnosis → partial benefit
• Early Identification & Intervention
• Focus on high-risk individuals:
1. Multiple ICAs in first-degree relatives
2. Multiple ICAs in general population
• Intervention during Stage 1 & 2 disease
• Example – Teplizumab
• Anti-CD3 monoclonal antibody (Fc receptor–nonbinding)
• Single 14-day course → delayed Stage 3 onset by median 32.5 months
• FDA-approved for Stage 2 Type 1 DM
• Used in selected centers for individuals with multiple autoantibodies +
dysglycemia
Pathogenesis of T1DM…
• Pathophysiology of TDM…
• Screening & Referral
• ICA screening becoming widely available
• If ICAs detected:
• Refer to specialized center
• Test for dysglycemia
• Consider treatment to delay clinical diabetes
• Adult-Onset Type 1 DM
• ICA measurement recommended in adults with:
• Younger age at diagnosis
• Ketoacidosis
• Rapid need for insulin
• Helps distinguish adult-onset Type 1 DM from other forms
• Other Islet Cell Types
• Alpha, delta, PP cells spared from autoimmune destruction
• Functional changes contribute to metabolic instability
• Alpha cell dysfunction:
• Fasting & postprandial hyperglucagonemia
• Impaired glucagon response to hypoglycemia
Pathogenesis of T1DM…
• Environmental Factors in T1DM
• Autoimmune process triggered in genetically susceptible individuals
• No single factor conclusively linked to Type 1 DM
• Challenge:
• Trigger may occur years before onset
• Proposed Environmental Triggers
• Viral infections:
• Coxsackievirus
• Rubella
• Enteroviruses
• Dietary factors:
• Bovine milk proteins
• Chemical exposures:
• Nitrosourea compounds
• Nutritional deficiencies:
• Vitamin D deficiency
• Environmental toxins
• Microbiome & T1DM
• Growing interest in the role of the gut microbiome
• Possible influence on immune regulation and autoimmunity
• Active area of ongoing research
Pathogenesis of T2DM
• Heterogeneous Disorder
• Encompasses a range of disorders with common phenotype:
hyperglycemia
• Central mechanisms:
1. Insulin resistance
2. Abnormal insulin secretion
• Primary defect debated:
• Most evidence → insulin resistance precedes secretory defect
• Diabetes develops when secretion becomes inadequate for
resistance level
• Population Insights
• Historically: studies focused on European descent
• Diverse populations reveal differences:
• Latinos → greater insulin resistance
• East & South Asians → more beta cell dysfunction
• Both defects present in all groups
Pathogenesis of T2DM…
• Ethnic Variations
• East & South Asians:
• Develop T2DM at younger age
• Occurs at lower BMI
• African Americans:
• More prone to nonketotic hyperosmolar presentations
• Ketosis-prone DM seen in obese individuals
• Ketosis-resistant DM seen in lean individuals
• Social Determinants of Health
• Major role in global T2DM prevalence
• Factors include:
• Access to healthcare
• Nutrition quality
• Physical activity opportunities
• Socioeconomic status
Pathogenesis of T2DM…
• Genetic Considerations in T2DM
• Strong genetic component
• Concordance in identical twins:
• 70–90%
• Family risk:
• One parent affected → increased risk
• Both parents affected → risk approaches 70%
• Insulin Resistance in Relatives
• Present in many nondiabetic, first-degree relatives
• Demonstrated by reduced glucose utilization in skeletal muscle
• Polygenic & Multifactorial Nature
• Type 2 DM = polygenic + multifactorial
• Environmental modulators:
• Obesity
• Poor nutrition
• Physical inactivity
• Increasing age
• Socioeconomic status
• Shared lifestyle/environment → high family concordance
• In Utero & Early Life Factors
• Birth weight extremes (↑ or ↓) →
• ↑ risk in adulthood
• Gestational hyperglycemia →
• Offspring at higher risk
Pathogenesis of T2DM…
• Genetic Considerations in T2DM…
• Genetic Loci Identified
• 600 loci identified via GWAS
• Each conveys small relative risk (1.06–1.5)
• Most prominent: TCF7L2 gene variant
• Associated with Type 2 DM & impaired glucose tolerance (IGT)
• Mechanisms unclear:
• Mostly noncoding regions
• Likely affect islet function, insulin secretion, or development
• Current Limitations
• <10% of genetic risk explained by known loci
• Combination of loci cannot reliably predict Type 2 DM
• Ongoing research into functional mechanisms
Pathogenesis of T2DM…
• Pathophysiology of T2DM
• Core Features
• Impaired insulin secretion
• Insulin resistance
• Excessive hepatic glucose production
• Abnormal fat metabolism
• Systemic low-grade inflammation
• Role of Obesity
• ≥80% of patients are obese
• Particularly visceral/central obesity (waist–hip ratio)
• Strong driver of insulin resistance
• Early Stage Compensation
• Despite insulin resistance → near-normal glucose tolerance
• Pancreatic beta cells compensate by ↑ insulin output
• Leads to compensatory hyperinsulinemia
Pathogenesis of T2DM…
• Pathophysiology of T2DM…
• Progression to:
• IGT
• As resistance + hyperinsulinemia progress:
• Beta cells fail to sustain insulin output
• Manifests as Impaired Glucose Tolerance (IGT)
• Elevated postprandial glucose
• Fasting Hyperglycemia
• Decline in insulin secretion + ↑ glucagon secretion
• ↑ hepatic glucose production
• Leads to fasting hyperglycemia
• Beta Cell Failure
• Combination of mechanisms → frank beta cell failure
• Results in overt Type 2 Diabetes Mellitus
Metabolic changes during the development of type 2 DM. Insulin secretion and insulin sensitivity are
related, and as an individual becomes more insulin resistant (by moving from point A to point B),
insulin secretion increases. A failure to compensate by increasing the insulin secretion results initially in
impaired glucose tolerance (IGT; point C) and ultimately in type 2 DM (point D).
Pathogenesis of T2DM…
• Metabolic Abnormalities in T2DM
• Insulin Resistance
• Core Feature
• Decreased ability of insulin to act on muscle, liver, fat
• Results from:
• Genetic susceptibility
• Obesity
• Metabolic inflammation
• Relative defect: supranormal insulin can normalize glucose
• Clinical Impact
• Glucose utilization ↓ 30–60% vs. nondiabetic individuals
• Skeletal muscle: impaired glucose uptake
• Liver: ↑ hepatic glucose output (with elevated glucagon)
• Consequences:
• ↑ Fasting plasma glucose (FPG) → hepatic output
• ↑ Postprandial glucose → reduced peripheral utilization
• Molecular Mechanisms
• Insulin receptor levels & tyrosine kinase activity ↓ in skeletal muscle
• Likely secondary to hyperinsulinemia
• Primary defect = postreceptor abnormalities in
phosphorylation/dephosphorylation
Pathogenesis of T2DM…
• Metabolic Abnormalities in T2DM…
• Postreceptor Defects
• Lipid intermediates accumulate in skeletal myocytes
• Impaired mitochondrial oxidative phosphorylation
• ↓ insulin-stimulated mitochondrial ATP production
• Impaired fatty acid oxidation → lipid accumulation → reactive oxygen
species (ROS)
• Inflammation & Feedback
• ROS + lipid peroxides → low-grade metabolic inflammation
• Inflammation worsens insulin resistance
• Creates a vicious cycle of metabolic dysfunction
• Selective Insulin Pathway Resistance
• Not all insulin pathways resistant:
• MAPK pathway (cell growth/differentiation) remains active
• Hyperinsulinemia → ↑ activity in mitogenic pathways
• May accelerate diabetes-related complications (e.g., atherosclerosis)
Pathogenesis of T2DM…
• Metabolic Abnormalities in T2DM…
• Obesity
• Central/visceral obesity = key pathogenic factor
• ≥80% of patients with T2DM are obese
• Visceral fat strongly linked to insulin resistance
• White vs. Brown Fat
• White fat depots → energy storage, adipokine secretion
• Brown fat → high thermogenic capacity
• Research focus: ↑ activity/quantity of brown fat to counter obesity
• Adipocyte Products
• Adipocytes secrete biologic products:
• Nonesterified free fatty acids (FFAs)
• Retinol-binding protein 4
• Leptin
• TNF-α
• Resistin
• IL-6
• Adiponectin (↓ in obesity)
Pathogenesis of T2DM…
• Metabolic Abnormalities in T2DM…
• Adipose Tissue & Inflammation
• Adipose-resident macrophages →
• Major source of metabolic inflammation
• Adipokines regulate:
• Body weight
• Appetite
• Energy expenditure
• Insulin sensitivity
• Pathogenic Effects of Adipokines & FFAs
• ↑ FFAs + pro-inflammatory adipokines →
• Insulin resistance in muscle & liver
• Portal drainage of visceral fat →
• Hepatic dysfunction
• FFAs impair:
• Skeletal muscle glucose utilization
• Beta cell function
• Promote hepatic glucose production
Pathogenesis of T2DM…
• Metabolic Abnormalities in T2DM…
• Adiponectin Deficiency
• Adiponectin = insulin-sensitizing peptide
• ↓ levels in obesity →
• Contributes to hepatic insulin resistance
• Inflammatory State
• Adipocyte products + adipokines →
• Systemic inflammation
• Explains ↑ markers in T2DM:
• IL-6
• C-reactive protein (CRP)
Pathogenesis of T2DM…
• Impaired Insulin Secretion in T2DM
• Interrelation of Secretion & Sensitivity
• Insulin secretion and sensitivity are closely linked
• Early stage: secretion ↑ to compensate for resistance
• Maintains near-normal glucose tolerance initially
• Early Secretory Defects
• Defect is mild and selective at onset
• Greatly reduced first-phase glucose-stimulated secretion
• Response to nonglucose secretagogues (e.g., arginine) preserved
• Overall beta cell function:
• ↓ by ~50% at diagnosis
• Progressive Decline
• Insulin secretory defect worsens over time
• Abnormal proinsulin processing → ↑ proinsulin secretion
• Leads to progressive beta cell dysfunction
Pathogenesis of T2DM…
• Impaired Insulin Secretion in T2DM…
• Possible Mechanisms
• Likely involves a second genetic defect superimposed on resistance
• Defects in:
• Beta cell function
• Beta cell mass
• Cellular identity/differentiation
• Islet Amyloid
• Beta cells co-secrete islet amyloid polypeptide (amylin)
• Forms amyloid fibrillar deposits in long-standing T2DM
• Role (primary vs. secondary) remains unclear
• Metabolic Environment Effects
• Glucose toxicity:
• Chronic hyperglycemia impairs islet function
• Worsens hyperglycemia
• Improved glycemic control → improves islet function
• Lipotoxicity:
• Elevated free fatty acids impair beta cell function
• Inflammation:
• Cytokines + islet-associated macrophages worsen dysfunction
Pathogenesis of T2DM…
• Increased Hepatic Glucose and Lipid Production in T2DM
• Insulin resistance in the liver
• Hyperinsulinemia fails to suppress gluconeogenesis
• Result: fasting hyperglycemia + reduced glycogen storage
postprandially
• Occurs early in diabetes, after onset of:
• Insulin secretory abnormalities
• Glucagon dysregulation
• Skeletal muscle insulin resistance
• Hepatic Glucose Production
• Persistent gluconeogenesis despite high insulin levels
• Fasting hyperglycemia hallmark of hepatic insulin resistance
• Decreased glycogen synthesis/storage in postprandial state
Pathogenesis of T2DM…
• Increased Hepatic Glucose and Lipid Production in
T2DM…
• Adipose Tissue Contribution
• Insulin resistance in adipose tissue → increased lipolysis
• Free fatty acid (FFA) flux to liver rises
• Liver efficiently clears FFAs →
• Substrate for VLDL-triglyceride synthesis
• Dyslipidemia in Type 2 DM
• Elevated triglycerides (↑ VLDL secretion)
• Reduced HDL cholesterol
• Increased small dense LDL particles
• Clinical consequence: atherogenic dyslipidemia
• Progression to Liver Disease
• Retained lipid → hepatic steatosis
• Risk of MASLD (Metabolic dysfunction-associated steatotic liver
disease)
• Abnormal liver function tests may appear
Pathogenesis of T2DM…
• Insulin Resistance Syndromes
• Insulin resistance = impaired biological response to insulin
• Spectrum of disorders with hyperglycemia as a key feature
• Associated with:
• T2DM
• Impaired Glucose Tolerance (IGT) / Impaired Fasting Glucose (IFG)
• Metabolic Syndrome
• Metabolic Syndrome
• Constellation of metabolic derangements:
• Insulin resistance
• Hypertension
• Dyslipidemia (↓ HDL, ↑ triglycerides)
• Central/visceral obesity
• Accelerated cardiovascular disease
Pathogenesis of T2DM…
• Insulin Resistance Syndromes…
• Rare Severe Insulin Resistance
• Genetic mutations in insulin receptor → impaired binding/signal
transduction
• Physical features:
• Acanthosis nigricans
• Hyperandrogenism (hirsutism, acne, oligomenorrhea in women)
• Type A vs Type B Syndromes
• Type A Syndrome
• Young women, severe hyperinsulinemia
• Obesity + hyperandrogenism
• Defect in insulin signaling pathway (undefined)
• Type B Syndrome
• Middle-aged women
• Severe hyperinsulinemia + hyperandrogenism
• Associated autoimmune disorders
• Autoantibodies against insulin receptor → block or stimulate receptor
• May cause intermittent hypoglycemia
Pathogenesis of T2DM…
• Insulin Resistance Syndromes…
• Polycystic Ovary Syndrome (PCOS)
• Common disorder in premenopausal women
• Features: chronic anovulation + hyperandrogenism
• Insulin resistance in significant subset
• ↑ Risk of T2DM independent of obesity
• Lipodystrophies
• Heterogeneous disorders with selective loss of adipose tissue
• Consequences:
• Severe insulin resistance
• Hypertriglyceridemia
• Can be inherited or acquired
• Variable degrees of adipose tissue loss
Prevention of T2DM
• Prediabetes as a Precursor
• Type 2 DM is preceded by:
• Impaired Glucose Tolerance (IGT)
• Impaired Fasting Glucose (IFG)
• Window of opportunity for prevention
• Lifestyle Modifications
• Structured programs recommended for at-risk individuals
• Goals:
• Reduce body weight
• Increase physical activity
• Diabetes Prevention Program (DPP):
• Diet + exercise (30 min/day, 5 days/week)
• ↓ risk of T2DM by 58% vs placebo
• Effective across age, sex, ethnic groups
• Weight loss: 5–7% body weight over 3 years
• Benefits persisted ≥ 15 years
Prevention of T2DM…
• Pharmacologic Prevention
• Metformin:
• ↓ risk by 31% vs placebo
• Other agents:
• α-glucosidase inhibitors
• Thiazolidinediones
• GLP-1 receptor agonists
• SGLT-2 inhibitors
• Orlistat
• Emerging therapies:
• GLP-1 + GIP receptor agonist (tirzepatide)
• Greater weight loss potential
• Global Evidence
• Finnish and Chinese studies:
• Diet + exercise effective in preventing/delaying T2DM
• Reinforces universal benefit of lifestyle intervention
• Intensive Diet Interventions
• Very-low-calorie intake → effective in prevention
• Supports weight reduction and metabolic improvement
Other Forms of Diabetes Mellitus
• Monogenic diabetes
• Aka MODY
• Caused by single-gene mutations
• Autosomal dominant inheritance
• Accounts for <5% of type 2 DM cases
• Genes involved:
• Transcription factors,
• Glucokinase,
• Insulin,
• Other islet factors…
• Key Genetic Mutations
• HNF-4α, HNF-1α, HNF-1β
• Expressed in liver, pancreatic islets, kidney
• Affect islet development, insulin secretion, beta-cell mass
• Glucokinase gene
• Alters glucose sensing in beta cells
• Pancreatic and duodenal homeobox 1 (PDX1)
• Regulates pancreatic development and insulin gene transcription
Other Forms of Diabetes Mellitus…
• MODY…
• Clinical Features of MODY Subtypes
• MODY 3 (HNF-1α mutation):
• Progressive decline in glycemic control
• Responds to sulfonylureas (may discontinue insulin)
• HNF-1β mutation:
• Progressive insulin secretion impairment + hepatic insulin resistance
• Requires insulin (minimal sulfonylurea response)
• Associated features: renal cysts, mild pancreatic exocrine insufficiency,
abnormal LFTs
• Glucokinase Mutation (MODY 2)
• Mild-to-moderate, stable hyperglycemia
• Does not respond to oral hypoglycemic agents
• Usually no treatment required (except during pregnancy)
• Mechanism: higher glucose threshold needed for insulin secretion
• PDX1 Mutation
• Homozygous mutation: pancreatic agenesis
• Heterozygous mutation: diabetes mellitus due to impaired insulin
transcription
Other Forms of Diabetes Mellitus…
• MODY…
• Permanent Neonatal Diabetes (PND)
• Onset < 6 months of age
• Heterogeneous group of disorders
• Caused by genetic mutations affecting:
• Beta cell function
• Pancreatic development
• Clinical overlap with type 1 DM
• Typically requires insulin therapy
• ATP-Sensitive Potassium Channel Mutations
• Genes: Kir6.2 and ABCC8
• Mechanism: impaired glucose-stimulated insulin secretion
• Clinical importance:
• Patients may respond to sulfonylureas
• Insulin therapy can sometimes be discontinued
• GATA6 Mutations
• Most common cause of pancreatic agenesis
• Leads to absent or severely impaired insulin secretion
• Glucokinase Mutations
• Homozygous mutations → severe neonatal diabetes
• Mechanism: altered glucose sensing in beta cells
• Higher glucose threshold required for insulin secretion
Other Forms of Diabetes Mellitus…
• MODY…
• PND…
• Mitochondrial DNA Mutations
• Associated with:
• Diabetes
• Deafness (syndromic presentation)
• Insulin Gene Mutations (MIDY)
• Mutant Ins-gene-induced diabetes of youth (MIDY)
• Mechanism: defective proinsulin folding, processing, bioactivity
• Results in impaired insulin secretion
• Extrapancreatic Manifestations
• Some neonatal diabetes syndromes associated with:
• Neurologic dysfunction
• Other systemic abnormalities
• Clinical Recommendations
• Any individual with diabetes onset < 6 months → genetic screening
• Tailor therapy based on mutation type:
• Sulfonylureas for ATP-sensitive K⁺ channel mutations
• Insulin for pancreatic agenesis or severe secretion defects
• Screen for associated syndromic features (renal, hepatic, neurologic, auditory)
Other Forms of Diabetes Mellitus…
• COVID-19 and Diabetes Mellitus
• Early Observations
• Strong connection noted between DM and SARS-CoV-2 infection
• Hyperglycemia more common in infected individuals
• Presence of DM worsened clinical outcomes in COVID-19 patients
• Impact on Diabetes Incidence
• Early studies suggested ↑ incidence of type 1 DM during pandemic
• Ongoing data collection → evidence remains inconclusive
• Most likely: SARS-CoV-2 does not directly cause type 1 or type 2 DM
• Pathophysiology & Mechanisms
• SARS-CoV-2 infection does not directly destroy beta cells
• Does not independently cause type 2 DM
• Instead:
• Increases ascertainment of DM (diagnosis in previously undiagnosed cases)
• Creates clinical conditions that worsen hyperglycemia (similar to other
serious illnesses)
Other Forms of Diabetes Mellitus…
• Pancreatic Exocrine Disease and DM (Type 3c DM)
• Sometimes termed:
• Type 3 / 3c DM
• Pancreatic DM
• Pancreatogenic DM
• Distinct from type 1 and type 2 DM
• Pathogenesis:
• Islet damage or destruction →
• Insulin + glucagon deficiency
• Pancreatic-Endocrine Interaction
• Increasing recognition of cross-talk between:
• Pancreatic endocrine compartment
• Pancreatic exocrine compartment
• Exact mechanisms remain unclear
• Clinical Associations
• Pancreatitis:
• Episode should prompt diabetes screening
• Pancreatic cancer:
• Associated with new-onset type 2 DM
• Cystic fibrosis: improved survival →
• ↑ prevalence of CF-related diabetes (~50%)
Other Forms of Diabetes Mellitus…
• Pancreatic Exocrine Disease and DM (Type 3c DM)…
• Therapy
• In most forms of pancreatic diabetes → insulin is preferred therapy
• Limited role for oral hypoglycemic agents
• Other Rare Forms of DM
• Immune Checkpoint–Related Diabetes
• Rapid onset of hyperglycemia, often with DKA
• Occurs after initiation of immune checkpoint therapy:
• Anti-PD-1
• Anti-PD-L1
• ± Anti-CTLA-4
• Incidence: <1% of treated individuals
• Pathogenesis of Immune Checkpoint–Related DM
• Similarities to type 1 DM:
• Genetics
• Occasional presence of islet cell autoantibodies (ICA)
• Likely distinct mechanism (not fully understood)
• Requires insulin therapy
Approach to the Patient with DM
• Initial Considerations
• Confirm diagnosis of DM
• Identify type of diabetes (Type 1, Type 2, others)
• Assess acute vs. chronic symptoms
• Screen for complications (microvascular, macrovascular)
• Acute Hyperglycemia Symptoms
• Polyuria, polydipsia
• Weight loss, fatigue, weakness
• Blurry vision (lens water content changes)
• Frequent superficial infections (vaginitis, fungal skin infections)
• Slow healing of minor skin lesions
• Chronic Hyperglycemia Symptoms
• Typically appear after 10–20 years of disease
• Neuropathy (sensory loss, pain)
• Retinopathy (vision changes, blindness risk)
• Nephropathy (proteinuria, renal impairment)
• Macrovascular disease (coronary artery disease, stroke, PAD)
Approach to the Patient with DM…
• History
• Key Elements
• Current weight and recent changes
• Family history of DM and complications
• Sleep history, exercise habits, smoking status
• Cardiovascular risk factors (HTN, dyslipidemia)
• History of pancreatic disease, alcohol use
• Prior diabetes care: therapies, HbA1c trends, glucose monitoring
• Frequency of hypoglycemia episodes (<3.0 mmol/L / <54 mg/dL)
• Patient’s knowledge of diabetes, nutrition, exercise, sleep
• Review of Systems
• Hyperglycemia-related symptoms
• Catabolic state: muscle breakdown, protein degradation
• Vision changes (reversible with glycemic control)
• Infections and wound healing issues
Approach to the Patient with DM…
• History….
• Diabetes-Related Complications
• Microvascular:
• Retinopathy,
• Nephropathy,
• Neuropathy
• Macrovascular:
• CAD,
• Stroke
• Peripheral arterial disease
• Other comorbidities:
• Hypertension
• Dyslipidemia
• Obesity
• Special Considerations
• Pregnancy plans in women of childbearing age
• ADA recommendation: HbA1c <6.5% before conception
Approach to the Patient with DM…
• Physical Examination in DM
• General Examination
• Complete physical exam
• Weight and BMI
• Blood pressure (including orthostatic BP)
• Cardiovascular exam (peripheral pulses)
• Skin and insulin injection sites
• Retinal Examination
• Fundoscopic exam for retinopathy
• Detect microaneurysms, hemorrhages, exudates
• Assess visual acuity and macular involvement
• Oral Examination
• Teeth and gums (periodontal disease more frequent in DM)
• Look for gingivitis, periodontitis, infections
Approach to the Patient with DM…
• Physical Examination in DM…
• Annual Foot Examination
• Key Components
• Blood Flow
• Palpate pedal pulses
• Sensation
• Vibratory sensation
• 128-Hz tuning fork at great toe
• Monofilament testing
• 5.07, 10-g monofilament
• Pinprick sensation
• Ankle reflexes
• Inspection
• Nail care
• Foot deformities
• Hammer toes,
• Claw toes,
• Charcot foot
• Sites of potential ulceration
Approach to the Patient with DM…
• Physical Examination in DM…
• Neuropathy Screening
• Distal symmetric polyneuropathy
• Annual screening from initial diagnosis
• Autonomic neuropathy
• Screening 5 years after Type 1 DM diagnosis
• At diagnosis of Type 2 DM
• Aim: Detect Loss of Protective Sensation (LOPS)
Approach to the Patient with DM…
• Classification of DM in an Individual Patient
• Importance of Classification
• Guides personalized therapy
• Identifies prognosis and complications
• Not always clear-cut at diagnosis
• Overlap between Type 1 and Type 2 DM
• Challenges in Classification
• Heterogeneity in immune markers, insulin requirements, beta-cell loss
• Age, obesity, and insulin use are not always reliable indicators
• Adults with new-onset DM may be difficult to classify
Approach to the Patient with DM…
• Classification of DM in an Individual Patient…
• Features Suggestive of Type 1 DM
• Younger age at diagnosis (<35 years)
• Non-obese BMI
• Ketoacidosis at presentation
• Markedly elevated plasma glucose at diagnosis
• Family/personal history of autoimmune disease:
• Autoimmune thyroid disease
• Adrenal insufficiency
• Pernicious anemia
• Celiac disease
• Vitiligo…
• Measurement of islet cell antibodies (ICA)
• Caveats in Type 1 DM
• Not all patients fit the classic profile
• Increasing prevalence of overweight/obesity in new-onset Type 1 DM
• Clinical features must be interpreted with caution
Approach to the Patient with DM…
• Classification of DM in an Individual Patient…
• Features Suggestive of Type 2 DM
• Obesity (80% of patients) but;
• Lean phenotype possible in elderly or South/East Asian populations
• May not require insulin therapy initially
• Associated conditions:
• Insulin resistance
• Hypertension
• Cardiovascular disease
• Dyslipidemia
• Polycystic ovary syndrome (PCOS)…
• Abdominal obesity and hypertriglyceridemia common
Approach to the Patient with DM…
• Classification of DM in an Individual Patient…
• Changing Epidemiology
• Type 2 DM increasingly diagnosed at younger ages
• Rising prevalence among overweight children and adolescents
• Expanding spectrum of diabetes phenotypes
• Ketosis-Prone Type 2 DM
• Phenotypic Type 2 DM presenting with diabetic ketoacidosis (DKA)
• Lack autoimmune markers
• May later be managed with oral glucose-lowering agents instead of
insulin
• Autoimmune Diabetes of Adults
• 5–10% of phenotypic Type 2 DM patients have autoimmune markers
(GAD, ICA)
• Initially not insulin-deficient
• Progress to insulin requirement within ~5 years
• Represents a form of autoimmune diabetes
Approach to the Patient with DM…
• Classification of DM in an Individual Patient…
• Monogenic Diabetes
• Consider in:
• Onset in childhood or early adulthood
• Diagnosis within first 6 months of life
• Autosomal inheritance pattern
• Diabetes without typical features of Type 1 or Type 2 DM
• Stable, mild fasting hyperglycemia
• Examples: MODY (Maturity-Onset Diabetes of the Young), neonatal
diabetes
• Other Atypical Forms
• Type 3c DM:
• Associated with pancreatic exocrine disease
• Diabetes with associated defects:
• Deafness
• Other endocrine disorders
• Patients who deviate from classic Type 1/Type 2 profiles should be
classified accordingly
• Classification Challenges
• Many individuals cannot be neatly categorized
• Overlap between phenotypes and pathophysiology
• Personalized/precision medicine is the aspirational goal
Approach to the Patient with DM…
• Laboratory Assessment in DM
• Diagnostic Criteria
• Confirm DM diagnosis (per ADA criteria)
• Fasting plasma glucose, OGTT, HbA1c, random plasma glucose
• Repeat testing for confirmation if asymptomatic
• Glycemic Control
• HbA1c (every 3–6 months)
• Self-monitoring blood glucose (SMBG)
• Continuous glucose monitoring (CGM) in select patients
• Screening for Associated Conditions
• Renal:
• Albuminuria (urine albumin-to-creatinine ratio)
• Lipid profile:
• Dyslipidemia (cholesterol, triglycerides)
• Thyroid function:
• TSH, especially in Type 1 DM
• Other labs: Liver function, electrolytes if indicated
Approach to the Patient with DM…
• Laboratory Assessment in DM…
• C-Peptide Measurement
• Reflects endogenous insulin secretion
• Must be interpreted with concurrent blood glucose level
• Low C-peptide + high glucose:
• Suggests insulin deficiency → need for insulin therapy
• Limitation: Cannot fully distinguish Type 1 vs. Type 2 DM
• Autoimmune Markers
• Islet cell antibodies (ICA)
• Glutamic acid decarboxylase antibodies (GAD)
• Useful when classification is unclear at onset
• Helps identify autoimmune diabetes in adults
Management and Therapies in DM
• Overall Goals of Treatment
• Core Goals of Therapy
1. Eliminate symptoms of hyperglycemia
2. Reduce or prevent long-term complications:
• Microvascular: retinopathy, nephropathy, neuropathy
• Macrovascular: cardiovascular disease, stroke, PAD
3. Enable patients to achieve as normal a lifestyle as possible
• Glycemic Targets
• Individualized glycemic control goals
• Avoid hypoglycemia
• Monitor and adjust therapy based on
• HbA1c,
• SMBG
• CGM
• Symptoms usually resolve when plasma glucose
• <200 mg/dL (<11.1 mmol/L)
Management and Therapies in DM…
• Overall Goals of Treatment…
• Patient-Centered Approach
• Patient participation, input, and enthusiasm are essential
• Education on:
• Nutrition,
• Exercise,
• Sleep, and
• Self-monitoring
• Empowerment for self-management
Management and Therapies in DM…
• Overall Goals of Treatment…
• Multidisciplinary Team
• Primary care provider / endocrinologist / diabetologist
• Advanced practice provider (APP)
• Pharmacist
• Certified diabetes educator
• Nutritionist
• Behavioral health professional
• Social worker (when needed)
• Subspecialists for complications:
• Ophthalmology,
• Neurology,
• Podiatry,
• Nephrology,
• Cardiology,
• Surgery
Management and Therapies in DM…
• Overall Goals of Treatment…
• ADA Chronic Care Model
• Proactive, team-based delivery
• Self-management support
• Decision support: evidence-based guidelines
• Health system design:
• Person-specific and
• Population-based approaches
• Community resources and policies:
• Promote healthy lifestyles
• Scope of Management
• Outpatient ongoing treatment
• Management of severe hyperglycemia
• Diabetes care in hospitalized patients
Management and Therapies in DM…
• Ongoing aspects of comprehensive diabetes care
• Concept of Comprehensive Care
• Goes beyond glucose management and medications
• Individualized, patient-centered approach
• Detect and modify risk factors for DM-associated disorders
• Manage DM-specific complications
• Key Elements
1. Glycemic control (HbA1c, SMBG, CGM)
2. Blood pressure management
3. Lipid management
4. Lifestyle modification (nutrition, exercise, sleep)
5. Screening for complications (retinopathy, nephropathy, neuropathy)
6. Vaccinations and preventive care
• Surveillance and Prevention
• Timely and consistent monitoring
• Detect complications early
• Prevent progression through intervention
• Reduce morbidity and mortality
Management and Therapies in DM…
• Ongoing aspects of comprehensive diabetes care…
• Addressing Complications
• Microvascular: retinopathy, nephropathy, neuropathy
• Macrovascular: CAD, stroke, PAD
• Foot care: annual exams, ulcer prevention
• Oral health: periodontal disease screening
• Social Determinants of Health
• Family support
• Financial constraints
• Cultural factors
• Employment-related issues
• Impact on adherence and access to care
• Global Perspective
• Resource availability varies worldwide
• Guidance tailored for settings with societal resources
• Emphasis on adaptable, scalable care models
Management and Therapies in DM…
• Lifestyle Management in Diabetes Care
• Core Components of Lifestyle Management
• Diabetes self-management education and support
• Nutrition therapy
• Physical activity guidance
• Psychosocial support
• Sick-day management
• Medication adherence
• Glucose monitoring strategies
• Complication prevention
• Patient Empowerment
• Education fosters responsibility and self-care
• Leads to improved compliance and outcomes
• Encourages active participation in management decisions
Guidelines for Ongoing, Comprehensive Medical Care for Individuals with Diabetes
Category Recommendations
• Individualized goals and therapy plans and
• Shared plan with patient
• Glycemic
• Blood glucose monitoring by
Monitoring
• CGM or capillary fingerstick device
• HbA1c (2–4 times/year)
• Diabetes education and support
• Lifestyle • Nutritional therapy
Management • Physical activity
• Psychosocial assessment (depression, anxiety, distress)
• Eye exam (annual/biannual)
• Foot exam
• Complication • 1–2x/year by provider
Screening and • Daily by patient
management • Kidney testing (annual)
• Other complications (annual)
• Fracture risk assessment in older adults

• Blood pressure (asses2–4x/year)

• Lipids (1–2 times/year)
• Screen &
• screening T2DM or prediabetes for metabolic dysfunction–associated steatotic
management of
liver disease if other risk factors are present
related conditions
• Consider antiplatelet therapy with low-dose aspirin Immunizations: influenza,
pneumococcal, hepatitis B, COVID-19, RSV (>60 years)
Management and Therapies in DM…
• Lifestyle Management in Diabetes Care…
• Diabetes Self-Management Education and Support (DSMES)
• Improves patient’s knowledge, skills, and abilities for diabetes self-care
• Emphasizes psychosocial issues and emotional well-being
• Goal: Empower patients to manage diabetes effectively and safely
• Timing of DSMES
• At diagnosis of diabetes
• Annually for reinforcement
• When treatment goals are not attained
• During transitions in life or medical care
• Delivery of DSMES
• Provided by certified diabetes educators
• Nurse, dietician, pharmacist
• Specialized training in patient education
• Certification:
• Association of Diabetes Care and Education Specialists, Certification
Board for Diabetes Care and Education
Management and Therapies in DM…
• Lifestyle Management in Diabetes Care…
• Diabetes Self-Management Education and Support…
• Education Topics
• Glucose monitoring: CGM or BGM
• Ketone monitoring (Type 1 DM)
• Insulin administration techniques
• Sick-day management guidelines
• Prevention and management of hypoglycemia
• Foot and skin care
• Diabetes management before, during, and after exercise
• Risk factor modification activities
• Patient-Centered Approach
• Individualized education tailored to patient’s needs
• Focus on psychosocial support and emotional well-being
• Encourage active participation and responsibility
• Ongoing Process
• Education is continuous, not a one-time event
• Reinforcement through regular visits
• More frequent contact (electronic, telephone, video) improves glycemic
control
Management and Therapies in DM…
• Lifestyle Management in Diabetes Care…
• Nutrition Therapy in Diabetes Care
• Also called Medical Nutrition Therapy (MNT)
• Coordination of caloric intake with therapy (insulin, exercise, weight loss)
• Individualized, patient-centered dietary management
• Aims to optimize glycemic control and reduce complications
• Goals of MNT
• Prevention/Delay of Type 2 DM in high-risk individuals (obesity,
prediabetes)
• Improve glycemic control through dietary strategies
• Manage complications: ASCVD, nephropathy
• Support weight reduction and healthy lifestyle
Management and Therapies in DM…
• Lifestyle Management in Diabetes Care…
• Medical Nutrition Therapy…
• Key Dietary Strategies
• Monitor carbohydrate intake
• Avoid simple sugars and excess fructose
• Emphasize high-quality, nutrient-dense foods
• Limit carbohydrate intake for weight management
• Consider glycemic index to reduce postprandial glucose excursions
• Similarities Across DM Types
• Type 1 and Type 2 DM:
• Nutrient-dense foods
• Carbohydrate moderation
• Weight management focus
Management and Therapies in DM…
• Lifestyle Management in Diabetes Care…
• Medical Nutrition Therapy…
• Obesity Management
• Medical treatment of obesity may include:
• Pharmacologic approaches for weight loss
• Metabolic/bariatric surgery in select patients
• Integrated with diabetes therapy for improved outcomes
• Eating Patterns & Lifestyle Factors
• Data inconclusive on specific eating patterns (e.g., intermittent fasting)
• Sleep deprivation and shift work → risk factors for weight gain & insulin
resistance
• Dietary advice should be individualized:
• Personal preferences
• Cultural traditions
• Religious practices
Management and Therapies in DM…
• Lifestyle Management in Diabetes Care…
• Medical Nutrition Therapy…
• MNT in Type 1 Diabetes
• Goal:
• Coordinate carbohydrate intake with insulin regimen
• Match carbs temporally and quantitatively with insulin doses
• Guided by CGM and/or BGM data
• Insulin-to-carbohydrate ratio determines bolus insulin dose
• Flexibility for exercise and variable caloric intake
• Minimize weight gain associated with intensive insulin therapy → limit
carbohydrate intake
Management and Therapies in DM…
• Lifestyle Management in Diabetes Care…
• Medical Nutrition Therapy…
• MNT in Type 2 Diabetes
• Primary goal:
• Weight loss
• Address cardiovascular risk factors: hypertension, dyslipidemia,
obesity
• Majority of patients are obese:
• Weight reduction strongly encouraged
• Very-low-carbohydrate diets may rapidly lower glucose in new-onset
Type 2 DM
• Emphasis on:
• Modest caloric reduction
• Increased physical activity
• Weight loss target:
• 5–10% of body weight
• Weight loss and exercise independently improve insulin sensitivity
Management and Therapies in DM…
• Lifestyle Management in Diabetes Care…
• Medical Nutrition Therapy…
• Special Considerations – Fasting (e.g., Ramadan)
• Fasting poses challenges for patients on glucose-lowering medications
• Risk stratification before fasting:
• Safe to fast with medical evaluation and supervision
• Not advised in high-risk individuals
• Patient education is critical:
• Adjust medications and insulin regimens
• Regular glucose monitoring during fasting
• Prevent hypoglycemia and hyperglycemia
Nutritional Recommendations for Adults with Diabetes/Prediabetes
Component Recommendations Notes/Considerations
• Emphasize vegetables, fruits, whole grains,
• General • Optimal diet composition/eating
legumes, low-fat dairy, high-fiber, low-glycemic
Guidelines patterns not fully established
foods
• Fat • Mediterranean-style diet rich in MUFA & PUFA • Minimize or avoid trans fats
• Consider limiting overall carbs;
• Monitor intake relative to calories; set meal
avoid fructose/sucrose beverages;
• Carbohydr limits to reduce postprandial glycemia
minimize added sugars
ates
• Estimate grams of carbs for flexible insulin • Glycemic index may help predict
dosing (Type 1 & insulin-dependent Type 2 DM) postprandial glucose rise
• Optimal percentage not
• Protein • Individualized intake
established
• Routine vitamin/antioxidant/trace
• Reduced-calorie & nonnutritive sweeteners may
element supplements not
be useful
• Other supported by evidence
Componen • Vitamin D & calcium supplementation as
ts • Promote bone health
recommended
• Sodium intake <2300 mg/day • Same as general population
• Religious fasting may increase
• Lifestyle • Minimize disruption to sleep/eating patterns
hypoglycemia risk → requires
Factors (chrononutrition)
monitoring
Management and Therapies in DM…
• Lifestyle Management in Diabetes Care…
• Physical Activity in Diabetes Care
• Benefits of Exercise
• Cardiovascular risk reduction
• Lower blood pressure
• Maintenance of muscle mass
• Reduction in body fat
• Weight loss
• Improves plasma glucose control during and after exercise
• Increases insulin sensitivity
• ADA Recommendations
• 150 min/week of moderate aerobic activity
• Spread over ≥3 days per week
• No gaps longer than 2 days
• Include:
• Resistance exercise
• Flexibility training
• Balance training
• Reduce sedentary behavior throughout the day
Management and Therapies in DM…
• Lifestyle Management in Diabetes Care…
• Physical Activity in Diabetes Care…
• Challenges in Diabetes
• Lack of normal glucoregulatory mechanisms during exercise
• Skeletal muscle:
• Major site of fuel consumption → increased demand during vigorous
activity
• Type 1 DM risks:
• Hyperglycemia
• Low insulin, high catecholamines, lactate →
• Ketones, risk of ketoacidosis
• Hypoglycemia
• Excess insulin →
• Reduced hepatic glucose production, increased muscle uptake)
• Type 2 DM risks:
• Hypoglycemia less common, but possible with insulin or secretagogues
Management and Therapies in DM…
• Lifestyle Management in Diabetes Care…
• Physical Activity in Diabetes Care…
• Precautions for Type 1 DM
• Monitor glucose:
• Before, during, and after exercise
• Delay exercise if:
• Glucose >250 mg/dL (>14 mmol/L) and
• Ketones present
• If glucose <90 mg/dL (<5.0 mmol/L),
• Ingest carbohydrate before exercise
• Monitor glucose during activity and ingest carbs as needed
• Adjust insulin doses before/after exercise (based on prior experience)
• Inject insulin into non-exercising areas
• Learn individual glucose responses to different exercise types
• Contraindications
• Vigorous exercise contraindicated in untreated proliferative retinopathy
• Risk: vitreous hemorrhage or retinal detachment
Management and Therapies in DM…
• Lifestyle Management in Diabetes Care…
• Psychosocial Care in Diabetes Mellitus
• Importance of Psychosocial Care
• Diabetes affects many aspects of daily life
• Psychosocial assessment and support are critical
• Patient should be seen as an active team member, not a passive recipient of
care
• Challenges in Glycemic Control
• Normoglycemia can be difficult to achieve
• Solutions to worsening control may not be easily identifiable
• Emotional stress can disrupt adherence to diet, exercise, and therapy
• Psychological Conditions in DM
• Depression
• Anxiety
• Diabetes distress (ADA definition: negative psychological reactions related
to emotional burdens of managing diabetes)
• May require referral to mental health specialists
Management and Therapies in DM…
• Lifestyle Management in Diabetes Care…
• Psychosocial Care in Diabetes Mellitus
• Behavioral Impact of Stress
• Emotional stress → changes in behavior
• Reduced adherence to dietary, exercise, or therapeutic regimens
• Worsening glycemic control
• Eating Disorders in DM
• More frequent in individuals with Type 1 and Type 2 DM
• Includes:
• Binge eating disorder
• Bulimia nervosa
• Anorexia nervosa
• Requires early recognition and specialized care
• Patient Empowerment
• Encourage patients to view themselves as essential members of the care
team
• Promote self-efficacy and active participation
• Psychosocial support improves adherence and outcomes
Management and Therapies in DM…
• Monitoring the level of glycemic control
• Complementary tools:
• CGM/BGM for short-term,
• HbA1c for long-term control
• CGM advantages:
• Continuous data,
• Ambulatory Glucose Profile (AGP) summary,
• TIR (Time in range)
• Monitoring,
• trend analysis
• HbA1c:
• Gold standard for average glycemia and complication risk assessment
• Integration:
• Lifestyle + monitoring = comprehensive diabetes care
Monitoring the level of glycemic control…
Aspect Method Key Features Clinical Use
• Sensor detects interstitial
glucose
• Data every 5 minutes
• Ambulatory Glucose Profile
• Identifies daily glucose patterns
• CGM (AGP):
• Prevents predicted hypo-
(Continuous • TIR (Time in range)
/hyperglycemia
Glucose • % above/below range
• Short- • Guides insulin/diet/exercise
Monitoring) • GMI (Glucose
Term adjustments
management indicator)
Control • Variability
• Real-time trends
(upward/downward)
• Fingerstick capillary glucose
• BGM (Blood • Patient self-monitoring
Provides immediate values
Glucose • Detects acute changes
• Used for calibration in some
Monitoring) • Supports insulin dosing decisions
CGMs
• Reflects average glycemia over • Provider assessment of overall
• Long-
• HbA1c 2–3 months control
Term
Measurement Correlates with GMI from • Guides therapy adjustments
Control
CGM • Monitors risk of complications
• Combine
• Improves glycemic control
• Integratio CGM/BGM with • Patient + care team
• Reduces diabetes-related
n diet & exercise collaboration
complications
history
Management and Therapies in DM…
• Monitoring the level of glycemic control…
• Assessment of Short-Term Glycemic Control…
• CGM technology
• Rapidly evolving with expanding features
• Real-time CGM generally more effective than intermittently scanned CGM
• Device selection should be individualized, considering patient, provider,
and system factors
• Certified diabetes educators play a critical role, but resources may be
limited
• Ongoing education and training are essential for success
• Reduces hypoglycemia risk in Type 1 DM, especially with insulin pumps
• Secure data sharing and EHR integration are critical for comprehensive care
• BGM remains essential even with CGM use
• Both CGM and BGM can be affected by interfering substances
• Type 2 DM requires less frequent monitoring but benefits from CGM
insights
CGM Device Technology – Key Considerations
Aspect Details Implications
• Types of • Real-time CGM (more effective) • Real-time preferred for continuous
CGM • Intermittently scanned CGM monitoring
• Most require provider prescription • Patient access varies by regulation and
• Access
• Some available without prescription insurance
• Patient: cost, convenience, insurance
• Selection coverage • Must balance patient needs, provider
Factors • Provider: access to patient data workflow, and system capacity
• Health system: EMR integration
• Role of • Certified diabetes educators optimize
• Not always available in all care settings
Educators selection and training
• Vendor-specific and multi-vendor • Patients/providers may need
• Resources
online resources independent investigation
• Based on patient preference, skill
• Individualiz • Tailored to maximize adherence and
level, ability to collect/use/upload
ation effectiveness
data
• Special • CGM may be managed by caregivers
• Requires caregiver training and support
Populations (children, cognitive impairment)
• Ongoing education for
• Ensures proper use and therapy
• Training patient/caregiver after device
adjustment
selection
Blood Glucose Monitoring (BGM) and CGM
Aspect Details Clinical Implications
• Essential backup for CGM
• Use <2 μL blood (fingerstick)
• BGM Devices malfunction, questionable
• Enzymatic reaction for rapid glucose measurement
results, or calibration
• CGM: hydroxyurea, acetaminophen, ascorbic acid,
• Interference mannitol, sorbitol • May affect accuracy of
Factors • BGM: uric acid, galactose, xylose, acetaminophen, L- readings; awareness critical
DOPA, ascorbic acid
• Daily CGM recommended
• Type 1 DM • Especially useful in hypoglycemia unawareness • Improves safety and control
• Reduces serious hypoglycemia (esp. nocturnal)
• Integration • CGM + infusion device → automated insulin delivery
• Enhances precision and
with Insulin • Predictive suspension to avoid hypoglycemia
reduces risk
Pumps • Closed-loop control adjusts insulin via algorithm
• Upload glucose data to manufacturer’s server
• Data • Secure provider access
• Critical for coordinated care
Management • Integration into electronic health records (EHR) still
needs improvement
• On oral therapy/diet: less frequent monitoring (3–5
• Lower intensity monitoring
• Type 2 DM times/week)
sufficient
• CGM or BGM both options
• Lifestyle • Real-time CGM assists with diet, activity, and • Improves patient engagement
Benefits medication decisions and glycemic control
Management and Therapies in DM…
• Monitoring the level of glycemic control…
• Assessment of Long-Term Glycemic Control
• HbA1c
• Gold standard for long-term monitoring

HbA1c – Standard Method

Aspect Details Clinical Implications
• Nonenzymatic glycation • Represents prior 2–3
• Principle of hemoglobin reflects months of glucose
average glycemia control
• Last month contributes • Sensitive to recent
• Contribution
~50% to HbA1c value changes
• Must correlate with DCCT • Ensures accuracy and
• Standards
reference assay comparability
• Assists in timely therapy
• Point-of-Care Testing • Provides rapid feedback
adjustment
• Primary predictor of • Should mirror short-term
• Predictive Value
long-term complications CGM/BGM data
Management and Therapies in DM…
• Monitoring the level of glycemic control…
• Assessment of Long-Term Glycemic Control: HbA1c…
• Frequency of Measurement
• At initial evaluation of all individuals with DM
• Stable control: at least twice per year
• Inadequate control or therapy changes: every 3 months
• Correlates with estimated average glucose (eAG)
Estimated Average Glucose Estimated Average Glucose
Hemoglobin A₁C (%)
(mg/dL) (mmol/L)
5 97 (76–120) 5.4 (4.2–6.7)
6 126 (100–152) 7.0 (5.5–8.5)
7 154 (123–185) 8.6 (6.8–10.3)
8 183 (147–217) 10.2 (8.1–12.1)
9 212 (170–249) 11.8 (9.4–13.9)
10 240 (193–282) 13.4 (10.7–15.7)
11 269 (217–314) 14.9 (12.0–17.5)
12 298 (240–347) 16.5 (13.3–19.3)
Management and Therapies in DM…
• Monitoring the level of glycemic control…
• Assessment of Long-Term Glycemic Control: HbA1c…
• Limitations of HbA1c
• Does not detect glycemic variability or recent illness
• Interindividual variability in HbA1c–mean glucose relationship (genetically
influenced)
• Race/ancestry differences:
• HbA1c ~0.3% higher in African Americans vs. non-Hispanic
whites/Hispanics for same mean glucose
• Altered by RBC-related conditions:
• Hemoglobinopathies,
• Anemia,
• Reticulocytosis,
• Transfusions
• Uremia
• G6PD variants,
• Hemodialysis,
• Erythropoietin therapy,
• HIV treatment
• Alternative Markers
• Fructosamine
• Glycated albumin
• Reflect glycemia over prior 2–4 weeks
• Useful when HbA1c is unreliable due to RBC abnormalities
Management and Therapies in DM…
• Pharmacologic Treatment of Diabetes
• Comprehensive care of Type 1 & Type 2 DM requires:
• Nutrition
• Exercise
• Monitoring glycemic control
• Glucose-lowering medications
• Medications for complications
• Establishing Glycemic Targets
• Key Principle:
• Complications of DM are related to glycemic control
• Goal:
• Normoglycemia or near-normoglycemia
• Historically difficult
• DCCT, UKPDS..
• New technologies & medications →
• More feasible
• Any improvement in glycemic control
• ↓ risk of complications (esp. microvascular)
Management and Therapies in DM…
• Pharmacologic Treatment of Diabetes…
• Establishing Glycemic Targets…
• Individualized HbA1c Goals
• Patient-centered care (ADA):
• Age
• Cognitive ability
• Hypoglycemia awareness
• Presence/severity of complications (e.g., ASCVD)
• Other medical conditions
• Lifestyle & occupation
• Family/social support
Management and Therapies in DM…
• Pharmacologic Treatment of Diabetes…
• Establishing Glycemic Targets…
• ADA Recommendations
• Most adults:
• Target HbA1c <7%
• Aim for near-normal glycemia without significant hypoglycemia
• Selected patients (younger, motivated, no comorbidities):
• Target HbA1c ≤6.5%
• More stringent goal if achievable safely
• Patients with cognitive impairment or limited life expectancy:
• Target HbA1c <7.5–8%
• Prioritize safety; avoid hypoglycemia and severe hyperglycemia
• Elderly (>65 years):
• With robust cognition and few comorbidities →
• HbA1c <7%
• With impaired cognition or in long-term care →
• Individualized goals focusing on safety, avoiding hypoglycemia
and severe hyperglycemia
Management and Therapies in DM…
• Pharmacologic Treatment of Diabetes…
• Establishing Glycemic Targets…
• Large Clinical Trials in Diabetes & Glycemic Control
• UKPDS
• ACCORD
• ADVANCE
• VADT
• DCCT/EDIC (Type 1 DM)
• Focus: Glycemic control & cardiovascular outcomes
• Key Findings – General
• Improved glycemic control
• ↓ microvascular complications
• Early intensive control in Type 1 DM →
• ↓ risk of MI, stroke, CV death decades later
• Intense glycemic control →
• Beneficial for ASCVD in some Type 2 DM populations
• Hypoglycemia in high-risk ASCVD populations →
• ↑ CV events & mortality
Management and Therapies in DM…
• Pharmacologic Treatment of Diabetes…
• Establishing Glycemic Targets…
• Large Clinical Trials in Diabetes & Glycemic Control…
• Clinical Implications
• Near-normal glycemia not the goal in high-risk ASCVD populations
• Balance between:
• Reducing complications
• Avoiding hypoglycemia
• Individualized targets remain essential
• Historical Context
• These trials conducted before:
• GLP-1 receptor agonists (GLP-1RAs)
• SGLT-2 inhibitors
• Modern agents → greater cardiovascular benefit than older therapies
Glycemic Goals for Adults with Diabetes
Elderly: Complex
Elderly: Intact
Index of Glycemic Adults Elderly: Serious Comorbidities / Poor
Cognition &
Control (Nonpregnant) Comorbidities Health / Impaired
Functional Status
Cognition
• <8.5% (64 mmol/mol)
• <7.0% • <7.0–7.5% • <8.0% with
• HbA1c
• (53 mmol/mol) • (53–57 mmol/mol) • (64 mmol/mol) • Avoidance of
hypoglycemia
• CGM
• >50%
• % Time in • >70% • >70% • >40%
• (100–200
Range • (70–180 mg/dL) • (80–180 mg/dL) • (120–220 mg/dL)
mg/dL)
• Time <70
mg/dL (Level 1 • <4% • <1% • 0% • 0%
Hypoglycemia)

• Time <54
mg/dL (Level 2 • <1% • <1% • 0% • 0%
Hypoglycemia)

• Glucose
Variability (% • ≤36% • ≤33% • N/A • N/A
CV)
• 90–150 mg/dL
• 80–130 mg/Dl • 80–130 mg/dL • 100–180 mg/dL
• Preprandial Glucose • (5.0–8.3
• (4.4–7.2 mmol/L) • (4.4–7.2 mmol/L) • (5.6–10.0 mmol/L)
mmol/L)
• <11.1 mmol/L • <13.9 mmol/L • <13.9 mmol/L
• <10.0 mmol/L
• Postprandial Glucose • (200 mg/dL) • (250 mg/dL) • (250 mg/dL)
• (<180 mg/dL)
Management and Therapies in DM…
• Pharmacologic Management of T1DM
• General Aspects
• Goal:
• Mimic physiologic insulin secretion
• Patients lack endogenous insulin →
• Basal insulin essential
• Regulates
• Glycogen breakdown,
• Gluconeogenesis,
• Lipolysis,
• Ketogenesis
• Meal-time insulin replacement:
• Matches carbohydrate intake
• Adjusted for insulin sensitivity
• Promotes normal glucose utilization & storage
• Challenge:
• Rising insulin costs → major barrier to care
• Legislative efforts ongoing, but affordability remains an issue
• Intensive Glycemic Management
• Aim:
• Normal or near-normal glycemia
• Requires:
• Ongoing patient education
• Detailed glucose & nutrition recording
• Flexible insulin regimen tailored to meals & exercise
Management and Therapies in DM…
• Pharmacologic Management of T1DM…
• Insulin Delivery Options
1. Multiple Daily Injections (MDIs)
2. Continuous Subcutaneous Insulin Infusion (CSII)
• Pump with manual basal/bolus adjustments
3. Sensor-Augmented Pump Systems
• Pump + CGM + algorithm
• Suspends insulin if glucose low or predicted to drop
4. Automated Insulin Delivery (AID) Systems
• Pump + CGM + algorithm
• Adjusts basal insulin in real time
• Some deliver correction bolus
• Still require patient input for carbs & activity
• Emerging Technologies
• Rapidly evolving field:
• Algorithms + artificial intelligence
• DIY systems:
• Developed by Type 1 DM user community
• Not FDA-approved
• Some individuals report success
• Future direction:
• Toward closed-loop systems
Management and Therapies in DM…
• Pharmacologic Management of T1DM…
• Intensive Insulin Therapy in T1DM
• Clinical Benefits
• Reduced acute metabolic complications
• Diabetic ketoacidosis (DKA)
• Severe hyperglycemia
• Reduced chronic microvascular complications
• Retinopathy
• Nephropathy
• Neuropathy
• Psychological & Lifestyle Benefits
• Greater sense of control over diabetes
• Improved well-being
• More flexibility in meal timing & content
• Ability to adjust insulin dosing with exercise
Management and Therapies in DM…
• Pharmacologic Management of T1DM…
• Intensive Insulin Therapy in T1DM…
• Pregnancy Benefits
• Intensive insulin therapy before & during pregnancy:
• ↓ risk of fetal malformations
• ↓ fetal morbidity
• Strongly encouraged in newly diagnosed patients with Type 1 DM
• Use of CGM recommended for tighter control
• Individualization of Care
• Intensive management offers impressive benefits
• But may not be appropriate for all individuals at all times
• Some patients prefer:
• Intermittent subcutaneous injections + CGM
• Rather than continuous insulin infusion devices
• Emphasizes the need for patient-centered care
Management and Therapies in DM…
• Pharmacologic Management of T1DM…
• Insulin Preparations in Diabetes Management
• General Aspects
• Produced by recombinant DNA technology
• Contain human insulin sequence or modified analogues
• Standard formulation:
• U-100 (100 units/mL)
• Other concentrations:
• U-200 (lispro, short-acting)
• U-300 (glargine, long-acting)
• U-500 (regular insulin, severe resistance)
• Pharmacokinetic Variations
• Native sequence insulins:
• Regular insulin
• Neutral Protamine Hagedorn (NPH)
• Genetically modified analogues:
• Alter absorption →
• Change onset & duration
• Classification:
1. Rapid-acting
2. Short-acting
3. Intermediate-acting
4. Long-acting
5. Ultralong-acting
Management and Therapies in DM…
• Pharmacologic Management of T1DM…
• Insulin Preparations…
• Rapid-Acting Analogues
1. Insulin lispro:
• B-chain amino acids 28 & 29 reversed (lysine ↔ proline)
• Biosimilars of lispro available
2. Insulin aspart, &
3. Glulisine:
• Modified analogues, similar properties to lispro
• Advantages:
• Faster absorption & onset
• Shorter duration →
• ↓ hypoglycemia risk
• Better match to post-meal glucose rise
• Preferred for prandial coverage over regular insulin
Management and Therapies in DM…
• Pharmacologic Management of T1DM…
• Insulin Preparations…
• Long-Acting Analogue
1. Insulin Glargine
• Structure modifications:
• Asparagine → glycine at position 21
• +2 arginine residues at B-chain C-terminus
• Forms microprecipitates at physiologic pH →
• Slow release
• Pharmacokinetics:
• Later onset
• Longer duration (~24 h)
• Less pronounced peak
• Clinical benefit:
• ↓ incidence of hypoglycemia, especially nocturnal
• Compared to NPH insulin
• Sometimes requires twice-daily injections for full 24h coverage
Management and Therapies in DM…
• Pharmacologic Management of T1DM…
• Insulin Preparations…
• Long-Acting Analogue…
2. Insulin Degludec
• Modified B-chain →
• Forms multihexamers in subcutaneous tissue
• Binds albumin →
• Duration >42h
• Similar glycemic control as glargine
• Less nocturnal & severe hypoglycemia
• Future: Weekly insulin formulations in clinical trials
• Basal Insulin Role
• Provides background insulin for hepatic glucose metabolism
• Options:
• NPH insulin
• Insulin glargine
• Insulin degludec
• Usually combined with rapid-acting insulin for meals (prandial coverage)
Management and Therapies in DM…
• Pharmacologic Management of T1DM…
• Insulin Preparations…
• Combination Insulins
• Past practice:
• NPH +
• Short-acting insulin mixed in syringe (less common now)
• Current formulations:
• 70/30 (70% NPH + 30% regular)
• 50/50 (equal NPH + regular)
• Analogue + protamine →
• Rapid + long-acting profile
• Advantages:
• Fewer injections (twice daily)
• Limitations:
• Cannot independently adjust basal vs prandial →
• Not appropriate for Type 1 DM
Management and Therapies in DM…
• Pharmacologic Management of T1DM…
• Insulin Preparations…
• Insulin Delivery Innovations
• Insulin Pens:
• More convenient & accurate than syringes
• Smart pens → track doses
• Inhaled Insulin:
• Rapid onset for mealtime coverage
• Requires baseline & periodic FEV1 monitoring
• Side effects: bronchospasm, cough
• Contraindicated in lung disease or smokers
• Fixed-Dose Combinations
• Long-acting insulin + GLP-1RA combinations:
• Degludec + liraglutide
• Glargine + lixisenatide
• Benefits:
• Effective glycemic control
• Less weight gain compared to insulin alone
Properties of Insulin Preparations

Preparation Onset (h) Peak (h) Effective Duration (h)

• Rapid-acting (Injected)
• Aspart <0.25 0.5–1.5 3–5
• Glulisine <0.25 0.5–1.5 3–5
• Lispro <0.25 0.5–1.5 3–5
• Short-acting (Injected)
• Regular 0.5–1.0 2–3 4–8
• Rapid-acting (Inhaled)
• Inhaled human insulin <0.25 1–2 3
• Intermediate-acting (Injected)
• NPH 2–4 4–10 10–16
• Long-acting / Ultralong-acting (Injected)
• Degludec 1–9 — 42
• Glargine 2–4 — 20–24
Properties of Insulin Preparations…
Preparation Onset (h) Peak (h) Effective Duration (h)

• Combination Insulins
• 75/25 (%)
<0.25 Dual 16–18
• (Protamine lispro + lispro)
• 70/30 (%)
<0.25 Dual 15–18
• (Protamine aspart + aspart)
• 50/50 (%)
<0.25 Dual 10–16
• (Protamine lispro + lispro)
• 70/30 (%)
0.5–1 Dual 10–16
• (NPH + regular)

• Long-acting insulin + GLP-1RA

Management and Therapies in DM…
• Pharmacologic Management of T1DM…
• Insulin Regimens in T1DM
• General Principles
• Basal insulin:
• NPH,
• Glargine, or
• Degludec
• Prandial insulin:
• Regular,
• Lispro
• Aspart, or
• Glulisine
• Timing:
• Rapid-acting analogues →
• Inject <10 min before meals
• Regular insulin →
• Inject 30–45 min before meals
• Sometimes rapid-acting given post-meal
• Gastroparesis, unpredictable intake…
• ADA/EASD consensus provides guidance on regimen selection
Management and Therapies in DM…
• Pharmacologic Management of T1DM…
• Insulin Regimens in T1DM…
• Physiologic Limitations
• Exogenous insulin enters systemic circulation directly
• Endogenous insulin →
• Secreted into portal vein
• Result:
• Liver exposed to subphysiologic insulin levels
• Higher peripheral insulin needed to suppress hepatic glucose
production
• No regimen fully replicates pancreatic islet secretion
• Most Physiologic Regimens
• More frequent injections
• Greater reliance on rapid-acting insulin
• Use of CGM or frequent BGM
• Typical daily requirement:
• 0.4–1.0 units/kg/day
• 30–50% basal
• Remainder prandial
• All patients should have a glucagon prescription
Management and Therapies in DM…
• Pharmacologic Management of T1DM…
• Insulin Regimens in T1DM…
• Multiple Daily Injection (MDI) Regimens
• Combination of basal + bolus insulin
• Basal:
• Glargine or degludec
• Bolus:
• Lispro, aspart, or glulisine before meals
• Dose adjustments based on:
• CGM/BGM results
• Anticipated food intake
• Physical activity
• Offers flexibility and best chance for near-normoglycemia
Management and Therapies in DM…
• Pharmacologic Management of T1DM…
• Insulin Regimens in T1DM…
• Multiple Daily Injection (MDI) Regimens…
• Insulin Dosing Algorithms
• Basal insulin dose:
• Adjusted by fasting glucose
• Prandial insulin dose:
• Based on:
• Preprandial glucose +
• Anticipated carbohydrate intake
• Insulin-to-carbohydrate ratio:
• Commonly 1 unit per 10–15 g carbs (individualized)
• Correction factor:
• 1 unit per 30–60 mg/dL above target
• Estimated by 1500 ÷ total daily insulin dose
• Must be individualized to patient’s insulin sensitivity
Management and Therapies in DM…
• Pharmacologic Management of T1DM…
• Insulin Regimens in T1DM…
• Automated Insulin Delivery (AID) Systems in T1DM
• Preferred delivery mechanism for most individuals with T1DM
• Combines:
• Basal insulin infusion
• Preprandial bolus insulin (patient-directed or algorithm-based)
• Advantages:
• Accurate micro-dose delivery (µL/hour)
• Multiple programmable basal rates (day vs night)
• Adjustable basal infusion during exercise
• Meal bolus waveforms tailored to meal composition
• Algorithms integrate prior insulin action + glucose values
• Clinical Considerations
• Cost & insurance coverage →
• Critical barriers
• Requires:
• Patient education
• Experienced health professional guidance
• Frequent interaction with diabetes care team
• Rapidly evolving technology → need to match with patient preferences
Management and Therapies in DM…
• Pharmacologic Management of T1DM…
• Insulin Regimens in T1DM…
• AID Systems in T1DM…
• Challenges & Risks
• Infusion site infections
• Obstructed infusion set →
• Unexplained hyperglycemia
• Device disconnection →
• Risk of DKA
• Short half-life of rapid-acting insulins (lispro, glulisine, aspart) →
• Quick deficiency if interrupted
• Safety essentials:
• CGM or frequent BGM
• Backup plan with long-/rapid-acting insulin injections
Management and Therapies in DM…
• Pharmacologic Management of T1DM…
• Insulin Regimens in T1DM…
• Sensor-Augmented Pumps:
• Integrate CGM data
• Threshold suspension →
• Stops insulin during hypoglycemia
• Predictive suspension →
• Prevents anticipated hypoglycemia (esp. nocturnal)
• Hybrid Closed-Loop Systems:
• Automated basal adjustments
• Patient-directed preprandial boluses
• Growing clinical experience and adoption
• Future Directions
• Bihormonal infusion devices:
• Deliver both insulin + glucagon
• Expanding use of closed-loop systems
• Ongoing innovation in algorithms, sensors, and integration
Management and Therapies in DM…
• Pharmacologic Management of T1DM…
• Other Agents That Improve Glucose Control
• Amylin:
• 37–amino acid peptide co-secreted with insulin
• Role in normal glucose homeostasis → uncertain
• Pramlintide
• Amylin analogue
• Approved for insulin-treated Type 1 & Type 2 DM
• Injected SC before meals
• Mechanism:
• Slows gastric emptying
• Suppresses glucagon
• Does not alter insulin levels
• Effect:
• Modest ↓ HbA1c,
• Dampens postprandial glucose excursions
Management and Therapies in DM…
• Pharmacologic Management of T1DM…
• Other Agents That Improve Glucose Control…
• Pramlintide Dosing
• Type 1 DM:
• Start: 15 µg SC before meals
• Titrate: up to 30–60 µg as tolerated
• Type 2 DM:
• Start: 60 µg SC before meals
• Titrate: up to 120 µg
• Side effects: nausea, vomiting → slow titration recommended
• Precautions:
• Slows gastric emptying →
• May affect absorption of other drugs
• Avoid with other agents that slow GI motility
• Reduce premeal rapid-acting insulin initially to avoid hypoglycemia
• Contraindicated in hypoglycemia unawareness (due to glucagon
suppression)
Management and Therapies in DM…
• Pharmacologic Management of T1DM…
• Other Agents That Improve Glucose Control…
• GLP-1 receptor agonists (GLP-1RAs):
• Modest HbA1c improvement
• SGLT-2 inhibitors:
• Modest HbA1c improvement
• ↑ risk of diabetic ketoacidosis (DKA)
• Generally not recommended in Type 1 DM
Management and Therapies in DM…
• Management of T2DM
• General Aspects
• Chronic, progressive metabolic disorder
• Characterized by:
• Insulin resistance
• Relative insulin deficiency
• Major global health burden
• Leading cause of morbidity and mortality via cardiovascular disease
• Goals of Therapy
• Similar to Type 1 DM:
• Individualized care
• Glycemic control plus:
• Obesity management
• Hypertension control
• Dyslipidemia treatment
• ASCVD risk reduction
• Prevention, detection, and management of complications
Management and Therapies in DM…
• Management of T2DM…
• General Aspects…
• Cardiovascular Risk
• ASCVD
• Leading cause of death in T2DM
• Risk reduction is paramount:
• Blood pressure control
• Lipid management (statins)
• Antiplatelet therapy (selected patients)
• Lifestyle interventions
• Initial Management
• Medical Nutrition Therapy (MNT)
• Exercise regimen:
• Improves insulin sensitivity
• Promotes weight loss
• Lifestyle modification
• Cornerstone of therapy
Management and Therapies in DM…
• Management of T2DM…
• General Aspects…
• Pharmacologic Therapy
• Oral glucose-lowering agents
• Injectable therapies (GLP-1 RAs, insulin)
• Mechanisms:
• Improve glycemic control
• Reduce “glucose toxicity” →
• Better β-cell function
• Progressive disorder →
• Often requires combination therapy
Essential elements in comprehensive care of type 2 diabetes.
Management and Therapies in DM…
• Glucose-Lowering Agents in T2DM
• Classification (Mechanisms of Action)
1. Increase insulin secretion
• E.g., sulfonylureas, meglitinides
2. Reduce hepatic glucose production
• E.g., biguanides – metformin
3. Increase insulin sensitivity
• E.g., thiazolidinediones
4. GLP-1 receptor agonists
• Enhance incretin effect
5. Promote urinary glucose excretion
• E.g., SGLT2 inhibitors
6. Insulin
• Used in severe hyperglycemia or catabolic states
Management and Therapies in DM…
• Glucose-Lowering Agents in T2DM…
• Biguanides: Metformin
• Mechanism:
• ↓ Hepatic glucose production
• ↑ Peripheral glucose utilization (modest)
• Clinical effects:
• ↓ Fasting plasma glucose (FPG)
• ↓ Insulin levels
• Improves lipid profile
• Promotes modest weight loss
• Dosing & Administration
• Extended-release form available →
• Fewer GI side effects
• Start low dose, titrate every 1–2 weeks
• Max tolerated dose: 2000 mg/day
• Effective as monotherapy or in combination therapy
• Adverse Effects
• Common:
• GI symptoms (diarrhea, anorexia, nausea, metallic taste)
• Rare but serious:
• Lactic acidosis
• Other:
• Vitamin B12 deficiency → monitor levels
Management and Therapies in DM…
• Glucose-Lowering Agents in T2DM…
• Biguanides: Metformin…
• Contraindications
• GFR <30 mL/min (renal insufficiency)
• Any form of acidosis
• Unstable CHF
• Liver disease
• Severe hypoxemia
• Special Considerations
• Discontinue in:
• Hospitalized patients
• Patients NPO (nothing orally)
• Those receiving radiographic contrast material
• Use insulin temporarily until metformin can be restarted
Management and Therapies in DM…
• Glucose-Lowering Agents in T2DM…
• Insulin Secretagogues in T2DM: agents that affect the ATP-
sensitive K+ channel
• Mechanism of Action
• Stimulate insulin secretion via ATP-sensitive K⁺ channel on β-cells
• Most effective in:
• Recent-onset T2DM (<5 years)
• Patients with residual endogenous insulin production
1. Sulfonylureas
• Reduce fasting and postprandial glucose
• Initiation:
• Low dose, titrate every 1–2 weeks (guided by CGM/BGM)
• Preferred agents:
• Glimepiride, Glipizide
• Once-daily dosing
• Safer in elderly compared to glyburide
Management and Therapies in DM…
• Glucose-Lowering Agents in T2DM…
• Insulin Secretagogues in T2DM: agents that affect the ATP-
sensitive K+ channel…
2. Glinides
• Non-Sulfonylurea Secretagogues
• Repaglinide, Nateglinide
• Also act on ATP-sensitive K⁺ channel
• Short half-life →
• Given immediately before meals
• Target postprandial glucose excursions
• Adverse Effects
• Hypoglycemia
• Especially long-acting agents, elderly patients
• Risk factors:
• Delayed meals, ↑ physical activity, alcohol, renal insufficiency
• Weight gain due to:
• ↑ insulin levels and improved glycemic control
Management and Therapies in DM…
• Glucose-Lowering Agents in T2DM…
• Insulin Secretagogues in T2DM: agents that affect the ATP-
sensitive K+ channel…
• Contraindications & Cautions
• Avoid in significant hepatic or renal dysfunction
• Repaglinide may be used cautiously in CKD
• Overdose →
• Prolonged, serious hypoglycemia →
• Hospital monitoring required
• Drug Interactions
• Alcohol
• Potentiates hypoglycemia
• Medications:
• Warfarin, aspirin, ketoconazole, α-glucosidase inhibitors, fluconazole
• Antibiotics: fluoroquinolones, clarithromycin, TMP-SMX,
metronidazole
• Recommendation: discontinue sulfonylureas when these
antimicrobials are added
Management and Therapies in DM…
• Glucose-Lowering Agents in T2DM…
• GLP-1RAs and GIP Receptor Agonists in T2DM
• Mechanism of Action
• “Incretins” amplify glucose-stimulated insulin secretion
• Suppress inappropriate glucagon secretion
• Slow gastric emptying
• GLP-1 receptors expressed in multiple tissues (pancreas, brain, GI tract)
• Clinical Benefits
• Weight loss
• Liraglutide,
• Semaglutide at higher doses
• Cardiovascular protection in T2DM + ASCVD
• Renal benefits
• Reduced diabetic kidney disease in some agents
• Do not cause hypoglycemia
• Unless combined with sulfonylureas/insulin)
Management and Therapies in DM…
• Glucose-Lowering Agents in T2DM…
• GLP-1RAs and GIP Receptor Agonists in T2DM…
• Commonly Used Agents
• Weekly injectables:
• Exenatide SR,
• Dulaglutide,
• Lixisenatide,
• Semaglutide
• Daily oral semaglutide:
• gastric absorption formulation
• Modified to resist DPP-4 degradation
• Evidence from Clinical Trials
• Liraglutide:
• ↓ CVD events,
• ↓ diabetic kidney disease
• Semaglutide:
• ↓ CVD events,
• ↓ kidney disease,
• ↑ retinopathy complications
• Dulaglutide:
• ↓ CVD events,
• ↓ microvascular complications (esp. renal)
Management and Therapies in DM…
• Glucose-Lowering Agents in T2DM…
• GLP-1RAs and GIP Receptor Agonists in T2DM…
• Dosing & Administration
• Start at low dose → minimize nausea/vomiting
• Can be combined with:
• Metformin
• Sulfonylureas
• Thiazolidinediones
• May require dose reduction of
• Insulin/secretagogues to avoid hypoglycemia
• Adverse Effects & Warnings
• GI side effects:
• Nausea, vomiting (most common)
• Black box warning (rodent studies):
• Thyroid C-cell tumors
• Contraindicated in:
• Medullary thyroid carcinoma
• Multiple endocrine neoplasia (MEN) syndromes
• Slow gastric emptying →
• May affect absorption of other drugs
Management and Therapies in DM…
• Glucose-Lowering Agents in T2DM…
• GLP-1RAs and GIP Receptor Agonists in T2DM…
• Dual/Triple Incretin Therapies and DPP-4 Inhibitors
• Tirzepatide (Dual GIPR + GLP-1R Agonist)
• Once-weekly subcutaneous peptide
• Dual agonism:
• GIP receptor + GLP-1 receptor
• Promotes greater weight loss than GLP-1RA alone
• Additional dual-acting and triple-acting molecules in clinical development
• DPP-4 Inhibitors:
• Eg Alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin...
• Mechanism
• Inhibit degradation of
• Native GLP-1 and GIP
• Enhance incretin effect →
• ↑ insulin secretion
• Do not cause hypoglycemia or weight gain
• Preferential effect on postprandial glucose
• Clinical Use of DPP-4 Inhibitors
• Used alone or in combination with other oral agents
• Dose adjustment required in renal insufficiency
• GLP-1RAs provide greater incretin activity than DPP-4 inhibitors
Management and Therapies in DM…
• Glucose-Lowering Agents in T2DM…
• GLP-1RAs and GIP Receptor Agonists in T2DM…
• Adverse Effects: Pancreatitis risk:
• Higher with GLP-1RAs
• Lower but present with DPP-4 inhibitors
• Contraindications & Precautions
• Avoid in patients with:
• Pancreatic disease
• Heavy alcohol use
• Severely elevated triglycerides
• Hypercalcemia
• Careful patient selection essential
• Adverse Effects: DPP-4 Inhibitors:
• Allergic reactions:
• Rash, hypersensitivity, anaphylaxis, angioedema, Stevens-Johnson
syndrome
• Severe joint pain reported
Management and Therapies in DM…
• Glucose-Lowering Agents in T2DM…
• SGLT-2 Inhibitors
• Mechanism of Action
• Selectively inhibit SGLT-2 co-transporter in proximal renal tubule
• ↓ Glucose reabsorption →
• ↑ urinary glucose excretion
• Insulin-independent glucose-lowering effect
• Not related to insulin sensitivity or secretion
• Clinical Effects
• Modest weight reduction
• Via urinary glucose loss
• Blood pressure reduction:
• 3–6 mmHg systolic
• Due to natriuresis/diuresis
• Cardiovascular benefits:
• Empagliflozin, canagliflozin
• ↓ ASCVD events,
• ↓ CV mortality Heart failure benefit: ↓ hospitalization for CHF
• Renal protection:
• Slows progression of diabetic kidney disease
Management and Therapies in DM…
• Glucose-Lowering Agents in T2DM…
• SGLT-2 Inhibitors…
• Adverse Effects
• Genitourinary infections
• Urinary & genital mycotic infections
• Volume depletion
• Hypotension, acute kidney injury
• ↑ Glucagon →
• ↑ hepatic glucose & ketone production
• Euglycemic DKA
• During illness or stress, despite normal glucose
• Contraindications & Precautions
• Not for Type 1 DM or pancreatogenic DM
• Avoid initiation in:
• Stage 3b CKD (eGFR <45 mL/min/1.73 m²)
• Stage 4 CKD (eGFR <30 mL/min/1.73 m²)
• Possible ↑ risk of bladder cancer with:
• Dapagliflozin
• Educate patients about DKA risk and symptoms
Management and Therapies in DM…
• Glucose-Lowering Agents in T2DM…
• Thiazolidinediones (TZDs)
• Agents: Pioglitazone, Rosiglitazone
• Class: Insulin sensitizers
• Mechanism of Action
• Bind to PPAR-γ nuclear receptor (heterodimer with RXR)
• Highest expression in adipocytes, lower in other tissues
• Effects:
• ↑ Adipocyte differentiation
• ↓ Hepatic fat accumulation
• ↑ Fatty acid storage
• Redistribution of fat: central → peripheral
• ↓ Circulating insulin levels → reduced insulin resistance
• Lipid Effects
• Rosiglitazone:
• ↑ LDL, ↑ HDL, ↑ triglycerides (slight)
• Pioglitazone:
• ↑ HDL (greater), ↑ LDL (less), ↓ triglycerides
• Clinical significance of lipid changes: uncertain
Management and Therapies in DM…
• Glucose-Lowering Agents in T2DM…
• Thiazolidinediones…
• Adverse Effects
• Weight gain:
• 2–3 kg
• Hematologic:
• Small ↓ hematocrit
• Volume expansion:
• Mild ↑ plasma volume
• Edema & CHF:
• Higher risk
• Ocular:
• Rare worsening of diabetic macular edema
• Bone health:
• ↑ fracture risk in postmenopausal women
• Reproductive:
• Induce ovulation in PCOS → risk of pregnancy
Management and Therapies in DM…
• Glucose-Lowering Agents in T2DM…
• Thiazolidinediones…
• Contraindications
• Hepatic insufficiency
• CHF class III–IV
• Use with caution in women of childbearing age (pregnancy safety not
established)
• Safety Alerts
• FDA warning:
• Pioglitazone →
• Possible ↑ risk of bladder cancer
• Rare cases of worsening macular edema
Management and Therapies in DM…
• Glucose-Lowering Agents in T2DM…
• α-Glucosidase Inhibitors
• Agents: Acarbose, Miglitol
• Class: Postprandial glucose regulators
• Mechanism of Action
• Inhibit α-glucosidase enzyme in intestinal lumen
• Delay cleavage of oligosaccharides → simple sugars
• ↓ Glucose absorption →
• ↓ postprandial hyperglycemia
• Taken just before meals
• Clinical Role
• Target postprandial hyperglycemia
• Major contributor in type 2 DM
• Less potent in lowering HbA1c compared to other oral agents
• Unique benefit:
• Blunts post-meal glucose rise
• Dosing Strategy
• Initiate at low dose with evening meal
• Gradually titrate upward over weeks–months
• Helps minimize GI side effects
Management and Therapies in DM…
• Glucose-Lowering Agents in T2DM…
• α-Glucosidase Inhibitors…
• Adverse Effects
• GI symptoms:
• flatulence, diarrhea, abdominal distention
• Mechanism: ↑ delivery of oligosaccharides to large bowel
• Reduced by slow titration
• Drug Interactions
• May ↑ sulfonylurea levels → ↑ hypoglycemia risk
• Avoid simultaneous use with:
• Bile acid resins
• Antacids
• Hypoglycemia management:
• Use glucose, not complex carbs
• Contraindications
• Inflammatory bowel disease
• Gastroparesis
• Renal impairment
• Serum creatinine > 177 μmol/L / 2 mg/dL
Management and Therapies in DM…
• Other Therapies for Type 2 Diabetes Mellitus
• Bile Acid–Binding Resins
• Mechanism:
• Bile acids signal through nuclear receptors →
• Role in metabolism
• Abnormal bile acid metabolism in type 2 DM
• Agent: Colesevelam
• Approved for hypercholesterolemia
• Also approved for type 2 DM
• Role in DM: Not yet clearly defined
• Bromocriptine
• Agent: Bromocriptine (Cycloset)
• Mechanism: Dopamine receptor agonist
• Approval: FDA-approved for type 2 DM
• Role in DM: Uncertain clinical utility
Management and Therapies in DM…
• Insulin Therapy in T2DM
• When to Consider Insulin
• Initial therapy in:
• Lean individuals
• Severe weight loss
• Renal or hepatic disease
• Contraindicating oral agents
• Hospitalized or acutely ill patients
• Long-Term Need
• Progressive nature of type 2 DM →
• Relative insulin deficiency
• Substantial number of patients ultimately require insulin
• Insulin therapy becomes necessary with long-standing diabetes
Management and Therapies in DM…
• Insulin Therapy in T2DM…
• Barriers to Initiation
• Physician reluctance
• Patient reluctance
• Often delays initiation despite clinical need
• Benefits of Insulin Therapy
• Improved glucose control
• Enhanced individual well-being
• Effective in patients not reaching glycemic targets with oral agents
Management and Therapies in DM…
• Insulin Therapy in T2DM…
• Initiating Insulin Therapy in Type 2 DM
• Rationale for Bedtime Insulin
• Endogenous insulin provides partial mealtime coverage
• Bedtime long-acting insulin
• NPH, glargine, degludec
• More effective than morning dose
• Targets fasting hyperglycemia and ↑ hepatic glucose production
• Glargine at bedtime →
• Less nocturnal hypoglycemia vs. NPH
• Dosing Strategies
• Weight-based:
• 0.1–0.4 U/kg/day
• Fixed dose:
• 10–15 units (common starting point)
• Dose adjustment:
• 10–20% increments guided by CGM or BGM
Management and Therapies in DM…
• Insulin Therapy in T2DM…
• Initiating Insulin Therapy in Type 2 DM…
• Combination Therapy
• Long-acting insulin may be combined with oral glucose-lowering agents
• Initially:
• Basal insulin sufficient
• Progression:
• Often requires prandial insulin coverage (multiple injections)
• Alternative Formulations
• Premixed insulin
• Rapid + long-acting→
• Convenient
• Limitations:
• No independent adjustment of basal vs. bolus
• Often less effective than basal/bolus regimens
• Advanced Insulin Delivery (AID)
• Consider AID in selected insulin-deficient type 2 DM patients
• CGM recommended for all individuals on insulin
Agents Used for Treatment of Type 1 or Type 2 Diabetes
HbA
Key
Class Mechanism Examples 1c ↓ Advantages Disadvantages
Considerations
(%)

Oral

• ↓ Hepatic • Weight neutral, • GI upset, • Avoid in GFR

glucose • No • lactic <30, CHF,
• Biguani 1–
production • Metformin hypoglycemia, acidosis, • Contrast
des 2%
• ↑ insulin inexpensive, • B12 studies,
sensitivity • ↓ CV events deficiency • Acidosis

• Genital
• ↓ CV events, infections,
• Avoid in
• Canagliflozi • ↓ HF, • Dehydratio
• SGLT-2 • ↑ Renal renal
n 0.5– • Renal protection, n
Inhibito glucose insufficiency
• Dapagliflozi 1.0% • Modest ↓ • Euglycemic
rs excretion • Hold before
n, etc. weight/BP, no DKA,
surgery
hypoglycemia • Hyperkalem
ia

• Rare
• ↑ GLP-1 angioedem
• DPP-4 • Sitagliptin, • Dose adjust
action → ↑ 0.5– • Well tolerated, a,
Inhibito • Saxagliptin, in renal
insulin, ↓ 0.8% • No hypoglycemia • Dermatolog
rs etc. insufficiency
glucagon ic reactions,
• Pancreatitis
Agents Used for Treatment of Type 1 or Type 2 Diabetes…
HbA1
Key
Class Mechanism Examples c↓ Advantages Disadvantages
Considerations
(%)

Oral…

• Glimepirid • Fast onset,

• Caution in
• Sulfonyl • ↑ Insulin e • ↓ postprandial • Hypoglycemia,
1–2% renal/liver
ureas secretion • Glipizide, glucose, • Weight gain
insufficiency
etc. • Inexpensive
• Nonsulf • Caution in
• Repaglinid
onylure • Fast onset, renal/liver
• ↑ Insulin e, 0.5–
a • ↓ postprandial • Hypoglycemia insufficiency
secretion • Nateglinid 1.0%
Secretag glucose (except
e
ogues repaglinide)
• Edema,
• Thiazoli • ↑ Insulin • Pioglitazon
• CHF, • Avoid in CHF,
dinedio sensitivity, e, 0.5– • ↓ insulin
• Weight gain, • Renal/liver
nes • ↑ glucose rosiglitazo 1.4% requirements
• Fractures, insufficiency
(TZDs) utilization ne
• Macular edema
• α-
Glucosid • ↓ GI • Avoid in
• Acarbose, 0.5– • ↓ Postprandial • Flatulence,
ase glucose renal/liver
• Miglitol 0.8% glucose • ↑ LFTs
Inhibitor absorption insufficiency
s
Agents Used for Treatment of Type 1 or Type 2 Diabetes…
HbA1 Key
Mechanism
Class Examples c↓ Weight Effect Side Effects Consideration
of Action
(%) s
Parenteral/Oral (GLP-1RA-related agents)

• Weight loss,
• Nausea,
• Dulaglutide • No • Renal disease,
• GI
• ↑ Insulin, • Exenatide, hypoglycemia • Agents slowing
intolerance,
• GLP- • ↓ glucagon • Liraglutide (unless with GI motility,
• Pancreatitis
1RA • Slow gastric • Lixisenatide 0.5–1.0 insulin/secretag • Medullary
risk,
s emptying, • Semaglutid ogues) thyroid
• Possible
• Satiety e (oral • ↓ CV events, carcinoma,
retinopathy
available) • Modest • Prior ileus
worsening
renoprotection

• Renal disease,
• Weight loss, • Nausea, GI • GI motility
• ↑ Insulin, • No intolerance, agents,
• GLP- • ↓ glucagon, hypoglycemia • Pancreatitis • Medullary
1/GI • Slow gastric • Tirzepatide 1.8–2.4 (unless with risk, thyroid
P RA emptying, insulin/secretag • possible carcinoma,
• Satiety ogues), retinopathy • Pancreatic
• ↓ CV events worsening disease,
• Gastroparesis
Agents Used for Treatment of Type 1 or Type 2 Diabetes…
HbA
Mechanism Weight Key
Class Examples 1c ↓ Side Effects
of Action Effect Considerations
(%)
Parenteral
• Injection,
• ↓ nausea,
• Amylin • Slow gastric
• Pramlinti 0.25– Postprandi • ↑ • Avoid with agents
Agonis emptying,
de 0.5 al glycemia hypoglycemia slowing GI motility
t • ↓ glucagon
• Weight loss risk with
insulin

• ↑ Glucose
• Injection,
utilization • Multiple Not • Known • Can be combined
• Weight gain
• Insulin • ↓ hepatic formulat limite safety with most other
• Hypoglycemi
glucose ions d profile agents
a
production

• Low-
calorie • Weight
• ↑ Insulin • Compliance
diet loss, • Generally safe
Lifestyle sensitivity difficult
• Carbohy 1–3 • Other • Broad health
Therapy • ↑ insulin • Long-term
drate health benefits
secretion success low
control, benefits
exercise
Management and Therapies in DM…
• Choice of Initial Glucose-Lowering Agent in T2DM
• Factors Influencing Choice
• Level of hyperglycemia
• Individualized glycemic goal
• Lifestyle modification always accompanies pharmacologic therapy
1. Mild Hyperglycemia
• FPG < 7.0–11.0 mmol/L (126–199 mg/dL)
• Often respond well to single oral agent
2. Moderate Hyperglycemia
• FPG 11.1–13.9 mmol/L (200–250 mg/dL)
• Usually require:
• Combination oral therapy OR
• Insulin
3. Severe Hyperglycemia
• FPG > 13.9 mmol/L (250 mg/dL)
• Oral therapy →
• Partial response,
• Unlikely to achieve normoglycemia
Management and Therapies in DM…
• Choice of Initial Glucose-Lowering Agent in T2DM…
• Insulin as initial therapy if:
• FPG 13.9–16.7 mmol/L (250–300 mg/dL)
• Symptomatic hyperglycemia
• Rationale:
• Rapid control reduces glucose toxicity,
• Improves β-cell function,
• May allow later oral therapy
• Guideline Recommendations
• Metformin:
• First-line agent (ADA, EASD, IDF, AACE)
• Efficacy, safety, low cost
• Promotes mild weight loss
• ↓ Insulin levels
• Slight improvement in lipid profile
Management and Therapies in DM…
• Choice of Initial Glucose-Lowering Agent in T2DM…
• Metformin: dose adjustment
• Guided by CGM/BGM results and HbA1c
• Increase metformin dose until:
• Glycemic target achieved OR
• Maximum tolerated dose reached
• Emerging Therapies
• GLP-1 receptor agonists (GLP-1RAs)
• SGLT-2 inhibitors
• Benefits:
• Glucose-lowering
• Weight loss
• Cardiovascular & renal protection
Management and Therapies in DM…
• Choice of Initial Glucose-Lowering Agent in T2DM…
• Approved Monotherapy Options
1. Insulin secretagogues
• Sulfonylureas, meglitinides
2. Biguanides (metformin)
3. α-Glucosidase inhibitors
4. Thiazolidinediones (TZDs)
5. GLP-1 receptor agonists (GLP-1RAs)
6. DPP-4 inhibitors
7. SGLT-2 inhibitors
8. Insulin
Management and Therapies in DM…
• Choice of Initial Glucose-Lowering Agent in T2DM…
• Generalizations
1. Efficacy
• Insulin secretagogues
• Biguanides
• GLP-1RAs
• TZDs
• HbA1c reduction:
• 1–2%
• More effective than:
• α-glucosidase inhibitors
• DPP-4 inhibitors
• SGLT-2 inhibitors
2. Onset of Action
• Immediate glucose-lowering:
• Secretagogues
• GLP-1RAs
• DPP-4 inhibitors
• α-glucosidase inhibitors
• SGLT-2 inhibitors
• Delayed effect (days):
• Biguanides
• TZDs
Management and Therapies in DM…
• Choice of Initial Glucose-Lowering Agent in T2DM…
• Generalizations…
3. Individual Response & Hypoglycemia
• Not all agents effective in all individuals
4. Do not directly cause hypoglycemia:
• Biguanides
• α-Glucosidase inhibitors
• GLP-1RAs
• DPP-4 inhibitors
• TZDs
• SGLT-2 inhibitors
5. Progression
• Most patients eventually require:
• Combination therapy OR
• Insulin
• Reflects progressive nature of type 2 DM
6. Durability of glycemic control:
• Slightly less with sulfonylureas compared to metformin or TZDs
Management and Therapies in DM…
• Combination Therapy in T2DM
• Changing Approach
• Evidence:
• GLP-1RAs &
• SGLT-2 inhibitors
• ↓ Cardiovascular events
• Slow CKD progression
• Should be used in most individuals with type 2 DM
• Therapy Dictated By Comorbidities
• ASCVD →
• prioritize GLP-1RA or
• SGLT-2 inhibitor
• Heart failure →
• SGLT-2 inhibitor preferred
• CKD →
• SGLT-2 inhibitor preferred
• Weight loss goal →
• GLP-1RA or
• SGLT-2 inhibitor
Management and Therapies in DM…
• Combination Therapy in T2DM…
• Common Combinations
• Metformin +
• SGLT-2 inhibitor
• Metformin +
• GLP-1RA
• Metformin +
• Insulin
• Long-acting insulin +
• GLP-1RA
• Mechanism differences →
• Additive glycemic effect
• Evidence – GRADE Study
• Addition of liraglutide or basal insulin to metformin →
• Better glycemic control
• Compared to:
• Glimepiride or
• Sitagliptin
• (SGLT-2 inhibitors not studied)
Management and Therapies in DM…
• Combination Therapy in T2DM…
• Escalation Strategy
• Reassess HbA1c:
• Every 3 months
• If inadequate control with 2 agents →
• Add a third agent (including basal insulin)

• Practical Considerations
• Medication costs vary:
• SGLT-2 inhibitors & GLP-1RAs → expensive
• Fixed-dose oral combinations available
• No clear evidence of superiority vs.
• Titration + add-on
• Regional Variations
• E.g South Asia (India): α-glucosidase inhibitors commonly used
• US/Europe: infrequent use
• May reflect physician preference or disease differences
Management and Therapies in DM…
• Combination Therapy in T2DM…
• Insulin
• Indications for Insulin
• Relative insulin deficiency phase of type 2 DM i.e.,
• Inadequate glycemic control with 1–2 oral agents
• Insulin alone or in combination required to reach targets
• Initial Combination Strategy
• Bedtime long-acting insulin +
• Metformin →
• Effective early regimen
• Addresses fasting hyperglycemia
• Progression of Therapy
• As endogenous insulin declines:
• Multiple injections needed
• Long-acting + rapid-acting insulin for postprandial control
• Regimens similar to type 1 DM, but higher doses due to insulin resistance
Management and Therapies in DM…
• Combination Therapy in T2DM…
• Insulin…
• Adverse Effects
• Weight gain
• Hypoglycemia
• Addition of GLP-1RA can:
• Limit weight gain
• Reduce insulin dose requirement
• Dose Requirements
• Daily insulin dose may reach 1–2 units/kg/day
• Higher doses needed with persistent insulin resistance and weight gain
Management and Therapies in DM…
• Combination Therapy in T2DM…
• Insulin…
• Combination Considerations
• Insulin + TZD →
• Promotes weight gain
• May cause edema
• Adding GLP-1RA or TZD →
• May require insulin dose reduction to avoid hypoglycemia
• Special Situations
• Patients needing >200 units/day:
• Use concentrated insulin formulations
• Benefits:
• ↓ injection volume,
• ↑ absorption
Glycemic management of type 2 diabetes.
Management and Therapies in DM…
• Other Therapies for Diabetes
• Metabolic (Bariatric) Surgery
• Highly effective in obese individuals with type 2 DM
• Can lead to dramatic resolution or major reduction in therapy needs
• Greater efficacy than medical management (pre-GLP-1RA era trials)
• ADA guidelines:
• Consider if BMI >30 kg/m² and
• Hyperglycemia uncontrolled despite optimal therapy
• Best performed in certified centers with nutritional support
• Very-Low-Calorie Diets
• Short-term intense caloric restriction (800–1000 kcal/day)
• Can dramatically improve or even resolve type 2 DM
• More effective in recent-onset diabetes
• Must be supervised by an expert
• Requires long-term weight maintenance program
Management and Therapies in DM…
• Other Therapies for Diabetes…
• Whole-Pancreas Transplantation
• Normalizes glucose in type 1 DM
• Often performed with or after kidney transplant →
• Protects against recurrent nephropathy
• Declining numbers due to success of CGM and AID
• Pancreatic Islet Transplantation
• Less invasive beta-cell replacement therapy
• FDA-approved islet product available
• Risks: chronic immunosuppression
• Considered for:
• Severe metabolic instability
• Patients already requiring immunosuppression (e.g., kidney transplant)
• Autologous Islet Transplantation
• For patients with chronic pancreatitis requiring pancreatectomy
• Preserved islet function →
• Autologous transplant may prevent or reduce postsurgical DM
Management and Therapies in DM…
• Emerging Therapies in Diabetes
• Stem Cell–Derived Insulin-Producing Cells
• Transplantation of cells from human pluripotent stem cells
• Early clinical trials show promise
• Challenges:
• Cost
• Durability
• Long-term safety
• Patient selection
• Beta-Cell Regeneration & Autoimmunity
• Some individuals with long-standing type 1 DM still produce small
amounts of insulin
• Suggests slow regeneration of beta cells
• Quickly destroyed by autoimmune process
• Goal: suppress autoimmunity to preserve beta-cell function
Management and Therapies in DM…
• Emerging Therapies in Diabetes…
• Teplizumab (Anti-CD3 Monoclonal Antibody)
• Targets T lymphocytes
• FDA-approved to delay onset of stage 3 type 1 DM
• Indication:
• Patients ≥8 years old with stage 2 (preclinical) disease
• Represents first therapy to modify disease progression
• TXNIP-Targeted Therapies
• Thioredoxin-interacting protein (TXNIP) implicated in diabetes
• Ca²⁺ channel blockers show promise:
• In recent-onset type 1 DM
• In rodent models of diabetes
Management and Therapies in DM…
• Adverse Effects of Therapy for Diabetes Mellitus
• Glycemic control improves outcomes
• Must balance against treatment risks
• Side effects vary by therapy class
• Hypoglycemia
• Most Serious Complication
• Intensive treatment →
• ↑ risk of severe hypoglycemia
• Prevention & treatment:
• Oral glucose
• Glucagon (intranasal or injection)
• Severe/recurrent/unexplained hypoglycemia →
• Reassess regimen & goals
• May require deintensification of insulin therapy
Management and Therapies in DM…
• Adverse Effects of Therapy for Diabetes Mellitus…
• Weight Gain
• Common with:
• Insulin
• Insulin secretagogues (sulfonylureas, meglitinides)
• Thiazolidinediones (TZDs)
• Mechanisms:
• Anabolic effects of insulin
• ↓ Glucosuria
• Therapies Without Weight Gain
• Metformin
• α-Glucosidase inhibitors
• GLP-1 receptor agonists (GLP-1RAs)
• SGLT-1 inhibitors
• DPP-4 inhibitors
• Patient Burden
• Intensive therapy →
• Greater demands on patients
• Requires:
• Frequent monitoring
• Lifestyle adjustments
• Vigilance for hypoglycemia
Acute Disorders Related to Severe Hyperglycemia
• Initial Assessment
• Evaluate clinical stability:
• Mentation, hydration
• Determine presence of:
• Diabetic ketoacidosis (DKA)
• Hyperglycemic hyperosmolar state (HHS)
• DKA
• Key Features
• Hyperglycemia +
• Ketones in blood +
• Metabolic acidosis
• Common in type 1 DM
• Symptoms:
• Nausea,
• Vomiting
• Abdominal pain
• Preferred test:
• Blood β-hydroxybutyrate
• Better than urine nitroprusside assays
Acute Disorders Related to Severe Hyperglycemia…
• HHS
• Key Features
• More severe hyperglycemia →
• Hyperosmolality +
• Marked dehydration
• No ketosis or acidosis
• Occurs mostly in type 2 DM
• Higher mortality risk
• Epidemiology & Trends
• Rising cases of DKA and HHS worldwide
• DKA:
• Mostly type 1 DM, but
• Can occur in obese young adults (Hispanic/African descent) →
• Ketosis-prone diabetes
• After recovery: insulin secretory capacity returns, insulin may be discontinued
• Special Situations
• SGLT-2 inhibitors →
• Risk of euglycemic DKA
• Glucose may be normal or mildly elevated due to glucosuria
• DKA and HHS exist on a continuum of hyperglycemia
• Up to one-third of patients show mixed features
Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis (DKA)
• Clinical Features
• Onset
• Develops over ~24 hours
• May be initial presentation of type 1 DM
• More often occurs in established diabetes
• Key Symptoms
• Nausea & vomiting →
• Warrant evaluation for DKA
• Abdominal pain
• Can mimic pancreatitis or ruptured viscus
• Polyuria & glucosuria →
• Volume depletion
• Tachycardia, hypotension
• Due to dehydration + vasodilation
• Classic Signs
• Kussmaul respirations
• Deep, rapid breathing
• Fruity breath odor
• Acetone
• Lethargy → CNS depression → coma in severe cases
• Must rule out other causes of altered mental status
• Infection
• Hypoxemia)
Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis…
• Clinical Features…
• Cerebral edema
• Serious Complications
• Especially in children
• Precipitating Factors
• Infections may precipitate DKA
• Even without fever
• Tissue ischemia (heart, brain)
• Failure to increase insulin during stress/illness
• Insulin omission:
• Pump malfunction or site occlusion
• Eating disorders, mental health issues, unstable psychosocial
environment
• Hospitalized patients with inadequate insulin administration
• Economic barriers:
• Rising insulin cost → rationing/omission
Manifestations of Diabetic Ketoacidosis
Category Details
• Nausea/vomiting
• Thirst/polyuria
• Symptoms
• Abdominal pain
• Shortness of breath
• Inadequate insulin administration
• Infection (pneumonia, UTI, gastroenteritis, sepsis…)
• Infarction (cerebral, coronary, mesenteric, peripheral)
• Precipitating Events
• Pancreatitis
• Drugs (e.g., cocaine)
• Pregnancy
• Tachycardia
• Dehydration/hypotension
• Tachypnea/Kussmaul respirations/respiratory distress
• Physical Findings
• Abdominal tenderness (may mimic pancreatitis or surgical
abdomen)
• Lethargy/obtundation/cerebral edema/possibly coma
Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis…
• Pathophysiology of DKA
• Core Mechanism
• Relative or absolute insulin deficiency combined with
• Counterregulatory hormone excess:
• Glucagon
• Catecholamines
• Cortisol
• Growth hormone
• Metabolic Consequences
• ↓ Insulin : Glucagon ratio →
• ↑ Gluconeogenesis
• ↑ Glycogenolysis
• ↑ Ketone body formation (liver)
• ↑ Substrate delivery to liver:
• Free fatty acids
• From adipose tissue
• Amino acids
• From muscle
Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis…
• Pathophysiology of DKA…
• Ketosis Development
• Marked increase in free fatty acid release from adipocytes
• Shift toward ketone body synthesis in liver
• Lipolysis enhanced by:
• ↓ insulin +
• ↑ catecholamines &
• Growth hormone
• Inflammatory Component
• Elevated markers in DKA and HHS:
• Cytokines
• C-reactive protein (CRP)
• Suggests role of systemic inflammation in pathophysiology
Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis…
• Laboratory Abnormalities & Diagnosis
• Timely diagnosis is crucial for prompt therapy
• Core triad of DKA:
• Hyperglycemia:
• Serum glucose >13.9 mmol/L (250 mg/dL)
• Ketosis
• Metabolic acidosis:
• Serum bicarbonate <15–18 mmol/L, with
• ↑ anion gap
• Special Presentation
• Euglycemic DKA:
• Serum glucose minimally elevated or normal
• Often seen in patients on SGLT-2 inhibitors
• Acid-Base Status
• Arterial pH:
• 6.8–7.3 (severity-dependent)
• Despite total-body potassium deficit:
• Serum potassium may be mildly elevated
• Due to acidosis + volume depletion
Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis…
• Laboratory Abnormalities & Diagnosis…
• Electrolyte & Volume Changes
• Total-body deficits:
• Sodium, chloride, phosphorus, magnesium
• Serum levels may appear misleading (hypovolemia + hyperglycemia)
• BUN & creatinine elevation →
• Intravascular volume depletion
• Other Laboratory Findings
• Leukocytosis
• Hypertriglyceridemia
• Hyperlipoproteinemia
• Hyperamylasemia (usually salivary origin, not pancreatic)
• Pancreatitis Consideration
• Abdominal pain + hyperamylasemia →
• Consider pancreatitis
• Amylase in DKA:
• Typically salivary, not diagnostic
• Lipase testing recommended if pancreatitis suspected
Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis…
• Laboratory Abnormalities & Diagnosis…
• Serum Sodium in DKA
• Measured serum sodium reduced due to hyperglycemia
• Correction formula:
• ↓ 1.6 mmol/L (1.6 meq) Na⁺ for each ↑ 5.6 mmol/L (100 mg/dL)
glucose
• Normal serum sodium in DKA →
• Indicates more profound water deficit
• Ketone Bodies
• β-hydroxybutyrate
• Synthesized at 3× rate of acetoacetate
• Detection bias: Nitroprusside reagent:
• Detects acetoacetate preferentially
• Commonly used for urine ketones
• False positives:
• Captopril, penicillamine, valproic acid
• Preferred test:
• Serum/plasma β-hydroxybutyrate assay →
• More accurate reflection of ketone levels
Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis…
• Laboratory Abnormalities & Diagnosis…
• Acidosis & Hyperglycemia
• Degree of acidosis ≠ degree of hyperglycemia
• Hyperglycemia influenced by:
• Oral intake
• Urinary glucose loss
• Consistent finding:
• Ketonemia →
• Distinguishes DKA from simple hyperglycemia
• Differential Diagnosis
• Starvation ketosis
• Alcoholic ketoacidosis
• Bicarbonate usually >15 meq/L
• Other causes of increased anion-gap acidosis
Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis…
• Treatment
• Classification of DKA Severity
• Serum
• Severity • pH Bicarbonate • Mental Status
(meq/L)
• Mild • 7.25–7.3 • 15–18 • Normal
• Moderate • 7.0–7.25 • 10–15 • Mildly reduced

• Severe • <7.0 • <10–15 • Reduced, coma possible

Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis…
• Treatment…
• General Management Principles
• Initiate IV fluid replacement +
• Insulin therapy
• Identify and treat precipitating event
• Infection, infarction…
• If vomiting or altered mental status →
• Insert nasogastric tube (aspiration prevention)
• Careful monitoring & frequent reassessment are central to success
• Use a comprehensive flow sheet:
• Vital signs
• Fluid intake/output
• Lab values vs. insulin administered
Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis…
• Treatment…
• Fluid Replacement Strategy
• Initial bolus:
• Normal saline or lactated Ringer’s
• Replace sodium + free water deficit over 24
• Deficit often 3–5 L
• Once hemodynamic stability & adequate urine output achieved:
• Switch IV fluids to 0.45% saline or lactated Ringer’s (based on
calculated deficit)
• Ringer’s lactate:
• Associated with faster DKA resolution
• Reduced risk of hyperchloremia later in course
Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis…
• Treatment…
• Insulin Therapy in DKA
• Initial bolus:
• IV regular insulin 0.1 units/kg
• Continuous infusion:
• IV regular insulin 0.1 units/kg per hour (preferred route)
• Alternative:
• SC short-acting insulin analogues
• For uncomplicated DKA
• As acidosis & insulin resistance resolve →
• Reduce infusion to 0.02–0.1 units/kg per hour
• Transition to Outpatient Regimen
• Once patient resumes eating:
• Add long-acting insulin + SC short-acting insulin
• Facilitates transition to outpatient regimen
• Reduces hospital stay duration
Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis…
• Treatment: Insulin Theray…
• Glucose & Rehydration Effects
• Hyperglycemia improves at:
• 50–100 mg/dL (4.2–5.6 mmol/L) per hour
• Mechanisms:
• Insulin-mediated glucose disposal
• ↓ hepatic glucose release
• Rehydration effects:
• ↓ catecholamines,
• ↑ urinary glucose loss,
• ↑ intravascular volume
• Early decline in glucose (first 1–2 h) →
• Mainly due to volume expansion
Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis…
• Treatment: Insulin Theray…
• Resolution of Ketoacidosis
• Insulin effects:
• ↓ lipolysis
• ↑ peripheral ketone body utilization
• ↓ hepatic ketone body formation
• ↑ bicarbonate regeneration
• Acidosis & ketosis
• Resolve more slowly than hyperglycemia
• Anion gap
• Normalizes faster than bicarbonate (depends on chloride rise)
• Hyperchloremic acidosis
• Bicarbonate 15–18 meq/L
• May follow treatment →
• Gradually resolves with
• Renal bicarbonate regeneration & chloride excretion
Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis…
• Treatment…
• Potassium in DKA
• Total-body deficit:
• 3–5 mmol/kg (3–5 meq/kg)
• Hypokalemia during treatment due to:
• Insulin-mediated K⁺ transport into cells
• Resolution of acidosis →
• K⁺ entry into cells
• Urinary loss of potassium salts of organic acids
• Repletion:
• Start once adequate urine output +
• Normal serum potassium documented
Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis…
• Treatment…
• Bicarbonate
• Bicarbonate replacement:
• Not shown to improve outcomes
• Indication:
• Severe acidosis (arterial pH <7.0)
• Sodium bicarbonate 50 mmol in 200 mL sterile water +
• 10 meq/L KCl per hour
• For 2 h until pH >7.0
• Other deficits:
• Hypophosphatemia →
• May require supplementation if severe
• Hypomagnesemia →
• May require supplementation if severe
Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis…
• Complications of DKA & Therapy
• Mortality rate:
• <1% (related to precipitating event) like:
• Infection (pneumonia, SARS-CoV-2/COVID-19)
• Pregnancy
• End-stage renal disease
• Myocardial infarction
• Occasional complications:
• Venous thrombosis
• Upper GI bleeding
• Acute respiratory distress syndrome (ARDS)
• Cerebral edema
• Major nonmetabolic complication
• Most often in children, during resolution
Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis…
• Complications of DKA & Therapy…
• Prevention & Long-Term Considerations
• Review sequence of events leading to DKA →
• Prevent recurrence
• Even a single episode →
• Greatly ↑ 1-year mortality risk
• Patient education:
• Symptoms of DKA
• Precipitating factors
• Sick-day management of diabetes
• Recurrent DKA may indicate:
• Mental health issues
• Structural barriers to care
• Insulin cost challenges
• Social determinants of health
Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis…
• Summary of management of DKA
1. Confirm diagnosis:
• ↑ Serum glucose
• ↑ Serum β-hydroxybutyrate
• Metabolic acidosis
2. Hospital admission:
• Severe DKA →
• ICU
• Mild–moderate DKA →
• Step-down unit with close monitoring
3. Initial Assessment
• Serum electrolytes:
• K⁺, Na⁺, Mg²⁺, Cl⁻, HCO₃⁻, phosphate
• Acid-base status:
• pH, HCO₃⁻, PCO₂, β-hydroxybutyrate
• Renal function:
• Creatinine, urine output
Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis…
• Summary of management of DKA…
4. Fluid Replacement
• First 1–3 h:
• 2–3 L of 0.9% saline or lactated Ringer’s or
• 10–20 mL/kg per hour
• Then:
• 0.45% saline at 250–500 mL/h
• When glucose ↓ to 250 mg/dL (13.9 mmol/L):
• Switch to 5–10% glucose +
• 0.45% saline or lactated Ringer’s at 150–250 mL/h
• Euglycemic DKA:
• Start dextrose infusion +
• Insulin early to prevent hypoglycemia
Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis…
• Summary of management of DKA…
5. Insulin Therapy
• Initial bolus:
• IV regular insulin 0.1 units/kg
• Continuous infusion:
• IV regular insulin 0.1 units/kg per hour
• Increase 2–3× if no response in 2–4 h
• Alternative (mild–moderate DKA):
• 0.1 unit/kg rapid-acting insulin analogue SC
• Then 0.1 units/kg SC every 1 h OR 0.2 units/kg SC every 2 h
• Continue insulin + dextrose infusion (5% or 10%) to prevent hypoglycemia
• If serum K⁺ <3.3 mmol/L →
• Correct potassium before insulin
Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis…
• Summary of management of DKA…
6. Identify precipitating event:
• Noncompliance, infection, trauma, pregnancy, infarction, cocaine
• Initiate appropriate workup:
• Cultures, chest X-ray, ECG, etc.
7. Monitoring
• Blood glucose:
• Every 1–2 h
• Electrolytes (K⁺, bicarbonate, phosphate) + anion gap:
• Every 4 h (first 24 h)
• Vital signs & status:
• BP, pulse, respirations, mental status, fluid intake/output
• Every 1–4 h
Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis…
• Summary of management of DKA…
8. Potassium Replacement
• If ECG, urine flow, creatinine normal →
• Replace K⁺
• K⁺ <3.5 mmol/L:
• 10–20 mmol/h until >3.5 mmol/L
• K⁺ 3.5–5 mmol/L:
• 10–20 mmol in each liter of IV fluid (maintain 4–5 mmol/L)
• K⁺ >5.0 mmol/L:
• Start insulin,
• Hold K⁺;
• Recheck every 2 h to determine when to start replacement
Acute Disorders Related to Severe Hyperglycemia…
• Diabetic Ketoacidosis…
• Summary of management of DKA…
9. Resolution Criteria
• Continue therapy until:
• Glucose
• 150–200 mg/dL (8.3–11.1 mmol/L)
• Normal
• Plasma ketones & pH
• Bicarbonate
• ≥18 mmol/L
• Insulin infusion
• May be decreased to 0.02–0.1 units/kg per hour
• Euglycemic DKA:
• Resolution based on bicarbonate correction,
• Not glucose
10. Transition to Long-Term Insulin
• Administer long-acting insulin
• Once patient is eating
• Allow 2–4 h overlap
• Between IV insulin infusion and SC long-acting insulin injection
Acute Disorders Related to Severe Hyperglycemia…
• Hyperglycemic Hyperosmolar State (HHS)
• Clinical Features
• Typical Patient Profile
• Elderly individual with
• Type 2 Diabetes Mellitus
• Several-week history of:
• Polyuria
• Weight loss
• Diminished oral intake
• Progression to
• Mental confusion, lethargy, or coma
• Physical Examination Findings
• Profound dehydration
• Hyperosmolality
• Hypotension
• Tachycardia
• Altered mental status
Acute Disorders Related to Severe Hyperglycemia…
• Hyperglycemic Hyperosmolar State…
• Clinical Features…
• Key Differences from DKA
• Absent symptoms:
• Nausea, vomiting, abdominal pain
• Kussmaul respirations
• Distinguishing feature:
• No significant ketoacidosis
• Precipitating Factors
• Serious concurrent illness:
• Myocardial infarction
• Stroke
• Infections:
• Sepsis
• Pneumonia
• Other severe infections
• Compromised water intake:
• Prior stroke
• Dementia
• Social situations limiting hydration
Acute Disorders Related to Severe Hyperglycemia…
• Hyperglycemic Hyperosmolar State…
• Pathophysiology
• Underlying Causes
• Relative insulin deficiency
• Inadequate fluid intake
• Together →
• Trigger hyperglycemia and dehydration
• Mechanisms of Hyperglycemia
• Insulin deficiency →
• ↑ Hepatic glucose production (glycogenolysis, gluconeogenesis)
• ↓ Skeletal muscle glucose utilization
• Result: Marked hyperglycemia
Acute Disorders Related to Severe Hyperglycemia…
• Hyperglycemic Hyperosmolar State…
• Pathophysiology…
• Osmotic Diuresis & Volume Depletion
• Hyperglycemia →osmotic diuresis
• Leads to intravascular volume depletion
• Worsened by inadequate fluid replacement
• Absence of Ketosis
• Not fully understood
• Possible explanations:
• Insulin deficiency is relative, less severe than DKA
• Lower levels of counterregulatory hormones
• Catecholamines, cortisol, glucagon
• Lower free fatty acids
• Liver less capable of ketone synthesis
• Insulin/glucagon ratio does not favor ketogenesis
Acute Disorders Related to Severe Hyperglycemia…
• Hyperglycemic Hyperosmolar State…
• Laboratory Abnormalities & Diagnosis
• Key Laboratory Features
• Marked hyperglycemia
• Plasma glucose often > 55.5 mmol/L (1000 mg/dL)
• Hyperosmolality
• 300 mOsm/L
• Prerenal azotemia
• Due to dehydration and volume depletion
• Serum Sodium
• Measured sodium:
• Normal or slightly low despite hyperglycemia
• Corrected sodium: usually increased
• Formula:
• Add 1.6 mEq/L to measured sodium
• For each 5.6 mmol/L (100 mg/dL) rise in serum glucose
Acute Disorders Related to Severe Hyperglycemia…
• Hyperglycemic Hyperosmolar State…
• Laboratory Abnormalities & Diagnosis…
• Acid-Base Status
• Acidosis and ketonemia:
• Absent or mild (contrast with DKA)
• Possible small anion-gap metabolic acidosis:
• Secondary to ↑ lactic acid
• Moderate ketonuria (if present):
• Usually due to starvation, not ketoacidosis
Laboratory Values in DKA, HHS, and Euglycemic DKA
Parameter DKA HHS Euglycemic DKA
• Glucose (mmol/L / mg/dL) 11.1–33.3 / 250–600 33.3–66.6 / 600–1200 5.5–13.9 / 100–250
• Sodium (mEq/L) 125–135 135–145 Normal
• Potassium Normal to ↑ Normal Normal to ↑
• Magnesium Normal Normal Normal
• Chloride Normal Normal Normal
• Phosphate Normal Normal Normal
• Creatinine Slight–moderate ↑ Moderate ↑ Slight ↑
• Osmolality (mOsm/mL) >300 >300 Normal
• Serum/Urine Ketones >++ +/– >++
• β-hydroxybutyrate
>3.0 <1.0 >3.0
(mmol/L)
• Bicarbonate (mEq/L) <18 >18 <18
• Arterial pH 6.8–7.3 >7.3 <7.3
• Arterial PCO₂ (mmHg) 20–30 Normal 20–30
• Anion Gap ↑ Normal to slight ↑ ↑
Acute Disorders Related to Severe Hyperglycemia…
• Hyperglycemic Hyperosmolar State…
• Treatment
• General Principles
• Therapy overlaps with DKA management
• Core elements:
• Careful monitoring of
• Fluid status,
• Labs,
• Insulin infusion
• Identify and treat underlying/precipitating illness
• Fluid losses and dehydration are more pronounced in HHS
• Patients typically
• Older,
• Altered mental status,
• Comorbidities
• Mortality higher than DKA (up to 15%)
Acute Disorders Related to Severe Hyperglycemia…
• Hyperglycemic Hyperosmolar State…
• Treatment…
• Fluid Replacement
• Initial Phase
• Goal: stabilize hemodynamics
• 1–3 L of 0.9% normal saline over first 2–3 hours
• Adjust fluid type based on sodium:
• If Na⁺ >150 mmol/L, use 0.45% saline
• Ongoing Phase
• After stabilization:
• Reverse free water deficit with hypotonic fluids
• Start with 0.45% saline
• Transition to D5W (5% dextrose in water)
• Free water deficit can be
• 9–10 L
• Replace over 1–2 days
• Infusion rates: 200–300 mL/h
Acute Disorders Related to Severe Hyperglycemia…
• Hyperglycemic Hyperosmolar State…
• Treatment…
• Electrolyte Management
• Potassium repletion:
• Guided by repeated serum K⁺ checks
• Diuretic use →
• Large potassium deficit,
• Possible magnesium deficiency
• Hypophosphatemia may occur during therapy
• Correct with KPO₄ and initiation of nutrition

• Insulin Therapy
• Rehydration lowers plasma glucose initially
• Insulin is required to normalize metabolism
• Therapy parallels DKA management
Acute Disorders Related to Severe Hyperglycemia…
• Hyperglycemic Hyperosmolar State…
• Treatment: Insulin Therapy…
• Initial Insulin Regimen • Transition to Maintenance
• Regular insulin IV bolus 0.1 unit/kg • Continue insulin infusion until:
• Continuous infusion: • Patient resumes eating
• Regular insulin 0.1 unit/kg per • Transition to subcutaneous
hour insulin regimen
• Discharge plan:
• If glucose does not fall →
• Patient should leave hospital on
• Double infusion rate
insulin
• Adjustment During Therapy • Some may later switch to oral
• When plasma glucose falls to 11.1– glucose-lowering agents
13.9 mmol/L (200–250 mg/dL):
• Add glucose to IV fluids
• Reduce insulin infusion to
0.02–0.1 unit/kg per hour
Management of Diabetes in Hospital or Facility
• Hyperglycemia →
• Predictor of poor outcomes in hospitalized patients
• Even without known diabetes DM
• Contributing factors for hyperglycemia :
• General anesthesia, surgery, infection, concurrent illness
• ↑ Counterregulatory hormones (cortisol, GH, catecholamines, glucagon)
• ↑ Cytokines → transient insulin resistance
• Effects:
• ↑ Glucose production
• ↓ Glucose utilization
• Variable insulin absorption
• Risk of hypoglycemia due to impaired oral intake
• Initial Assessment
• On admission:
• HbA1c for glycemic control baseline
• Electrolytes, renal function, intravascular volume status
• High prevalence of ASCVD T2DM →
• May require preoperative CV evaluation
• CGM
• Not FDA-approved in hospital/ICU
• Patients already using CGM/AID may continue if safe and agreed upon
Management of Diabetes in Hospital or Facility…
• Goals of Management
• Near-normoglycemia
• Avoid hypoglycemia
• Transition back to outpatient regimen
• Frequent glycemic monitoring from admission
• Plan for post-discharge diabetes management
• Evidence & Outcomes
• Hyperglycemia linked to worse:
• Cardiac
• Neurologic
• Infectious outcomes
• Even modest glucose elevations in non-diabetics →
• Benefit from insulin therapy
• NICE-SUGAR trial:
• Very strict control (81–108 mg/dL) →
• ↑ mortality
• ↑ severe hypoglycemia
• Moderate control (<180 mg/dL) →
• Safer outcomes
Management of Diabetes in Hospital or Facility…
• ADA Recommended Glycemic Targets
• Critically & non-critically ill:
• 140–180 mg/ dL (7.8–10.0 mmol/L)
• Selected patients:
• 110–140 mg/dL (6.1–7.8 mmol/L) with
• Hypoglycemia avoidance
• Perioperative period:
• 80–180 mg/dL (4.4–10.0 mmol/L)
Management of Diabetes in Hospital or Facility…
• Critical Aspects of Optimal Diabetes Care in Hospital Settings
• System-Level Approach
• Hospital-wide protocols for:
• Treatment of hyperglycemia
• Prevention of hypoglycemia
• Inpatient diabetes management teams:
• Nurse practitioners + physicians
• Standardized protocols improve safety and outcomes
• Transition Planning
• Focus on transitions:
• ICU → general ward
• Inpatient → outpatient
• Adjust discharge regimen if HbA1c shows poor control on admission
• Vigilant Monitoring
• Monitor plasma glucose during:
• Perioperative period
• Infection or serious illness
• Fasting for diagnostic procedures
• Provide glucose infusion as needed
• Hypoglycemia is frequent but often avoidable
Management of Diabetes in Hospital or Facility…
• Critical Aspects of Optimal Diabetes Care in Hospital
Settings…
• Preventing Hypoglycemia
• Frequent glucose monitoring
• Anticipate ↓ insulin requirements due to:
• Declining renal function
• Lower glucocorticoid doses
• Interrupted nutrition (PO, enteral, parenteral)
• Hospital protocols essential for prevention
Management of Diabetes in Hospital or Facility…
• Insulin Therapy…
• Options
1. Insulin infusion (IV):
• Preferred in
• ICU or
• Unstable patients
• Short half-life →
• Rapid control
• Variable absorption of SC insulin in such situations
• Useful perioperatively or when NPO
2. SC insulin:
• Suitable for stable patients or
• Short procedures (<4h)
• Regular insulin used for IV infusion
• Cost-effective
• Equally effective vs analogues
Management of Diabetes in Hospital or Facility…
• Insulin Therapy…
• Insulin Infusion Protocols
• Must consider:
• Patient’s insulin sensitivity
• Frequent glucose monitoring
• Trends in glucose changes
• Algorithms jointly developed by nursing + physician staff
recommended.
• Administer long-acting insulin
• 2–4h before stopping infusion to avoid insulin deficiency
• Non-Critically Ill Patients
• Basal–Bolus Approach
• Basal insulin (SC, long-acting) →
• Scheduled coverage
• Supplemented by:
• Prandial insulin (rapid-acting) for meals
• Corrective insulin for elevated glucose
• Sliding scale alone
• Short/rapid insulin only when glucose is high →
• Inadequate
Management of Diabetes in Hospital or Facility…
• Insulin Therapy: non-critically ill patients…
• Prandial & Corrective Insulin
• Preprandial rapid-acting insulin dose:
• Coverage for anticipated carbohydrate intake
• Corrective insulin based on sensitivity & glucose level
• Example correction factors:
• Thin, insulin-sensitive:
• 1 unit per 2.7 mmol/L (50 mg/dL) above target
• Obese, insulin-resistant:
• 2 units per 2.7 mmol/L (50 mg/dL) above target
• Individualization & Adjustment
• Regimen must be individualized
• Adjust basal + prandial doses frequently based on corrective insulin
needs
• Consistent carbohydrate-controlled meal plan:
• Predictable carbs per meal
• Avoid concentrated sweets
Management of Diabetes in Hospital or Facility…
• Insulin Therapy…
• T1DM– Special Considerations
• During general anesthesia, surgery, or serious illness:
• Continuous insulin required
• IV infusion,
• Device, or
• SC long-acting
• Rapid-acting insulin alone is insufficient
• Risks:
• Prolonged surgery or recovery →
• Insulin deficiency → DKA
Management of Diabetes in Hospital or Facility…
• Insulin Therapy…
• T1DM– Special Considerations…
• Perioperative Insulin Strategy
• Prolonged procedures or serious illness
• Preferred: IV insulin infusion
• 0.5–1.0 units/h regular insulin
• Brief procedures (<4h):
• Reduced SC basal dose
• 20–50% reduction
• Rapid-acting correctional insulin as needed
• Prevent interruptions in initial insulin therapy
• Facilitates transition back to basal/bolus regimen post-procedure
• Monitoring
• Frequent blood glucose checks during illness or perioperative period
Management of Diabetes in Hospital or Facility…
• Inpatient Management of T2DM
• Insulin-Based Management
• Options:
• IV insulin infusion
• SC long-acting insulin
• 20–50% reduction depending on clinical setting
• Supplemented with preprandial rapid-acting insulin
• Oral agents →
• Discontinued upon admission
• For SGLT-2 inhibitors:
• Stop up to 1 week prior to planned admission
• Why oral agents are avoided
• Rapidly changing insulin requirements & glucose intake →
• Oral agents ineffective
• Risks if continued:
• Sulfonylureas:
• Hypoglycemia (especially if fasting)
• SGLT-2 inhibitors:
• Euglycemic DKA
• Metformin:
• Lactic acidosis
• Risk ↑ with renal decline, CHF, contrast media
Management of Diabetes in Hospital or Facility…
• Inpatient Management of T2DM…
• Resumption of Oral Agents
• Once clinically stable, oral agents may be restarted
• Plan for discharge regimen should be individualized and structured
• Long-Term & Rehabilitation Facilities
• Principles similar to hospital management
• Glycemic goals →
• Individualized based on clinical status
• Often, avoidance of hypoglycemia is the major goal
• Less intense glycemic targets may be appropriate
 Special Considerations in Diabetes
• Total parenteral nutrition (TPN)/total enteral nutrition
(TEN)
• Impact on Insulin Requirements
• TPN/TEN greatly increase insulin needs
• Even individuals without known DM may develop hyperglycemia
• Insulin therapy often required
• Total Parenteral Nutrition
• Preferred treatment:
• IV insulin infusion
• Rapid titration possible with separate insulin infusion
• Once total insulin dose determined:
• A proportion can be added directly to TPN solution
• Adjust with rapid-acting insulin as needed
 Special Considerations in Diabetes…
• TPN/TEN…
• Total Enteral Nutrition
• Hyperglycemia may be limited with high-protein formulations
• Often requires insulin treatment
• Bolus feedings:
• SC rapid-acting insulin prior to each bolus
• Starting dose:
• 1 unit per 10–15 g carbohydrate
• Basal Insulin Coverage
• Patients with insulin deficiency (Type 1 DM, pancreatogenic DM):
• Require long-acting insulin (0.1–0.2 units/kg/day)
• Purpose: cover basal needs if TPN/TEN is interrupted or cycled
 Special Considerations in Diabetes…
• Glucocorticoids
• Effects on Glucose Homeostasis
• ↑ Insulin resistance
• ↓ Glucose utilization
• ↑ Hepatic glucose production
• ↓ Insulin secretion
• Result:
• Worsening glycemic control in DM, or
• New-onset hyperglycemia
• Steroid-Induced Diabetes
• Chronic supraphysiologic doses
• >5 mg prednisone or equivalent→
• Steroid-induced diabetes
• Features:
• Dose-related
• Usually reversible
• Most pronounced in postprandial period
• Dependent on timing & type of glucocorticoid
 Special Considerations in Diabetes…
• Steroid-Induced Diabetes…
• Treatment Approach
• If FPG near normal →
• Oral agents may suffice (sulfonylureas, metformin…)
• If FPG >11.1 mmol/L (200 mg/dL) →
• Oral agents insufficient →
• Insulin therapy required
• Tailor regimen to severity and timing of steroid administration
• Insulin Strategy
• If steroids given in the morning:
• Short-acting insulin in morning
• ± NPH insulin in morning
• Goal:
• Control postprandial glucose excursions
 Special Considerations in Diabetes…
• Diabetes Management in Older Adults
• ~25% of individuals >65 years have diabetes
• Increasingly includes those with long-standing Type 1 DM
• Growing importance in geriatric care
• Individualized Therapeutic Goals
• Consider:
• Biologic age
• Comorbidities & risk factors (HTN, CVD)
• Neurocognitive & physical functional status
• Living arrangements & social support
• Other medications
• Goals differ between
• Highly functional elderly vs
• Frail or cognitively impaired patients
 Special Considerations in Diabetes…
• Diabetes Management in Older Adults….
• HbA1c Targets
• Highly functional older adults (e.g., active 80-year-old):
• HbA1c goal: <7.0–7.5%
• Therapy similar to younger individuals
• Complex/poor health or cognitive impairment:
• HbA1c goal: <8.0–8.5%
• Less intensive therapy appropriate
• Key Management Principles
• Avoid hypoglycemia →
• Critical in all older adults
• Hypoglycemia worsens cognitive impairment & CVD
• Choose medications carefully:
• Consider adverse effects like→
• HF, renal insufficiency, hypoglycemia risk
• Treat hypertension →
• Clear benefit
• Treat dyslipidemia →
• Benefit less clearly demonstrated in elderly
 Reproductive Issues in Diabetes
• General Reproductive Capacity
• Men and women with DM →
• Normal reproductive capacity
• Women:
• Menstrual cycles may cause glycemic fluctuations
• Pregnancy & Insulin Resistance
• Pregnancy →
• Marked insulin resistance
• May precipitate gestational diabetes mellitus (GDM)
• Maternal hyperglycemia:
• Glucose crosses placenta →
• Insulin does not
• Fetal hyperinsulinism →
• Macrosomia
 Reproductive Issues in Diabetes…
• Gestational Diabetes Mellitus
• Complicates ~7% of pregnancies (range 1–14%)
• Higher incidence in Black and Hispanic women
• Screening:
• 24–28 weeks gestation in women not known to have DM
• Therapy:
• Medical Nutrition Therapy (MNT)
• Insulin if hyperglycemia persists
• Oral agents not approved, but
• Metformin/glyburide studied with efficacy
• Outcomes & Long-Term Risks
• With current practices →
• Maternal & fetal outcomes similar to non-DM population
• Women with GDM →
• High risk of future Type 2 DM
• Require periodic screening post-delivery
• Children of GDM mothers →
• ↑ risk of obesity, glucose intolerance, diabetes in adolescence
 Reproductive Issues in Diabetes…
• Pregnancy in Known Diabetes
• Requires meticulous preconception planning
• Goals:
• Intensive insulin therapy
• HbA1c <6.5% before conception
• Consider
• Insulin infusion (AID) &
• CGM for tighter control
• Crucial period:
• Soon after fertilization
• Poor control at conception →
• ↑ risk of fetal malformations (4–10x higher)
• Glycemic Targets During Pregnancy
• HbA1c monitored every 2 months
• Maintain HbA1c <6.0–6.5% → reduces:
• Fetal macrosomia
• Neonatal hypoglycemia (due to fetal hyperinsulinism)
 Complications of DM
• Leading cause of:
1. New blindness in adults
2. Renal failure
3. Non-traumatic lower extremity amputation
• Major contributor to coronary heart disease (CHD)
• Microvascular complications
• Retinopathy, nephropathy, neuropathy→
• Typically appear after second decade of hyperglycemia
• Macrovascular complications (ASCVD):
• May develop before hyperglycemia is established
• Driven by
• Insulin resistance &
• Dyslipidemia
• T2DM at Diagnosis
• Long asymptomatic hyperglycemia before detection
• Many patients already have:
• Glucose-related complications
• Insulin resistance–related complications
 Complications of DM…
• Prevention & Mitigation
• Aggressive control of:
• Glycemia
• Lipids
• Blood pressure
• Early detection strategies
• Lifestyle & pharmacologic interventions
• Age of Onset Matters
• Younger age at diagnosis →
• Higher complication burden
• Estimate:
• 3–4 years reduced life expectancy per decade earlier diagnosis
• Highlights critical role of prevention or delay
 Complications of DM…
• Complications are similar in type 1 and type 2 DM
• Divided into:
1. Vascular complications
2. Nonvascular complications
• Vascular Complications
• Microvascular (Diabetes-specific):
• Retinopathy
• Neuropathy
• Nephropathy
• Macrovascular (Shared with general population):
• ASCVD (atherosclerotic cardiovascular disease)
• Peripheral arterial disease (PAD)
• Cerebrovascular disease
• Heart failure
 Complications of DM…
• Nonvascular Complications
• Infections
• Skin changes
• Cheiroarthropathy (limited joint mobility)
• Hearing loss
• Increased risk of:
• Fractures
• Dementia
• Impaired cognitive function
• Additional Comorbid Conditions
• Relationship to hyperglycemia uncertain
• Depression
• Obstructive sleep apnea
• Fatty liver disease
• Hip fracture, osteoporosis
• Cognitive impairment/dementia
• Low testosterone in men
Diabetes-Related Complications
Heart
Microvascular Macrovascular Other
Failure
• Eye disease:
• Retinopathy • Gastrointestinal:
• Coronary heart
(nonproliferative • Gastroparesis,
disease
/proliferative), diarrhea
• Macular edema
• Neuropathy:
• Sensory & motor
• Genitourinary:
(mono- • Peripheral arterial
• Uropathy, sexual
/polyneuropathy) disease
• Heart dysfunction
,
• Autonomic failure

• Dermatologic
• Infectious
• Nephropathy:
• Albuminuria, • Cerebrovascular • Cataracts, Glaucoma
• Declining renal disease • Cheiroarthropathy
function
• Periodontal disease
• Hearing loss
 Complications of DM…
Glycemic Control and Complications
Aspect Key Points
• Microvascular • Result from chronic hyperglycemia (Type 1 & Type 2 DM)
complications • Includes retinopathy, nephropathy, neuropathy
• Role of hyperglycemia less conclusive
• Macrovascular
• Dyslipidemia & hypertension play stronger roles
complications
• ASCVD events & mortality 2–4× higher in Type 2 DM
• Events correlate with fasting & postprandial glucose
• Correlation with
• HbA1c strongly linked to risk
Glycemia
• Intensive management reduces complications
• >1400 patients randomized to intensive vs conventional therapy
• DCCT Trial (Type 1 • Intensive group: HbA1c 7.3% vs 9.1% conventional
DM) • Follow-up: 6.5 years
• Proof: lowering hyperglycemia prevents complications
• >40 years of ongoing follow-up
• EDIC Follow-up • After DCCT, both groups HbA1c ~8.0%
• Allowed study of “legacy effect” of early near-normoglycemia

DCCT- Diabetes Control and Complications Trial

EDIC- Epidemiology of Diabetes Intervention and Complications trial
 Complications of DM…
• Glycemic Control and Complications…
• DCCT Phase – Key Outcomes
• Improved glycemic control reduced:
• Retinopathy: ↓47%
• Albuminuria: ↓39%
• Clinical nephropathy: ↓54%
• Neuropathy: ↓60%
• Slowed progression of early diabetic complications
• Benefits observed across the entire range of elevated HbA1c values
• Risks During Intensive Therapy
• Weight gain:
• +4.6 kg
• Severe hypoglycemia:
• More common, requiring assistance
• Despite risks, benefits outweighed adverse effects
• Predicted Benefits of Intensive Therapy
• +7.7 years of vision
• +5.8 years free from ESRD
• +5.6 years free from amputations
• >15.3 years of life without significant microvascular complications
• +5.1 years of life expectancy overall
 Complications of DM…
• Glycemic Control and Complications…
• EDIC Long-Term Follow-Up
• Continued reduction in:
• Retinopathy
• Nephropathy
• Cardiovascular disease
• Cardiovascular outcomes:
• ↓57% reduction in CV events
• MI, stroke, CV death
• ↓33% reduction in mortality
• Fewer cases of
• Blindness,
• Amputations,
• Dialysis
• Other Complications Reduced
• Autonomic neuropathy
• Bladder & sexual dysfunction
• Cardiac autonomic neuropathy
• Cheiroarthropathy
• Hearing loss
 Complications of DM…
• Glycemic Control and Complications…
• Context of DCCT/EDIC
• Initial DCCT results reported in 1993
• Insulin formulations & delivery systems were less advanced
• Glucose monitoring via fingerstick meters (pre-CGM era)
• Results remain impressive given older technology
Relationship of glycemic control and diabetes duration to diabetic retinopathy in DCCT
trial
 Complications of DM…
• Glycemic Control and Complications…
• The United Kingdom Prospective Diabetes Study (UKPDS)
• 5000 individuals with
• Type 2 DM
• Follow-up: >10 years
• Randomized to:
1. Intensive management (insulin, sulfonylurea, metformin)
2. Conventional therapy (dietary modification ± pharmacotherapy)
• Parallel randomization to antihypertensive regimens
• Glycemic Control Findings
• Intensive group HbA1c: 7% vs 7.9% in standard group
• Each 1% reduction in HbA1c →
• 35% reduction in microvascular complications
• Continuous relationship:
• Lower HbA1c = fewer complications
• Long-term follow-up:
• Reduced cardiovascular event rate
 Complications of DM…
• Glycemic Control and Complications…
• UKPDS…
• Blood Pressure Control
• Strict BP control
• Reduced macro- and microvascular complications
• Benefits of BP control > benefits of glycemic control
• Moderate BP goal (144/82 mmHg) reduced risk of:
• DM-related death
• Stroke
• Microvascular endpoints
• Retinopathy
• Heart failure
• Risk reductions:
• 32–56%
• ADA recommendation:
• <130/80 mmHg
 Complications of DM…
• Glycemic Control and Complications…
• UKPDS…
• Long-Term Outcomes
• Early glycemic control with sulfonylurea, insulin, or metformin →
• Reduced risk of death & MI
• Reinforced importance of early intervention in type 2 DM
• Legacy effect:
• Early control yields long-term benefits
• Other Supporting Trials
• ACCORD Trial:
• Intensive glycemic control reduced microvascular complications
• ADVANCE Trial:
• Similar findings, confirming UKPDS results
• Together:
• Strong evidence that glycemic control + BP management = reduced
complications
 Complications of DM…
• Glycemic Control and Complications…
• Hyperglycemia and Complications
• Large trials (DCCT, UKPDS) show:
• Chronic hyperglycemia →
• Causative role in microvascular & macrovascular complications
• Cardiovascular events reduced at
• >10 years follow-up
• Benefit persisted even after glycemic control equalized
• Legacy Effect (Metabolic Memory)
• Lasting benefit of prior improved glycemic control
• Positive impact continues for 10+ years
• Demonstrates importance of early intensive management
• Genetic Susceptibility
• Not all individuals with long-standing DM develop complications
• Some remain free of retinopathy or nephropathy
• Suggests genetic predisposition influences risk of complications
 Complications of DM…
• Mechanisms of Diabetes-Related Complications
• Chronic hyperglycemia
• Key etiologic factor
• Mechanisms are multifactorial and not fully understood
• Emerging hypothesis:
• Epigenetic changes influence gene expression
• Advanced Glycosylation End Products (AGEs)
• Examples: pentosidine, glucosepane, carboxymethyllysine
• Bind to cell surface receptors →
• Cellular dysfunction
• Nonenzymatic glycosylation →
• Protein cross-linking
• Consequences:
• Glomerular dysfunction
• Endothelial dysfunction
• Altered extracellular matrix
• Accelerated atherosclerosis
 Complications of DM…
• Mechanisms of Diabetes-Related Complications…
• Growth Factors
• VEGF-A elevated in proliferative retinopathy
• Decreases after laser photocoagulation
• Targeted by intravitreal injection therapy
• Growth factors contribute to microvascular complications
• Oxidative Stress Pathway
• Hyperglycemia →
• ↑ mitochondrial reactive oxygen species (ROS)
• ROS activates multiple downstream pathways
• Possible unifying mechanism for diverse complications
• Macrovascular Complications
• Include MI and stroke…
• Mechanisms:
• Dyslipidemia
• Hypertension
• Insulin resistance
• Inflammation
 Complications of DM…
• Mechanisms of Diabetes-Related Complications…
• Insulin Resistance in T2DM and dyslipidemia
• Present years before diagnosis
• Associated with:
• Obesity & ectopic lipid accumulation (liver, muscle)
• Insulin fails to suppress lipolysis →
• ↑ fatty acid delivery
• Leads to accumulation of:
• Triglycerides
• Diacylglycerol
• Ceramides
• Consequence: tissue dysfunction
• Endothelium, cardiac, muscle
 Complications of DM…
• Ophthalmologic Complications
• DM = leading cause of new blindness (ages 20–74, U.S.)
• Glaucoma and cataracts occur earlier & more frequently in diabetes
• Severe vision loss →
• primarily due to progressive diabetic retinopathy
• Causes: macular edema, neovascularization
• Diabetic Retinopathy
• Classification
• Nonproliferative Retinopathy
• Appears late in 1st decade or early 2nd decade of hyperglycemia
• Features:
• Retinal microaneurysms
• Blot hemorrhages
• Cotton-wool spots
• Proliferative Retinopathy
• Characterized by new vessel formation
• Leads to severe vision loss
 Complications of DM…
• Ophthalmologic Complications…
• Nonproliferative Retinopathy
• Progression of
• Mild → more extensive disease
• Features:
• Venous caliber changes
• Intraretinal microvascular abnormalities
• ↑ microaneurysms & hemorrhages
• Pathophysiology of Retinopathy
• Loss of retinal pericytes
• ↑ retinal vascular permeability
• Altered retinal blood flow
• Abnormal microvasculature → retinal ischemia
 Complications of DM…
• Ophthalmologic Complications…
• Proliferative Retinopathy
• Neovascularization
• Hallmark of proliferative retinopathy
• Response to retinal hypoxemia
• New vessels near optic nerve and/or macula
• Fragile vessels → rupture →
• Vitreous hemorrhage,
• Fibrosis,
• Retinal detachment
• Progression Risk
• Not all nonproliferative cases progress
• Severity of nonproliferative disease
• Higher risk of progression
• Evolution to proliferative retinopathy often within 5 years
• Opportunity for early detection & treatment
 Complications of DM…
• Ophthalmologic Complications…
• Macular Edema
• Can occur in nonproliferative or proliferative retinopathy
• Fluorescein angiography & OCT useful for detection
• Associated with
• ↑ risk of moderate visual loss within 3 years
• Predictors of Retinopathy
• Duration of DM
• Degree of glycemic control
• Other risk factors:
• Hypertension
• Nephropathy
• Dyslipidemia
• Genetic Susceptibility
• Genetic predisposition exists
• Influence is less significant than
• Duration of DM or
• Glycemic control
Diabetic retinopathy results in scattered hemorrhages, yellow exudates, and
neovascularization. This patient has neovascular vessels proliferating from the optic disc,
requiring urgent panretinal laser photocoagulation.
 Complications of DM…
• Treatment of Diabetic Retinopathy
• Most effective therapy = prevention
• Intensive glycemic control →
• Delays onset,
• Slows progression
• Blood pressure control →
• Additional protective effect
• Early detection and screening are critical
• Paradoxical Early Worsening
• During first 6–12 months of improved glycemic control:
• Retinopathy may transiently worsen
• Progression is temporary
• Long-term: improved glycemic control →
• Less retinopathy
• Pharmacologic Considerations
• GLP-1 receptor agonists:
• Associated with
• ↑ risk of retinopathy worsening when glycemia improves rapidly
• Important consideration in therapy selection
• Fenofibrate:
• Lowering triglycerides may reduce progression
 Complications of DM…
• Treatment of Diabetic Retinopathy…
• Ophthalmologic Interventions
• Prophylactic laser photocoagulation:
• Considered when initiating intensive therapy
• Especially prior to pancreas or islet transplantation
• Rapid normalization of glycemia
• Appropriate ophthalmologic care →
• Prevents most blindness
• Special Populations
• Women with DM planning pregnancy:
• Screen prior to conception
• Screen during pregnancy
• Once advanced retinopathy is present:
• Improved glycemic control imparts less benefit
 Complications of DM…
• Treatment of Diabetic Retinopathy…
• Eye Examinations
• Importance
• Regular, comprehensive eye exams
• Essential for all DM patients
• Early detection →
• Most diabetic eye disease can be successfully treated
• Routine nondilated exams by PCP/diabetes specialist
• Inadequate
• Requires:
• Dilated eye exam
• Optometrist/ophthalmologist
• OR retinal photography with remote reading
• Referral and Specialist Care
• Subsequent management →
• Retinal specialist
• Ensures timely intervention and vision preservation
 Complications of DM…
• Treatment of Diabetic Retinopathy…
• Treatment Options
• Severe nonproliferative / proliferative retinopathy or macular edema:
1. Panretinal laser photocoagulation therapy
2. Anti-VEGF therapy (intravitreal injection)
• Usually successful in preserving vision
• Role of Antiplatelet/Anticoagulation Therapy
• Aspirin therapy:
• No effect on natural history of retinopathy
• Antiplatelet agents & anticoagulation:
• May be continued during anti-VEGF injections
3. Surgical Management
• Vitrectomy indicated for:
• Severe proliferative retinopathy
• Vitreous hemorrhage
• Traction involving the macula
 Complications of DM…
• Renal Complications of Diabetes Mellitus
• Key complications
1. DM nephropathy
2. Type IV Renal Tubular Acidosis
3. Radiocontrast Nephrotoxicity in Diabetes
• DM nephropathy
• Leading cause of
• CKD and
• Stage 5 CKD (ESRD)
• Requires renal replacement therapy (dialysis/transplant)
• Poor prognosis for diabetics on dialysis
• CKD in diabetes →
• ↑ risk of cardiovascular disease
• Association with Retinopathy
• Type 1 DM:
• Nephropathy often coexists with retinopathy
• Type 2 DM:
• Weaker association
• CKD without retinopathy in Type 1 →
• Investigate other causes
 Complications of DM…
• DM nephropathy ….
• 20–40% of diabetics develop nephropathy
• Risk factors:
• Family history of diabetic nephropathy
• Genetic & environmental susceptibility
• Smoking →
• Accelerates renal decline
• Higher prevalence in
• Black,
• Native American,
• Hispanic populations
 Complications of DM…
• DM nephropathy ….
• Pathogenesis
• Driven by chronic hyperglycemia
• Mechanisms:
• Soluble factors:
• Growth factors,
• Angiotensin II,
• Endothelin,
• AGEs
• Epigenetic changes
• Hemodynamic alterations:
• Hyperfiltration, ↑ glomerular pressure
• Structural changes:
• Basement membrane thickening,
• Mesangial expansion,
• Fibrosis
• Tubular dysfunction:
• Tubulointerstitial damage,
• Fibrosis
 Complications of DM…
• DM nephropathy…
• Natural history
1. Early Changes
• Defined initially in Type 1 DM
• Similar in Type 2 DM
• First years after DM onset:
• Glomerular hyperperfusion
• Renal hypertrophy
• ↑ estimated GFR
2. Intermediate Stage
• First 5 Years
• Thickening of glomerular basement membrane
• Glomerular hypertrophy
• Mesangial expansion
• GFR returns to normal
3. Irreversible Stage
• Marked albuminuria + ↓ GFR
• Pathologic changes become irreversible
 Complications of DM…
• Diabetic nephropathy…
• Importance of Early Detection
• Early detection allows effective therapy
• Decline in GFR may occur
• Without albuminuria
• Assessment should include:
1. Urinary albumin-to-creatinine ratio (UACR)
2. Estimated GFR (eGFR)
• Screening Recommendations
• Type 1 DM:
• Start screening 5 years after onset
• Type 2 DM:
• At diagnosis
• Screening: annually
• Confirm elevated UACR on
• 2–3 occasions over 3–6 months
• False elevations:
• Exercise,
• Infection,
• Fever,
• CHF,
• Hyperglycemia,
• Hypertension,
• Prostate disease
 Complications of DM…
• Diabetic nephropathy…
• ADA Definitions of Albuminuria (UACR)
1. Albuminuria:
• UACR > 30 mg/g
• Persistent
2. Moderate increase:
• 30–299 mg/g creatinine
3. Severe elevation:
• >300 mg/g creatinine
• UACR is a continuous variable →
• Higher values→
• More likely ↓ GFR
• ↑ UACR →
• ↑ risk of cardiovascular disease
• Monitoring
• Once UACR is elevated →
• Measure 2–4 times/year
• Track progression and adjust therapy accordingly
Time course of development of diabetic nephropathy. The relationship of time from onset of
diabetes, albuminuria (urinary albumin-to-creatinine ratio [UACR]), and the glomerular
filtration rate (GFR) are shown. This figure is typical for type 1 diabetes; individuals with
type 2 diabetes may present with a lower GFR at the time of diagnosis.
 Complications of DM…
• Type IV Renal Tubular Acidosis
• Hyporeninemic Hypoaldosteronism
• Occurs in Type 1 or Type 2 DM
• Pathophysiology:
• ↓ renin → ↓ aldosterone →
• Impaired distal tubular
• K⁺ and
• H⁺ secretion
• Clinical features:
• Hyperkalemia
• Metabolic acidosis
• Exacerbated by medications:
• ACE inhibitors
• ARBs
• Mineralocorticoid receptor antagonists
 Complications of DM…
• Radiocontrast-Induced Nephrotoxicity
• Patients with DM are predisposed
• Risk factors:
• Preexisting nephropathy
• Volume depletion
• Mechanism:
• Direct tubular toxicity + renal vasoconstriction
• Prevention Strategies
• Ensure adequate hydration before and after contrast exposure
• Monitor serum creatinine
• 24–48 h post-procedure
• Hold metformin
• Until kidney function is confirmed post-intervention
 Complications of DM…
• Treatment of Diabetic Nephropathy
• Optimal therapy = Prevention
• Control of:
• Glycemia (per ADA goals)
• Blood pressure
• < 130/80 mmHg
• RAAS Inhibitors
• ACE inhibitors / ARBs:
• Do not prevent nephropathy if no:
• Hypertension or
• Albuminuria
• Effective in slowing progression when
• Albuminuria or
• Hypertension present
 Complications of DM…
• Treatment of Diabetic Nephropathy…
• Effective Interventions
• Improved glycemic control
• Strict blood pressure control
• ACE inhibitor or ARB therapy
• SGLT-2 inhibitors
• Type 2 DM
• Mineralocorticoid receptor antagonists
• Esp. finerenone
• Treat dyslipidemia

• Glycemic Control & Disease Progression

• Reduces rate of:
• Albuminuria onset/progression (Type 1 & 2 DM)
• Once moderate albuminuria develops →
• Harder to slow progression
• Pancreas transplantation with 10 years of normoglycemia →
• Regression of mesangial lesions
 Complications of DM…
• Treatment of Diabetic Nephropathy…
• Late Phase Considerations
• Declining renal function →
• ↓ insulin requirements
• Kidney = site of insulin degradation
• As GFR decreases:
• Reevaluate glucose-lowering agents
• Sulfonylureas & metformin
• Contraindicated in advanced renal insufficiency
• Glinides & DPP-4 inhibitors
• May need dose adjustment
• SGLT2 inhibitors
• Ineffective if eGFR < 20 mL/min/1.73 m²
Diabetic glomerular changes in a patient with type 1 diabetes are reversed by 10 years of normoglycemia as a result
of pancreas transplantation. Left panel shows diabetic glomerulosclerosis (arrow) and arteriolar hyalinosis
(arrowhead) on kidney biopsy. Right panel shows a near-normal glomerulus in the same patient after 10 years of
normoglycemia from pancreas transplantation
 Complications of DM…
• Management of Albuminuria or CKD in Diabetes
• First-Line Therapy
• ACE inhibitors or ARBs
• Reduce albuminuria
• Slow decline in GFR
• Considered equivalent in diabetes
• ARBs: alternative if ACEi causes cough or angioedema
• Monitoring & Targets
• Initiate and titrate to maximum tolerated dose
• Monitor:
• Serum creatinine
• Serum potassium
• UACR (repeat 1–4 times/year)
• Acceptable:
• Creatinine rise up to 30%
• Goal:
• ≥30% reduction in UACR if
• Baseline >300 mg/g
 Complications of DM…
• Management of Albuminuria or CKD…
• Add-On Therapies
• SGLT-2 inhibitors
• Type 2 DM,
• eGFR >20 mL/min/1.73 m²)
• Reduce CKD progression
• Lower cardiovascular events
• GLP-1 receptor agonists
• E.g., semaglutide
• Improve kidney outcomes
• Reduce CV mortality
• Nonsteroidal mineralocorticoid receptor antagonists
• E.g., finerenone
• Reduce albuminuria
• Lower CV risk
• Special Considerations
• Type 1 DM or insulin-deficient Type 2 DM:
• Use SGLT-2 inhibitors with caution
• Risk of euglycemic diabetic ketoacidosis
• Patient education: ketone monitoring, DKA recognition
 Complications of DM…
• Management of Albuminuria or CKD…
• Indications for Nephrology Referral
• eGFR < 30 mL/min/1.73 m²
• Albuminuria > 300 mg/g creatinine
• Atypical features:
• Hematuria
• Rapidly declining renal function
• Nutritional Recommendations
• Protein intake:
• 0.8 g/kg body weight/day (ADA guideline)
• Cardiovascular Risk
• ASCVD complications
• Leading cause of death in diabetic nephropathy
• Treat hyperlipidemia aggressively
 Complications of DM…
• Management of Albuminuria or CKD…
• Transplantation Options
• Preemptive kidney transplantation
• Before dialysis
• From a living donor →
• Preferred in stage 5 CKD
• Simultaneous pancreas-kidney transplantation:
• Option for Type 1 DM
• Option for insulin-deficient Type 2 DM
• Usually from deceased donor
• Hemodialysis in Diabetes
• Compared with non-diabetic patients, DM patients have:
• More frequent hypotension
• Autonomic neuropathy, impaired reflex tachycardia)
• More difficult vascular access
• Accelerated retinopathy progression
• Greater mortality
 Complications of DM…
• Hypertension in Diabetes
• Common in Type 1 and Type 2 DM
• Accelerates complications:
• ASCVD (atherosclerotic cardiovascular disease)
• Nephropathy
• Retinopathy
• Monitoring
• Measure blood pressure at every clinic visit
• Encourage home BP monitoring
• Target:
• <130/80 mmHg
• Lower targets may be considered in:
• High ASCVD risk
• CKD progression risk
• Special Considerations
• Type 2 DM:
• High prevalence of ASCVD →
• Consider renovascular hypertension if BP is resistant to control
 Complications of DM…
• Hypertension in Diabetes…
• Treatment
• Lifestyle Modifications
• Weight loss
• Exercise
• Stress management
• Sodium restriction
• DASH-style diet
• Smoking cessation
• Pharmacologic Therapy
• If BP >150/90 mmHg →
• Start with two antihypertensive agents
• Multiple agents often required for control
• In pregnant individuals with DM + chronic hypertension →
• BP control improves pregnancy outcomes
 Complications of DM…
• Hypertension in Diabetes…
• Treatment…
• Antihypertensive Therapy in DM + No CKD
• ACE Inhibitors & ARBs
• Effective antihypertensives
• No more effective than:
• Thiazide-like diuretics
• Dihydropyridine calcium channel blockers
• No benefit of:
• Intervention before albuminuria onset
• Combining ACE inhibitor + ARB
• Alternative Agents
• If ACE inhibitors/ARBs not tolerated or BP uncontrolled:
• Diuretics
• Calcium channel blockers (nondihydropyridine class)
• Beta blockers (use cautiously in patients at risk of hypoglycemia)
• Refractory Cases
• Mineralocorticoid receptor antagonists
• E.g., spironolactone, eplerenone, finerenone
• Can reduce BP and albuminuria
• Require close monitoring of serum potassium
 Complications of DM…
• Neuropathy and Diabetes Mellitus
• After long-standing Type 1 & Type 2 DM
• Affects ~50% of individuals with diabetes
• Types of Diabetic Neuropathy
1. Diffuse neuropathy
• Distal symmetrical polyneuropathy
• Autonomic neuropathy
2. Focal neuropathy
• Mononeuropathy
3. Radiculopathy / Polyradiculopathy
• Risk Factors
• Duration of diabetes
• Poor glycemic control
• High BMI →
• Greater risk
• Smoking
• Associated comorbidities
• ASCVD
• Elevated triglycerides
• Hypertension
 Complications of DM…
• Neuropathy and Diabetes Mellitus…
• Pathophysiology
• Loss of:
• Myelinated and unmyelinated nerve fibers
• Progressive nerve damage linked to metabolic and vascular factors
• Clinical Considerations
• Symptoms overlap with other neuropathies
• Diagnosis of diabetic neuropathy:
• Only after excluding other possible etiologies
• Careful clinical evaluation required
 Complications of DM…
• Neuropathy and Diabetes Mellitus…
• Distal Symmetric Polyneuropathy (DSPN)
• Most common form of diabetic neuropathy
• Frequently presents with
• Distal sensory loss and
• Pain
• Up to 50% of patients are asymptomatic
• Symptoms:
• Numbness
• Tingling
• Sharpness
• Burning
• Begins in feet →spreads proximally
• Hyperesthesia
• Paresthesia
• Dysesthesia
• Pain characteristics:
• Lower extremities
• Present at
• Rest
• Worsens at
• Night
 Complications of DM…
• Neuropathy and Diabetes Mellitus…
• Distal Symmetric Polyneuropathy (DSPN)…
• Forms of Painful DSPN
• Acute form
• <12 months
• Sometimes treatment-related (improved glycemic control)
• Chronic form
• Pain subsides over time
• Sensory deficit persists
• Motor defects may develop
• Physical Examination Findings
• Sensory loss:
• 10-g monofilament
• Vibration sense
• Loss of:
• Ankle deep-tendon reflexes
• Abnormal
• Position sense
• Muscular atrophy or foot drop
 Complications of DM…
• Neuropathy and Diabetes Mellitus…
• Distal Symmetric Polyneuropathy (DSPN)…
• Screening Recommendations
• Type 1 DM:
• Begin 5 years after diagnosis
• Type 2 DM:
• At time of diagnosis
• Aim:
• Detect Loss of Protective Sensation (LOPS)
• Clinical Significance: DSPN + LOPS →
• Major risk factors for:
• Foot ulceration
• Falls (small & large fiber dysfunction)
• Lower extremity amputation
 Complications of DM…
• Neuropathy and Diabetes Mellitus…
• Autonomic Neuropathy in Diabetes Mellitus
• Occurs in long-standing Type 1 & Type 2 DM
• Involves
• parasympathetic (cholinergic) and
• Sympathetic (adrenergic) systems
• Organ Systems Affected
• Cardiovascular
• Gastrointestinal (GI)
• Genitourinary
• Sudomotor
• Metabolic
• Cardiovascular Autonomic Neuropathy
• Decreased heart rate variability
• Resting tachycardia
• Orthostatic hypotension
• Late/unusual complication
• Associated with ASCVD
• Risk of sudden death due to:
• Severe hypoglycemia
• QTc prolongation
 Complications of DM…
• Neuropathy and Diabetes Mellitus…
• Autonomic Neuropathy in Diabetes Mellitus…
• Hypoglycemia & Autonomic Dysfunction
• Reduced:
• Counterregulatory hormone release (esp. epinephrine)
• Hypoglycemia unawareness →
• Inability to sense hypoglycemia
• Increased risk of severe hypoglycemia
• Gastrointestinal & Genitourinary Manifestations
• Gastroparesis →
• Delayed gastric emptying
• Bladder-emptying abnormalities →
• Urinary retention, infections
• Sudomotor Dysfunction
• Hyperhidrosis of
• Upper extremities
• Anhidrosis of
• Lower extremities
• Anhidrosis of feet →
• Dry skin, cracking →
• ↑ risk of foot ulceration
 Complications of DM…
• Neuropathy and Diabetes Mellitus…
• Mononeuropathy in DM
• Less common than:
• Polyneuropathy
• Presents with:
• Pain and
• Motor weakness
• Dysfunction of isolated
• Cranial or
• Peripheral nerves
• Sites of occurrence:
• Entrapment
• E.g., carpal tunnel
• Noncompressive lesions
 Complications of DM…
• Neuropathy and Diabetes Mellitus…
• Mononeuropathy in DM…
• Most common cranial nerve involved:
• CN III
• Diplopia
• Ptosis,
• Ophthalmoplegia
• Pupillary constriction preserved
• Other Cranial Nerve Involvement
• CN IV, CN VI →
• Diplopia
• CN VII →
• Bell’s palsy
• May involve multiple nerves simultaneously
• Mononeuropathy multiplex
 Complications of DM…
• Neuropathy and Diabetes Mellitus…
• Diabetic Radiculopathy / Polyradiculopathy
• Less common than:
• Polyneuropathy
• Presents with:
• Pain and
• Motor weakness
• Severe disabling pain:
• Distribution of:
• One or more nerve roots
• May be accompanied by motor weakness
 Complications of DM…
• Neuropathy and Diabetes Mellitus…
• Diabetic Radiculopathy / Polyradiculopathy…
• Patterns:
• Intercostal/truncal radiculopathy →
• Thoracic/abdominal pain
• Lumbar plexus or femoral nerve →
• Thigh/hip pain + weakness
• Diabetic amyotrophy →
• Hip flexor/extensor weakness
• Clinical Course
• Polyradiculopathies are usually self-limited
• Resolution typically within:
• 6–12 months
 Complications of DM…
• Neuropathy and Diabetes Mellitus…
• Treatment of Diabetic Neuropathy
• Prevention is critical
• Current treatment options remain less than satisfactory
• Improved glycemic control →
• Reduces risk of neuropathy
• Limitation:
• Hypoglycemia unawareness in long-standing diabetes
• Lifestyle modifications:
• Exercise
• Diet
• Management of Comorbidities
• Treat hypertension
• Treat hypertriglyceridemia
• Address ASCVD risk factors
• Avoid neurotoxins:
• Alcohol,
• Smoking
 Complications of DM…
• Neuropathy and Diabetes Mellitus…
• Treatment of Diabetic Neuropathy…
• Consider vitamin supplementation:
• B12,
• Folate
• Metformin:
• May reduce B12 absorption (Type 2 DM)
• Type 1 DM:
• Pernicious anemia (anti–parietal cell antibodies) →
• May require sublingual/parenteral B12 replacement
• Patient Education
• Loss of sensation in feet →
• ↑ risk of ulceration and sequelae
• Daily foot checks for:
• Patients with neuropathy or LOPS
• Precautions:
• Proper footwear to prevent calluses/ulcerations
• Foot deformities →
• Involve podiatrist
 Complications of DM…
• Neuropathy and Diabetes Mellitus…
• Treatment of Chronic Painful Diabetic Neuropathy (DSPN)
• Symptomatic treatment only
• Improved glycemic control →
• Limited evidence for pain relief
• Associated Conditions
• Sleep disorders →
• Treat appropriately
• Mood disorders →
• Address depression/anxiety
• Both frequently accompany DPN
 Complications of DM…
• Neuropathy and Diabetes Mellitus…
• Treatment of Chronic Painful Diabetic Neuropathy (DSPN)…
• Symptomatic Pain Management
• First-line agents with some efficacy:
1. Gabapentinoids:
• Pregabalin,
• Gabapentin
2. SNRIs:
• Duloxetine,
• Venlafaxine
• Desvenlafaxine
3. Sodium channel blockers
4. Tricyclic antidepressants
5. Capsaicin patch
 Complications of DM…
• Neuropathy and Diabetes Mellitus…
• Treatment of Chronic Painful Diabetic Neuropathy (DSPN)…
• Opioid Use
• Tapentadol:
• FDA-approved,
• Centrally acting opioid
• Modest efficacy
• Addiction risk →
• Not first-line
• Other opioids:
• Less desirable due to risk profile
• Treatment Strategy
• No direct comparisons between agents available
• Switch agents if:
• No response
• Side effects develop
• Referral to pain management center may be necessary
 Complications of DM…
• Neuropathy and Diabetes Mellitus…
• Therapy of Orthostatic Hypotension in Autonomic Neuropathy
• Management is challenging
• Combination of
• Nonpharmacologic and
• Pharmacologic measures
• Nonpharmacologic Measures
• Adequate salt intake
• Avoid dehydration
• Avoid diuretics
• Lower extremity support hose
• Regular physical activity
 Complications of DM…
• Neuropathy and Diabetes Mellitus…
• Therapy of Orthostatic Hypotension in Autonomic
Neuropathy…
• Pharmacologic Options
• Midodrine →
• FDA-approved for orthostatic hypotension
• Any etiology
• Droxidopa →
• FDA-approved for orthostatic hypotension
• Any etiology
• Limited success overall
• Special Considerations
• Resting tachycardia
• Cautious use of beta blockers →
• Risk: may worsen hypoglycemia unawareness
• Type 1 DM with orthostatic hypotension →
• Evaluate for:
• Primary adrenal insufficiency (Addison’s disease)
• Possible autoimmune polyendocrine syndrome
 Complications of DM…
• Gastrointestinal Dysfunction
• Long-standing Type 1 & Type 2 DM →
• Affects motility & function of GI and GU systems
• Underlying mechanism:
• Diabetic autonomic neuropathy
• Often associated with:
• Microvascular complications (retinopathy, neuropathy)
• Key Symptoms
• Gastroparesis
• Delayed gastric emptying
• Anorexia, nausea, vomiting
• Early satiety, abdominal bloating
• Altered bowel motility
• Constipation
• Diarrhea:
• Often nocturnal, alternating with constipation)
 Complications of DM…
• Gastrointestinal Dysfunction…
• Gastroparesis
• Pathophysiology & Diagnosis
• Parasympathetic dysfunction due to:
• Chronic hyperglycemia
• Hyperglycemia itself impairs gastric emptying
• Diagnosis:
• Nuclear medicine scintigraphy (radiolabeled meal)
• May document delayed emptying, but
• Poor correlation with symptoms
• Special Considerations in Type 1 DM
• GI symptoms:
• Evaluate for celiac disease →
• Associated with anti-tissue transglutaminase autoantibodies
• Increased frequency in Type 1 DM
 Complications of DM…
• Genitourinary Dysfunction in Diabetes
• Long-standing Type 1 & Type 2 DM →
• Affects motility & function of GI and GU systems
• Underlying mechanism:
• Diabetic autonomic neuropathy
• Often associated with:
• Microvascular complications (retinopathy, neuropathy)
• Cystopathy
• Early signs:
• Impaired bladder sensation, incomplete emptying
• Progression:
• Increased bladder capacity & postvoid residual
• Urinary hesitancy
• Decreased frequency
• Incontinence
• Recurrent UTIs
 Complications of DM…
• Genitourinary Dysfunction in Diabetes…
• Sexual Function
• Female:
• Reduced sexual desire
• Dyspareunia
• Decreased vaginal lubrication
• Male:
• Erectile dysfunction &
• Retrograde ejaculation
• Common, early signs of neuropathy
• Frequency ↑
• With age & duration of diabetes
• Erectile dysfunction
• May occur in absence of other signs of diabetic autonomic
neuropathy.
 Complications of DM…
• Treatment of GI dysfunction in Diabetes
• Current treatments are inadequate & nonspecific
• Improved glycemic control:
• Desirable, but benefit not clearly proven
• Focus on
• Symptom management & quality of life
• Gastroparesis
• Lifestyle & Diet
• Dietary modifications:
• Smaller, more frequent meals
• Liquid meals easier to digest
• Low fat & low fiber content
• Avoid medications that slow gastric emptying:
• Opioids
• GLP-1 receptor agonists
 Complications of DM…
• Treatment of GI dysfunction in Diabetes…
• Gastroparesis…
• Pharmacologic & Device Therapy
• Metoclopramide:
• For severe symptoms
• Restricted to short-term use (US & Europe)
• GERD symptoms:
• Acid-blocking therapy (H2 receptor antagonists, PPIs)
• Gastric electrical stimulatory devices:
• Available option
• Diabetic Diarrhea
• In absence of bacterial overgrowth →
• Symptomatic treatment
• Supportive care emphasized
 Complications of DM…
• Treatment of GU dysfunction in Diabetes
• Current treatments are inadequate & nonspecific
• Improved glycemic control:
• Desirable, but benefit not clearly proven
• Focus on
• Symptom management & quality of life
• Cystopathy
• Scheduled voiding
• Self-catheterization for incomplete emptying
• Goal: reduce residual urine, prevent infections
• Sexual Function
• Erectile dysfunction:
• PDE-5 inhibitors
• E.g., sildenafil
• Effective
• Slightly lower efficacy in
• DM vs. non-diabetic population
• Female sexual dysfunction:
• Symptom-based management
• Lubricants, counseling
 Complications of DM…
• Cardiovascular Morbidity & Mortality in Diabetes
• ASCVD (Atherosclerotic Cardiovascular Disease)
• Major cause of mortality in DM
• Includes:
• Peripheral Artery Disease (PAD)
• Coronary Heart Disease (CHD)
• Heart Failure (HF)
• Cerebrovascular Disease (stroke)
• Occurs more frequently in Type 1 & Type 2 DM
• Coronary Heart Disease (CHD) in Diabetes
• Prognosis worse than in nondiabetics
• More likely to involve:
• Multiple vessels
• Risk equivalence:
• Type 2 DM without prior MI ≈ risk of nondiabetic with prior MI
• American Heart Association:
• DM = controllable risk factor
 Complications of DM…
• Cardiovascular Morbidity & Mortality in Diabetes…
• Trends in ASCVD Outcomes
• Outcomes have improved over the last decade
• Due to:
• Modification of multiple risk factors
• Applies to both diabetics and nondiabetics
• Heart Failure in Diabetes
• Twice as common in DM (Type 1 & Type 2)
• Related to:
• Diabetes duration
• Hypertension
• Presentations:
• HFpEF (preserved EF)
• HFmEF (mildly reduced EF)
• HFrEF (reduced EF)
• Diabetic Cardiomyopathy
• Some DM patients have LV dysfunction:
• Without CHD or hypertension
• Termed “diabetic cardiomyopathy”
• Pathogenesis HF & Diabetic Cardiomyopathy → unclear
 Complications of DM…
• Cardiovascular Morbidity & Mortality in Diabetes…
• Key risk factors for ASCVD & heart failure in diabetes
• Duration of diabetes
• Hypertension
• Dyslipidemia
• Chronic Kidney Disease (CKD)
• Albuminuria
• Obesity
• Smoking
• Many are modifiable →
• Require patient &
• Provider action
• Core Prevention & Management Targets
• Integrated focus on:
1. Glycemia
2. Blood pressure
3. Lipids
4. Therapies with CV & kidney outcome benefits
• Evidence strongest in Type 2 DM, but
• Strategies also relevant to Type 1 DM
 Complications of DM…
• Cardiovascular Morbidity & Mortality in Diabetes…
• Cardiovascular Risk Assessment
• Individualized approach, e.g.:
• Younger patient, short DM duration →
• Lower risk
• Older patient, long-standing DM →
• Higher risk
• Risk stratification must be nuanced & patient-specific

• ASCVD Evaluation in Diabetes

• High prevalence of underlying ASCVD in DM
• Symptomatic patients (even atypical symptoms):
• Cardiac stress test
• Peripheral arterial evaluation
• Carotid arterial evaluation
• Screening asymptomatic patients for CHD:
• Not recommended
• Not cost-effective
• Silent Ischemia & Surgical Considerations
• Absence of chest pain common in DM →
• “silent ischemia”
• Thorough cardiac evaluation prior to major surgery recommended
• Prevents perioperative complications
 Complications of DM…
• Treatment of Cardiovascular Disease in Diabetes
• Treatment of coronary disease in DM
• Similar to nondiabetic population
• Standard approaches:
• Medical therapy,
• PCI,
• CABG
• Outcomes differ due to diabetes-related factors
• Percutaneous Coronary Intervention (PCI)
• Initial success rates:
• Similar to nondiabetics
• Limitations in DM:
• Higher rates of restenosis
• Lower long-term patency
• Reduced survival rates
 Complications of DM…
• Treatment of Cardiovascular Disease in Diabetes…
• Treatment of coronary disease in DM…
• Coronary Artery Bypass Grafting (CABG)
• CABG + optimal medical management →
• Better outcomes than PCI in DM
• Preferred in:
• Multivessel disease
• Long-term survival advantage
• Role of Glycemic Control
• Very strict glucose control →
• Limited benefit on CV outcomes in established disease
• Other factors play major roles:
• Insulin resistance
• Dyslipidemia
• Inflammation
 Complications of DM…
• Treatment of Cardiovascular Disease in Diabetes…
• Treatment – ASCVD in Type 2 Diabetes
• Foundational Management
1. Lifestyle management
2. Blood pressure control
3. Lipid management
4. Integrated therapy with CV & kidney outcome benefits
• SGLT-2 Inhibitors & GLP-1 RAs
• SGLT-2 inhibitors:
• Preferred if CKD or
• Heart failure present/likely
• GLP-1 receptor agonists:
• Reduce cardiovascular events in ASCVD or risk factors
• Combination therapy:
• Likely provides additive risk reduction
• CKD with Albuminuria
• On maximum ACE inhibitor or ARB:
• Add SGLT-2 inhibitor or
• Finerenone →
• Slows CKD progression & improves CV outcomes
• Combination
• SGLT-2 inhibitor + finerenone:
• Reduces risk of hyperkalemia
 Complications of DM…
• Treatment of Cardiovascular Disease in Diabetes…
• Heart Failure & Cardiovascular Disease Care
• Involve cardiovascular specialist
• Standard therapy:
• ACE inhibitor or ARB
• Beta blocker
• Metformin:
• Continue at reduced dose if eGFR >30 mL/min/1.73 m²
• Safety Considerations – SGLT-2 Inhibitors
• Risk of euglycemic diabetic ketoacidosis (DKA)
• Patient education:
• Recognize symptoms of DKA
• Importance of ketone measurement if clinical suspicion arises
 Complications of DM…
• Treatment of Cardiovascular Disease in Diabetes…
• Antiplatelet Therapy in Diabetes
• Secondary Prevention
• Aspirin (75–162 mg/day):
• Reduces cardiovascular events in DM with ASCVD
• Clopidogrel:
• Alternative for aspirin allergy or intolerance
• Primary Prevention
• ADA Recommendations:
• Consider aspirin in:
• Age >50 years
• At least one CV risk factor:
• Hypertension
• Dyslipidemia
• Smoking
• Family history of premature ASCVD
• Albuminuria
• Not recommended in:
• Age <50 years
• No CV risk factors
 Complications of DM…
• Cardiovascular Risk Factors
• Dyslipidemia in Diabetes
• Additive risk:
• Hyperglycemia + hyperlipidemia →
• ↑ ASCVD risk
• Lipid abnormalities:
• Must be assessed & treated as part of comprehensive diabetes care
• Most evidence from Type 2 DM:
• Due to higher frequency of dyslipidemia
• Common Lipid Patterns in DM
• Hypertriglyceridemia
• Reduced HDL cholesterol
• LDL cholesterol:
• Levels not increased by DM itself, but
• Small dense LDL particles in Type 2 DM:
• More atherogenic→
• Easily glycated
• Susceptible to oxidation
 Complications of DM…
• Cardiovascular Risk Factors…
• Dyslipidemia in Diabetes…
• Evidence from Interventional Studies
• Statins:
• LDL reduction →
• Similar benefit in diabetic & nondiabetic populations
• Type 1 DM:
• No prospective studies yet
• Children & young adults with DM:
• ASCVD frequency low →
• Risk assessment incorporated into guidelines
• Statins & Diabetes Risk
• Statin use →
• Mild ↑ risk of developing Type 2 DM
• Risk-benefit balance:
• Cardiovascular benefits outweigh diabetes risk
• Statins remain cornerstone of dyslipidemia management
 Complications of DM…
• Cardiovascular Risk Factors…
• Dyslipidemia Management in Diabetes – ADA Guidelines
• Lifestyle Modification
• Foundation
• All individuals with diabetes should be advised:
• Dietary changes
• Weight loss
• Increased physical activity
• Lifestyle modification = cornerstone of ASCVD risk reduction
• Triglycerides & HDL
• Thresholds
• Elevated triglycerides:
• >1.7 mmol/L (150 mg/dL)
• Low HDL cholesterol:
• <1 mmol/L (40 mg/dL) in men
• <1.3 mmol/L (50 mg/dL) in women
• Emphasize:
• Lifestyle modification + improved glycemic control
 Complications of DM…
• Cardiovascular Risk Factors…
• Dyslipidemia Management in Diabetes: Severe
hypertriglyceridemia
• Triglycerides >5.7 mmol/L (500 mg/dL):
• Despite statin therapy:
• Consider
• Icosapent ethyl or
• Fenofibrate
• Goal:
• Reduce ASCVD risk
• Fenofibrate + statin:
• May require statin dose reduction to minimize risk of myopathy
 Complications of DM…
• Cardiovascular Risk Factors…
• Dyslipidemia Management in Diabetes…
• LDL Management in Diabetes
• Lifestyle modification = foundation
• Statins = cornerstone of LDL therapy
• Goals:
• % LDL reduction +
• Absolute LDL targets
1. Patients with Diabetes & ASCVD
• High-intensity statin therapy:
• Atorvastatin 40–80 mg
• Rosuvastatin 20–40 mg
• Goal:
1. 50% LDL reduction
2. LDL <55 mg/dL
• If goals not met →
• Add ezetimibe or PCSK9 inhibitor
 Complications of DM…
• Cardiovascular Risk Factors…
• Dyslipidemia Management: LDL Management in Diabetes…
2. Patients Aged 40–75 Years Without ASCVD
• Moderate-intensity statin therapy
• Other statins or
• Lower-dose atorvastatin/rosuvastatin
3. Patients Aged 40–75 Years With ASCVD Risk Factors
• High-intensity statin therapy
• Goal:
• 50% LDL reduction
• LDL <70 mg/dL
• If LDL ≥70 mg/dL on max statin →
• Add ezetimibe or PCSK9 inhibitor
 Complications of DM…
• Cardiovascular Risk Factors…
• Dyslipidemia Management: LDL Management in Diabetes…
4. Patients Aged >75 Years
• If already on statin →
• Continue
• If not on statin →
• Consider moderate-intensity statin after patient discussion
5. Patients Aged 20–39 Years
• With additional risk factors →
• Consider moderate-intensity statin therapy
• If ASCVD + statin intolerance:
PCSK9 inhibitor (monoclonal antibody or inclisiran)
Bempedoic acid
• Statin + fibrate or niacin →
• No added benefit for LDL reduction
 Complications of DM…
• Lower Extremity Complications in Diabetes
• DM = leading cause of nontraumatic lower extremity amputation in
the U.S.
• Foot ulcers & infections →
• Major source of morbidity
• Pathogenic Factors
• Neuropathy
• Sensory,
• Motor,
• Autonomic
• Abnormal foot biomechanics
• Peripheral Artery Disease (PAD)
• Poor wound healing
• Sensory Neuropathy
• Loss of protective sensation →
• Unnoticed trauma
• Repeated minor injuries →
• Ulcers/infections
• Disordered proprioception:
• Abnormal weight bearing →
• Callus/ulcer formation
 Complications of DM…
• Lower Extremity Complications in Diabetes…
• Pathogenic Factors…
• Motor Neuropathy
• Leads to abnormal foot muscle mechanics
• Structural deformities:
• Hammer toe
• Claw toe deformity
• Prominent metatarsal heads
• Charcot joint
• Autonomic Neuropathy
• Anhidrosis → dry skin
• Altered superficial blood flow
• Promotes fissure formation →
• Entry point for infection
• PAD & Poor Wound Healing
• PAD impairs circulation →
• Delayed healing
• Minor breaks in skin enlarge →
• Infection risk increases
• Contributes to progression toward amputation
 Complications of DM…
• Lower Extremity Complications…
• Foot Ulcers in Diabetes
• Common sites:
• Great toe &
• Metatarsophalangeal areas
• Significant subset →
• Amputation risk (14–24%) with ulcer or subsequent ulceration
• Ulcers
• Major morbidity source
• Risk Factors for Foot Ulcers/Amputation
• Male sex
• Diabetes duration >10 years
• Peripheral neuropathy
• Abnormal foot structure:
• Bony abnormalities
• Callus formation
• Thickened nails
• Peripheral Artery Disease (PAD)
• Smoking
 Complications of DM…
• Lower Extremity Complications…
• Foot Ulcers in Diabetes…
• Additional Risk Factors
• History of previous ulcer or amputation
• Visual impairment →
• Delayed detection of injury
• Poor glycemic control
• Diabetic nephropathy (especially dialysis)
• Large calluses →
• Precursors to or overlie ulcerations
 Complications of DM…
• Treatment of Lower Extremity Complications in Diabetes
• Optimal therapy = Prevention
• Identify high-risk patients early
• Educate patients on foot care
• Implement preventive measures to avoid ulceration and amputation
• Screening & Risk Identification
• Annual foot exam for all patients with diabetes
• Use monofilament test or other sensory tests →
• Diagnosis of LOPS
• Screen for asymptomatic PAD
• Patients >50 years with diabetes +
• Risk factors
• Method: Ankle-Brachial Index (ABI)
 Complications of DM…
• Treatment of Lower Extremity Complications in
Diabetes…
• Patient Education
1. Careful selection of footwear
2. Daily foot inspection for trauma or poor fit
3. Daily foot hygiene →
• Keep skin clean & moist
4. Avoid:
• Self-treatment of foot abnormalities
• High-risk behaviors
• E.g., walking barefoot
5. Seek prompt medical consultation if abnormalities arise
 Complications of DM…
• Treatment of Lower Extremity Complications in
Diabetes…
• Podiatry
• Indicated for high-risk patients:
• History of foot ulcers or amputation
• Dialysis patients
• PAD
• Foot deformities
• Management of calluses and nail deformities
• Orthotic shoes/devices for pressure relief
• Risk Factor Modification
• Orthotic devices, callus management, nail care
• Reduce skin pressure from abnormal bony architecture
• Address vascular risk factors:
• Smoking cessation
• Dyslipidemia management (esp. LDL)
• Hypertension control
• Improve glycemic control
 Complications of DM…
• Treatment of lower extremity complications in diabetes:
management of foot ulceration & infection in diabetes
• Clinical Challenge
• Despite preventive measures
• Foot ulceration & infection remain common
• Serious problem due to
• Multifactorial pathogenesis
• Requires multidisciplinary management:
• Orthopedics
• Vascular surgery
• Endocrinology
• Podiatry
• Infectious diseases
• Sites & Types of Ulcers
• Most common site:
• Plantar surface of the foot
• Ulcer types:
1. Neuropathic ulcers (no infection)
2. Ulcers with cellulitis
3. Ulcers with osteomyelitis
 Complications of DM…
• Treatment of lower extremity complications in diabetes:
management of foot ulceration & infection…
• Cellulitis Without Ulceration
• Treat with empiric antibiotics
• Coverage should match likely pathogens
• Clinical judgment guides therapy
• Diagnosis of Infected Ulcer
• Clinical diagnosis
• Not culture-based
• Superficial cultures →
• Multiple species,
• Often non-significant
• Infection usually polymicrobial
• Common Pathogens
• Aerobic gram-positive cocci:
• Staphylococci (including MRSA)
• Group A & B streptococci
• Gram-negative bacilli (aerobic)
• Anaerobes as co-pathogens
 Complications of DM…
• Treatment of lower extremity complications in diabetes:
management of foot ulceration & infection…
• Gas Gangrene & Cultures
• Gas gangrene may occur without:
• Clostridial infection
• Cultures should be obtained from:
• Debrided ulcer base
• Purulent drainage
• Aspiration of wound
• Wound Assessment
• Determine wound depth by inspection +
• Probing with blunt sterile instrument
• Probe-to-bone test:
• Positive →
• Highly likely underlying osteomyelitis
• Imaging Modalities
• Plain radiographs:
• First-line for chronic ulcers not responding to therapy
• MRI:
• Most specific for osteomyelitis
• Alternatives:
• PET
• CT/SPECT
• Labeled white cell studies
 Complications of DM…
• Treatment of lower extremity complications in diabetes:
management of foot ulceration & infection…
• Surgical Management
• Surgical debridement often necessary
• Remove necrotic tissue and infected bone when possible
• Osteomyelitis Treatment
• Combination therapy:
• Prolonged antibiotics
• Debridement of infected bone
• Consider contribution of vascular insufficiency
• Vascular Interventions
• Peripheral arterial bypass procedures:
• Promote wound healing
• Reduce risk of amputation in ischemic limbs
 Complications of DM…
• Treatment of lower extremity complications in diabetes:
management of foot ulceration & infection…
• Interventions for diabetic foot ulcers & wounds (proven
efficacy)
1. Off-loading
• Complete avoidance of weight bearing on ulcer
• Removes mechanical trauma →
• Promotes healing
2. Surgical debridement of nonviable tissue
3. Physiologic, topical wound dressings
4. Revascularization procedures
5. Treatment of infections with appropriate antibiotics
• Amputation
• Should be limited initially
• Reserved for cases where other interventions fail or
• Limb is unsalvageable
 Complications of DM…
• Treatment of lower extremity complications in diabetes:
management of foot ulceration & infection…
• When Standard Therapy Fails
• If no significant improvement after 4 weeks →
• Consider advanced wound therapy
• Advanced Wound Therapies
• Topical growth factors
• Acellular matrix tissues
• Bioengineered cellular therapies
• Negative-pressure wound therapy
• Electrical stimulation
• Pulsed radiofrequency
• Extracorporeal shockwave therapy
• Hyperbaric oxygen therapy
• Topical oxygen therapy
 Complications of DM…
• Treatment of lower extremity complications in diabetes:
management of foot ulceration & infection…
• Important Considerations
• Advanced modalities require interdisciplinary expertise
• Must be individualized to patient and clinical setting
• Avoid antiseptic agents
• Delays healing
• Topical antibiotics →
• Limited value
• Rehabilitation & Supportive Care
• Referral for:
• Physical therapy
• Orthotic evaluation
• Rehabilitation services
• Initiate once infection is controlled
 Complications of DM…
• Treatment of lower extremity complications in diabetes:
management of foot ulceration & infection…
• Mild / Non-Limb-Threatening Infections
• Oral antibiotics targeting:
• Methicillin-susceptible Staphylococcus aureus (MSSA)
• Streptococci
• Examples:
• Dicloxacillin
• Early-generation cephalosporins
• Amoxicillin-clavulanate
• MRSA Considerations
• If prior MRSA history or high local prevalence:
• Trimethoprim-sulfamethoxazole
• Doxycycline
• Linezolid
• Clindamycin
• Choice guided by local antibiogram data
• Supportive Measures
• Surgical debridement of necrotic tissue
• Local wound care
• Off-loading (avoid weight bearing over ulcer)
• Optimization of glycemic control
 Complications of DM…
• Treatment of lower extremity complications in diabetes:
management of foot ulceration & infection…
• Severe Infections
• Require IV antibiotics +
• Off-loading +
• Wound care
• Coverage should include:
• S. aureus (including MRSA)
• Streptococci
• Gram-negative aerobes
• Anaerobes
• Empiric IV Regimens
• Vancomycin +
• β-lactam/β-lactamase inhibitor or
• Carbapenem
• Vancomycin +
• Quinolone +
• Metronidazole
• Alternatives (consult ID specialist):
• Daptomycin
• Ceftaroline
• Linezolid
 Complications of DM…
• Treatment of lower extremity complications in diabetes:
management of foot ulceration & infection…
• Severe Infections…
• Reassessment & Step-Down Therapy
• If infection not improving:
• Reassess antibiotic coverage
• Consider surgical debridement or
• Revascularization
• With clinical improvement:
• Transition to oral antibiotics
• Continue local wound care
• Outpatient management with close follow-up
 Complications of DM…
• Infections in Diabetes Mellitus
• Individuals with diabetes →
• Greater risk of infections
• Contributing factors:
• Abnormalities in cell-mediated immunity
• Impaired phagocyte function (linked to hyperglycemia)
• Diminished vascularization
• Role of Hyperglycemia
• Promotes colonization & growth of organisms
• Especially:
• Candida species
• Other fungal pathogens
• Common Infections in DM
• More frequent and severe compared to general population
• Examples:
• Skin and soft tissue infections
• Urinary tract infections
• Respiratory infections
 Complications of DM…
• Infections in Diabetes Mellitus…
• Rare but Characteristic Infections
• Seen almost exclusively in diabetes:
• Rhinocerebral mucormycosis
• Emphysematous infections of gallbladder & urinary tract
• Malignant (invasive) otitis externa
• Malignant Otitis Externa
• Usually due to Pseudomonas aeruginosa
• Involves soft tissue around external auditory canal
• Clinical features:
• Pain
• Discharge
• May rapidly progress to:
• Osteomyelitis
• Meningitis
• These infections should be suspected in patients with:
• Severe hyperglycemia
• Unusual or aggressive infection presentations
• Require early recognition & aggressive management
 Complications of DM…
• Infections in Diabetes Mellitus…
• Pneumonia in Diabetes
• More frequent and severe in diabetic population
• Pathogens similar to non-diabetics, but higher prevalence of:
• Gram-negative organisms
• Staphylococcus aureus
• Mycobacterium tuberculosis
• Vaccination Recommendations
• Adults with diabetes should receive:
• Pneumococcal vaccine
• RSV vaccine
• Annual influenza vaccine
• SARS-CoV-2 vaccine (COVID-19)
• Rationale:
• Increased morbidity & mortality in DM and obesity
• Antimicrobial Therapy
• Early antibiotic therapy for presumed bacterial infections
• Early antiviral therapy when indicated:
• Influenza → antivirals
• Varicella-zoster virus → antivirals
• SARS-CoV-2 → antivirals
 Complications of DM…
• Infections in Diabetes Mellitus…
• Urinary Tract Infections (UTIs)
• Common pathogens:
• Escherichia coli
• Yeast species (Candida albicans, C. glabrata)
• Complications:
• Emphysematous pyelonephritis
• Emphysematous cystitis
• Bacteriuria common in diabetic cystopathy
• Treat only in pregnancy or before urologic procedures
• Skin & Soft Tissue Infections
• Increased susceptibility to:
• Furunculosis
• Superficial candidal infections
• Vulvovaginitis
• Poor glycemic control = common denominator
• Increased colonization of S. aureus in skinfolds & nares
• Postoperative Infections
• Higher risk of postoperative wound infections
• Mitigation:
• Perioperative insulin protocols
• Maintain glycemic control
 Complications of DM…
• Dermatologic Manifestations of Diabetes Mellitus
• Common Skin Findings
• Xerosis (dry skin)
• Pruritus (itching)
• Usually relieved by moisturizers
• Protracted wound healing and skin ulcerations
• Diabetic Dermopathy
• Also called pigmented pretibial papules or
• “diabetic skin spots”
• Begins as:
• Erythematous macules/papules →
• Circular hyperpigmentation
• Results from minor trauma in pretibial region
• More common:
• Elderly men with DM
• Bullous Diseases
• E.g. Bullosa diabeticorum:
• Shallow ulcerations or erosions in pretibial region
• Painful, recurrent lesions
 Complications of DM…
• Dermatologic Manifestations of Diabetes Mellitus…
• Necrobiosis Lipoidica Diabeticorum
• Uncommon,
• Seen in young women with DM
• Starts as:
• Erythematous plaques/papules in pretibial region
• Gradually
• Enlarge, darken, irregular margins
• Atrophic centers with central ulceration
• Often painful
• Autoimmune Associations (Type 1 DM)
• Vitiligo
• Depigmented patches
• Alopecia areata
• Patchy hair loss
 Complications of DM…
• Dermatologic Manifestations of Diabetes Mellitus…
• Acanthosis nigricans:
• Hyperpigmented, velvety plaques
• Common sites:
• Neck, axilla, extensor surfaces
• Associated with severe insulin resistance
• Other Dermatologic Conditions
• Granuloma annulare:
• Erythematous plaques
• On extremities/trunk
• Lichen planus:
• Violaceous papules,
• May involve oral/genital mucosa
• Scleredema:
• Skin thickening on back/neck,
• Often post-infection
• Injection-Site Changes
• Lipoatrophy (loss of fat)
• Lipohypertrophy (fat accumulation)
• Now rare with human insulin
• Prevented by rotating injection sites
Thank you