DIABETES MELLITUS

What is diabetes?

Diabetes mellitus (DM) is a chronic condition that is characterized by raised blood

glucose levels (Hyperglycemia).
 Syndrome : metabolic, vascular and neuropathic components – interrelated

Metabolic disorder: hyperglycemia due to defects in insulin secretion , insulin action or

both

Metabolic syndrome: Type 2 Diabetes Mellitus, Central obesity, Hypertension,

Hyperlipidemia [hypertriglyceridemia , reduced HDL]
 TYPES
 TYPE I : Absolute insulin deficiency / Autoimmune disease

 TYPE 2 : Insulin resistance , inadequate insulin secretory response

 TYPE 3 : Pathology - Pancreas, drugs.

 GESTATIONAL DIABETES
 Therapy of diabetes : Comprehensive Diabetic Care
 Alleviate the symptoms related to hyperglycemia (fatigue, polyuria, weight loss)
 To prevent or reduce the acute metabolic decompensation and chronic end-organ complications.
Components of Comprehensive DiabeticCare

Managementof diabetes

Screen for / manage

complications
Treat associated conditions
Glycemiccontrol Retinopathy
Dyslipidemia
Diet /life style exercise Neuropathy
Hypertension
/drugs Nephropathy
Obesity
CVS Disease
Others
Treatment Goals
INDEX GOAL
1. Hb A1C < 7.0 %
2. Pre-prandial plasma glucose 90–130 mg/dL
3. Peak post prandial plasma glucose <180 mg/dL
4. Blood pressure <130/80 mm of hg
5. LDL-C <100 mg/dL
6. HDL-C >40 mg/dL
7. Triglycerides <150 mg/dL

 To maintain normoglycemia
 to normalize Hb A1c
 To prevent complications
 To improve QOL
 Modalities of treatment

TYPE 1 : Insulin

Type 2 :

 Monotherapy: Oral anti diabeticagents

 Combination : Oral anti diabetic agents
 Combination: Insulin + oral anti diabeticagents
 Insulin

Weight loss ,regular physical activity, medical nutrition

therapy

Lifestyle changes
Insulin
 Evolution of insulin : Exogenous insulin available for more than 90 yrs

 Top medical breakthroughs

 Most powerful diabetic agent

 Limited only by hypoglycemia

 Based on species of origin Classify ??
Human
Porcine
Bovine

Clinical use
• Meal time insulin: rapid & short acting
• Basal insulin : IA& LA
• Premixed insulins : SA & IA
ANALOG ONSET PEAK DOA
REGULAR 30-45 m 2 -4 h 5-8 h
LISPRO 15 m 1-1.5 h 2-5 h
ASPART 15 m 1h 3-5 h
GLULISINE 15 m 1-1.5 h 1-2 h
NPH 1- 2 h 6-12 h 18-24 h
ULTRALENTE 4 -6 h 16-18 h 20-36 h
GLARGINE 2 -5 h FLAT 18- 24
DETEMIR 1- 2 h FLAT 6-24
Traditional Insulin preparations

 Short Acting : Insulin Regular

 Intermediate Acting : Isophane Insulin Suspension ( NPH) , Insulin

Zinc Suspension ( Lente)

 Slow Acting : Extended Insulin Zinc Suspension ( Ultralente)

 Traditional insulins

 Traditional insulins : Solutions of regular insulin, dissolved in a buffer

at neutral pH

 Forms a hexamer when stored in the

presence of Zn ions ( self aggregation )

 S/C Injection : dissociate into dimers

& then into monomers / time : 30 - 45 mins

 Limitations of regular insulins
 Regular insulin : Delayed onset [1/2 hr -1 hr ] POST PRANDIAL HYPERGLYCEMIA

 Peak : 2-3 hrs

 Duaration of action : 5-8 hrs LATE POST PRANDIAL HYPOGLYCEMIA

has to be administered 30-45 mins before meals : dose cannot be adjusted according to size of meals

 Absorption varies with injection site and exercise [variability as much as 25%]
 Regular insulins cause a mismatch between need & availability of bolus insulin and does not mimic
normal pattern

 Lipodystrophy
 Allergy
 Antibody related insulin resistance
 Hypoglycemia
Insulin analogs

Rapid acting Lispro

Aspart

Glulisine

Long acting Glargine

Detemir

Ultra long acting Degludec

Inhaled insulin Afrezza

Insulin combinations Mixture : short acting (25%–50%) and long

acting (50%–75%)
 Designer insulins
Modified recombinant insulins
 Regular insulin : altered through an amino

acid / substitution / addition / deletion

 Rearrangement impart a particular

physicochemical /PK property

 Proline and lysine at b 28 and b 29

 Prolineat b 28 withan aspartic acid

Glutamic acid replaces lysine at b 29

& lysine replaces asparagine at 3

 Rapid acting analogues

 Rapid onset : 5 - 15 mins – better postprandial control

 PEAK : 1-2 hrs, DURATION : 4-5 hrs - decreased risk of late postprandial
hypoglycemia

 Mimics physiology : less propensity to cause hexamers , Dissociate rapidly

/ associate with less cohesive force - Physical &chemical stability - faster
absorption & onset- closely resembles physiological secretion
 Can be taken just before or just after meals – allows dose adjustment
with size of meal
 MODIFIED LONG ACTING ANALOGUES
 Substitution of Glycine for Asparagine at A 21 / Provides Stability + 2 Arginines at B
Chain
 Addition of Fatty Acid to the Amino Group Of Lys B 29 / Myristoylated Insulin
 Modified long acting analogues
Glargine : Peakless Insulin
 CLEAR SOLUTION : pH of 4 that stabilizes the hexamer

 Acidic pH - injected into the subcutaneousspace ( normal pH)

- forms micro precipitates.

 dissociate to hexamers to dimers to monomers – absorbed

across the capillaries

 Slows absorbtion / predictable sustained action

 LONG ACTING / PEAKLESS - Relatively constant

concentration – time profile with no pronounced peak

Owing to insulin glargine’s acidic pH, it cannot be mixed with

short-acting insulin preparationsthat are formulated at a neutral
pH.
 DETEMIR

 New long-acting insulin analogue

threonine in B30 replaced by Myrsitic acid

 Addition of C-14 fatty acid chain to the amino group of LYS B 29 /

Myristoylated insulin

 Increase self aggregation in SC tissue & reversible binding to albumin

 Detemir : has the Most reproducible effect of the IA & LA insulins

 DETEMIR VS GLARGINE
MECHANISM OF PROTRACTION
GLARGINE
pH 4.0 SC Tissue
pH 7.4

MICRO-PRECIPITATION

MAY CAUSE VARIABILITY IN ABSORPTION,

HENCE, IN ACTION

DETEMIR
PH 7.4
SC Tissue
pH 7.4
No Precipitation
Binding to Albumin

MORE PREDICTABLE IN ABSORPTION,

HENCE IN ACTION
 Insulin Degludec
Newest ULTRA long acting basal insulin,

 Modified insulin with one amino acid deleted (threonine at position

B30) and is conjugated to hexadecanedioic acid via γ-l-glutamyl spacer
at the amino acid lysine at position B29.

 Active at a physiologic pH, forms multihexamers complexesthat slow

absorption on subcutaneous injection ; Also binds well to albumin

 These two characteristics contribute to the prolonged effect of degludec

(>24 h at steady state). T 1 ⁄ 2- (25-40 hr) /100U & 200U/ML [PEN]

 Unlike Glargine it is effective at physiological pH

 less severe hypoglycemiathan glargine.

 Unlike Glargine & Detemir, it can be mixed with other insulins

 Glargine, Degludec, and Detemir have minimal peak activity at steady-state

👉A major concern about all newer insulin analogues is their altered

mitogenic properties and resultant risk of carcinogenicity on long
term use.
 Inhaled insulin (Afrezza)
Inhaled insulin first made an appearance on the US market in 2011, withdrawn

 Recently introduced AfrezzaMeal time insulin

 FDA approvalin both type 1 and type 2 diabetes [ Add on therapy for uncontrolled type 2].

 Monomeric formulation

 Decreases the risk of hypoglycemia and weight gain

 Kinetics similar to ultra short acting insulins / Alternative to ultra SA insulins [ More rapid onset and shorter duration
than injected insulin analogues ] /

 Used in combination with a long-acting insulin in type 1 DM.

 It is not widely used / Expensive

 Adverse events include cough and throat irritation. Not to be used in individuals who smoke, Asthma ,COPD .
Non-Insulin Antidiabetic
Drugs
ORAL : 1. Insulin secretagogues:
 KATP Channel Modulators: Sulfonylureas
Nonsulfonylureas ;Meglitinides : Nateglinide ,Repaglinide
DPP 4 inhibitors : Alogliptin, Linagliptin, Saxagliptin, Sitagliptin, Vildagliptin
[Link] sensitizers :

 Drugs which reduce insulin resistance : [ PPAR activators] Thiazolidinediones: The Glitazones
 Inhibitors of gluconeogenesis [AMPK activators ] Biguanides : Metformin
3. Inhibitors of intestinal alpha glucosidases : Acarbose, Miglitol
4. Inhibitors of SGLT 2 : Dapagliflozin ,Canagliflozin ,Empaglifozin,Ertugliflozin : The Gliflozins
5. Dopamine agonists : Bromocriptine
PARENTRAL : GLP 1 agonists : Albiglutide , Dulaglutide , Exenatide , Liraglutide, Lixisenatide, semaglutide
Amylinomimetics: Pramlintide
 Insulin Secretagogues and Glucose-Lowering Agents
KATP Channel Modulators: Sulfonylureas

1. Tolbutamide, Tolazamide,And Chlorpropamide: Rarely Used Now

[Link] (Glibenclamide), Glipizide, And Glimepiride [ Extended-release Glipizide & Micronized Glyburide
Formulation ]

MOA : Stimulate insulin release - β cell KATP channel complex (SUR) and inhibiting its activity - cell membrane
depolarization -leading to insulin secretion .

👉Chronic administration : Decrease insulin to pre treatment levels but reduced plasma glucose levels are maintained

Absence of acute stimulatory effect is due to downregulation of cell surface receptors

👉Increase in cardiovascular mortality remains controversial. [ Ischemic preconditioning ]

ADR : Hypoglycemia and weight gain , secondary failure [Drug metabolism & β cell failure ]

 Glipizide & Glimepiride : safer than longer-acting sulfonylureas in elderly [ even the short-duration agents should be
used with caution in elderly patients].
 K ATP Channel Modulators:Nonsulfonylureas
Repaglinide. Oral insulin secretagogue of the Meglitinide class, stimulates insulin release by closing KATP channels

 Metabolized by the liver (CYP3A4) to inactive derivatives, ~10% is metabolized by the kidney

 Hypoglycemia

 secondary failure

Nateglinide : orally effective insulin secretagogue, block KATP channels

 Rapid but less-sustained secretion of insulin

 Effective in reducing postprandial glycemic elevations in patients with type 2 diabetes.

 It is metabolized primarily by hepatic CYPs (2C9, 70%; 3A4, 30%) and should be used cautiously in patients with
hepatic insufficiency.

 secondary failure
 Biguanides : Metformin
Mechanism of Action: Reduction of HGP primarily by limiting gluconeogenesis.

 Mitochondrial respiration

 AMP-dependent protein kinase (AMPK) - hepatic fatty acid oxidation, glucose uptake, and nonoxidative
glucose metabolism and reduction of lipogenesis and gluconeogenesis.

Beneficial effects : Rarely causes hypoglycemia

Reduces microvascular complications , beneficial effect on macrovascular disease as well.

Weight reduction

Prediabetes

Treatment of infertility in women with polycystic ovarian syndrome

[improve ovulation & menstrual cyclicity]

 Side effects (10%–25%) of metformin are GI , metformin ER has less GI effects, lower
blood levels of vitamin B12 [monitored] , Lactic acidosis

 The ADA : used safely when the GFR is greater than 45 ml/ min/1.73 m2, and that the
dose should be reduced by 50%–75% when GFR is 30–45 ml/min/1.73 m2. Assess
renal function

 Discontinue : before radiographic procedures that use contrast dyes and during
admission to the hospital for severe illness.

 CI: severe pulmonary disease, decompensated heart failure, severe liver disease, or
chronic alcohol abuse, along with Cationic drugs
 Thiazolidinediones
Ligands for the PPAR γ receptor : Rosiglitazone And Pioglitazone

MOA : Activate PPAR γ receptors- adipocyte differentiation, increased tissue sensitivity to insulin [ liver,
adipose tissue, and skeletal muscle]

 Pioglitazone reduces plasma triglycerides by 10%–15%, raises HDL cholesterol levels, and increases LDL
cholesterol.

ADR: Weight gain and Edema

 Increased incidence of heart failure of up to 2-fold [plasma volume expansion]

 Rosiglitazone increased the risk of cardiovascular events (myocardialinfarction, stroke). FDA has lifted
the previous ban

 Increased risk of bone fracture in women

 Affect transaminases, liver function monitored

 Alpha GlucosidaseInhibitors : Acarbose,Miglitol, And Voglibose

 Reduce intestinal absorption of starch, dextrin, and disaccharides by inhibiting the action of α-glucosidase in the
intestinal brush border.

 Increase the release of the glucoregulatory hormone GLP-1 - contribute to their glucose-lowering effects.

Adverse Effects: Malabsorption, flatulence, diarrhea, and abdominal bloating.

• Elevations of hepatic transaminases ,cutaneous hypersensitivity rarely.

• Hypoglycemia.

• contraindicated in patients with stage 4 renal failure.

Indication : as adjuncts to diet and exercise in type 2 diabetic patients not reaching glycemic targets. They can also be
used in combination with other oral antidiabetic agents or insulin.
•
 GLP-1–Based Agents
 Incretins [GI hormones released after meals and stimulate insulin secretion in β cells] : GLP-1 and GIP ;

 GLP-1 - successful drug target in DM. [rapidly inactivated by the enzyme DPP-4]

 GLP-1 based therapeutics: Injectable, GLP-1 receptor Agonists [GLP-1 R A]

DPP-4 inhibitors

 GLP-1 Receptor Agonists : Exenatide, Liraglutide,Albiglutide, Dulaglutide, lixisenatide

 All GLP-1RA s : common mechanism, activation of the GLP-1 receptor, a member of glucagon receptor family of
GPCRs (class B GPCRs).

 activates the cAMP-PKA pathway and several GEFs. [ Guanine nucleotide exchange factor]

 Also initiates signaling via PKC and PI3K and alters the activity of several ion channels.

 In β cells : increase insulin biosynthesis and exocytosis in a glucose-dependentmanner.

 Exenatide.
 [ Exendin-4 ] 39–amino acid reptilian peptide with 53% sequence homology to GLP-1.

 It is not metabolized by DPP-4 and so has extended activity following injection.

 Approved for monotherapy and as adjunctive therapy for patients with type 2 diabetes not
achieving glycemic targets with other drugs.

 Improves glycemic control, 1% decrease in A1c and weight loss Evidence from clinical trials
indicated that exenatide can also be used in conjunction with basal insulin.

 An extended-release form of exenatide is administered by subcutaneous injection once a

week with greater effectiveness than twice-daily treatment.
 Liraglutide
 The liraglutide peptide is a long-acting, DPP-4-resistant form of GLP-1, but with a Lys34Arg substitution
and addition of an α-glutamic acid spacer coupled to a C16 fatty acyl group at Lys26. .

 The pharmacodynamic profile of liraglutide mimics GLP-1 and exenatide.

 Improvement in glycemiccontrol and weightloss

 Adjunctive therapy in patients not achieving glycemic control with oral agents.

 Liraglutide reduced the risk of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke
in patients with type 2 diabetes and established cardiovascular disease.

 Semaglutide : under development with similarities to liraglutide

 Exenatide and Lixisenatide are neutral with regards to cardiovascular risk in the trials completed to
date.
Albiglutide : Fusion protein , two sequential GLP-1 moieties linked to human albumin;

The GLP-1 sequences are modified to prevent DPP-4 cleavage.

Dulaglutide : Fusion protein consisting of two linked molecules that have a modified version of GLP-1 linked

to the fc portion of a human immunoglobulin;

Lixisenatide : A slightly longer form of exenatide

GLP-1RA s : Pharmacodynamics are comparable to each other & can be used with other oral antidiabetic

agents and basal insulin.

 While all of the GLP-1RAS have demonstrated efficacy as monotherapy,none is considered as a first-line

agent.

 The differences in efficacy are small relative to the overall effect of the drugs, and definitive differences

await more comprehensive studies.

Adverse Effects : Nausea and vomiting [neural activation of specific CNS neurons].

 GI side effects.

 Hypoglycemia associated with GLP-1 agonist treatment is rare, but the combination of GLP-1 agonist with

sulfonylurea drugs causes an increased rate of hypoglycemia compared to sulfonylurea treatment alone.

 Because of the reliance on renal clearance, exenatide, and probably lixisenatide, should not be given to persons with

moderate-to-severerenal failure (creatinine clearance < 30 mL/min).

 possible association of exenatide treatment with pancreatitis;

 The GLP-1 receptor is expressed by thyroid C cells. Although there is not an established clinical association with

medullary carcinoma of the thyroid, GLP-1 agonists should not be given to these patients.
 DPP-4 Inhibitors

 Dipeptidyl peptidase IV : serine protease .

 inactivation of GLP-1 and GIP.

Sitagliptin, Saxagliptin, Linagliptin,

alogliptin & Vildagliptin

• Mechanism of Action: Alogliptin, linagliptin, and sitagliptin are competitive inhibitors of DPP-4; vildagliptin
and saxagliptin bind the enzyme covalently.

• 2-fold elevation of active GIP and GLP-1 and is associated with increased insulin secretion, reduced
glucagon levels, and improvements in both fasting and postprandial hyperglycemia.

• No direct effects on insulin sensitivity, gastric motility, or satiety& No effect body weight.

• DPP-4 inhibitors, used as monotherapy in type 2 diabetic patients, reduce A1c levels by an average of about
0.8%.

• Additive effect with other antidiabetic drugs and insulin

•Adverse Effects. No impact on the incidence of cardiovascular events in diabetic patients;

saxagliptin had an increase in hospitalization for HF .

 Na+Glucose Transporter 2 Inhibitors
 SGLT2 is a Na+-glucose cotransporter : proximal

portion of the renal tubule.

 SGLT 2 is a high-affinity, low- capacity transporter that

moves glucose against a concentration gradient from the

tubular lumen using energy generated from Na+ flux

through the epithelial cells.

 Renal retention of glucose is nearly complete in nondiabetic persons, and SGLT2 accounts for 80%–
90% of this reclamation; the remainder is recovered by SGLT1 more distally in the tubule.

 Drugs that are specific inhibitors of SGLT 2 have been developed to treat diabetes .
Mechanism of Action: SGLT2 inhibitors reduce the rate of glucose reclamation in the proximal tubule and shift the renal
threshold for glucose excretion from about 180 to 50 mg/dL (10 to 2.8 mM).

• In monotherapy: reduce A1c by 0.7%–1.0%, cause weight loss of 2–4 kg, and decrease BP by 2–4 mm hg.

•Canagliflozin, Dapagliflozin and Empagliflozin. Available in combination with metformin and dpp-4 inhibitors;

ADME. Good oral bioavailability. Dapagliflozin 5 and 10 mg, Canagliflozin 100 and 300 mg, Empagliflozin 10 and 25 mg .

Adverse Effects: increase in lower urinary tract infections and a increase in genital mycotic infections.

• hypotension , No hypoglycemia , Increase the risk of fractures (FDA warning), and affect mineral balance and
circulating levels of parathyroid hormone and 1,25-hydroxy vitamin d.

• In phase 3 clinical trials, there was no evidence that SGLT2 inhibitors had adverse effects on cardiovascular disease.

• Data from controlled trials indicate that empagliflozin and canagliflozin reduce the risk for major cardiovascular events.
Canagliflozin is associated with an increased risk of lower extremity amputation.
Bromocriptine
 Approved for the treatment of type 2 diabetes

 Bromocriptine is an established treatment of parkinson

disease and hyperprolactinemia

 Effects on blood glucose are modest and

may reflect an action in the CNS.

 The dose range for bromocriptine is 1.6 to 4.8 mg,

taken with food in the morning within 3 h of awakening.

 Side effects include nausea, fatigue, dizziness,

Orthostatic hypotension, vomiting, and headache.

 COMBINATION ANTIDIABETICS

1. Thiazolidinedione + Biguanide

2. DPP-4 inhibitors + Biguanide

3. SGLT2 inhibitor + Biguanide

4. DPP-4 inhibitor + SGLT2 inhibitor

5. GLP-1 agonist + Degludec insulin

6. GLP-1 agonist + Glargine insulin

 Insulin & Pregnancy category [ Not used after 2015 ]

INSULIN PREGNANCY CATEGORY

Regular B[U-100,500] LOW RISK

Aspart B LOW RISK

Lispro B [U- 100,200] LOW RISK

Glulisine C NO HUMAN DATA

NPH B LOW RISK

Glargine NO HUMAN DATA [Prev C] NO WELL CONTROLLED CLINICAL

STUDIES
Detemir B LOW RISK

Degludec C [U-100 ,200] NO HUMAN DATA

Inhaled insulin C NO HUMAN DATA

NOTHING LIKE DIET ,EXERCISE &
ADHERENCE TO
LIFE STYLE CHANGES

thank you