Gastro-intestinal system

Gastrointestinal system

• Mouth

• Stomach and
duodenum
• Pancreas
• Small intestine

• Liver and other organs

 Liver functions

• Production – plasma proteins,

blood clotting proteins, bile
pigments

• Storage – vitamins, minerals,

fat, glucose as glycogen

• Conversion/utilization – fats,
carbohydrates, proteins

• Removal – aged blood cells,

drugs or toxins, waste products
 Energy source for body

• Proteins: 10-12%

• Fats: 30%
• Carbohydrates: 60%
 Journey of Glucose

Food Carbohydrates Formation

formed of glucose

Glucose Glucose Glucose enters

enters reaches different blood
Cell body parts
Mediated
by Insulin

Glucose used for various functions

Extra glucose stored in a different form
Steps in utilization of glucose

Entry of glucose in cell

Phosphorylation of glucose

Release of energy
 Insulin-Carbohydrate Metabolism

• Facilitates the transport of glucose into muscle and adipose

cells
• Facilitates the conversion of glucose to glycogen for storage
in the liver and muscle.
• Decreases the breakdown and release of glucose from
glycogen by the liver
 Insulin - Protein Metabolism

• Stimulates protein synthesis

• Inhibits protein breakdown; diminishes gluconeogenesis

 Insulin - Fat Metabolism

• Stimulates lipogenesis- the transport of triglycerides to

adipose tissue
• Inhibits lipolysis – prevents excessive production of ketones
or ketoacidosis
 Pancreas
• Exocrine function
– Digestive enzymes
• Pancreatic amylase

• Pancreatic lipase

• Trypsin

• Chymotrypsin

• Carboxypolypeptidase

• Nuclease

• Endocrine function
– Hormones
• Insulin

• Glucagon

• somatostatin
 Endocrine function

• Hormones act on target tissues to exert its effect

• Produced by the islet of Langerhans – number of cells in each islet
vary from several hundred to millions
• Glucagon – alpha cells
– Secreted when blood glucose levels fall

• Insulin – beta cells

– Secreted when blood glucose levels rise

• Somatostatin – delta cells

– Secreted in response to any kind of food intake – suppresses both
insulin and glucagon and may extend the period of nutrient absorption
and utilization
 What is insulin?

• A hormone
– (from Greek - "to set in motion") is a chemical messenger from
one cell (or group of cells) to another.

• Insulin is the protein hormone produced by cells in the

pancreas that regulate levels of glucose and regulate
metabolism in glucose, fats, and proteins.
• Insulin is composed of 51 amino acids.
• Amino acids are the basic structural building units of proteins
• Its formula is C254 H377 N65 O75 S6.
 Role of Insulin

• Hormone secreted by beta cells of

pancreas
• Controls the rate of entry of
glucose inside the cell
• Increases glucose utilization rate in
the cell
Hexamer of insulin • Increases rate of glucose transport
in the cell by more than 10 times.
Role of Insulin

[Link]
 Regulation of Hormone Secretion

• Non-hormonal
– Control of release dependent
upon concentration of other
non-hormonal substance
(i.e., glucose)
 Few Important Definitions...

• Glycolysis: Breakdown of glucose to release energy

• Glycogenesis: Formation of glycogen for storage from

unutilized glucose

• Glycogenolysis: breakdown of stored glycogen into

glucose

• Gluconeogenesis: formation of glucose from sources

other than carbohydrate (fat/protein) to meet energy

requirement
 C-peptide

• Insulin manufactured and stored

as proinsulin (86 AA)
• C-peptide (31 AA) ensures correct
folding of protein
• Enzymatic cleavage (4 AA lost)
and equal amount released along
with insulin (51 AA)
• C-peptide levels measured to
assess insulin production
• No physiological role – used as an
insulin marker
How the body uses Food

GLUCOSE
INSULIN

CELL Energy
Insulin Biosynthesis in the Beta Cell

Insulin gene codes for Proinsulin

pre-proinsulin

C-peptide

Glucose Insulin storage in

vesicles

Release by exocytosis
 Physiological Effects of Insulin

• Major target organs:

– Liver: insulin increases storage of glucose as
glycogen
– Muscle: insulin stimulates glycogen and protein
synthesis.
– Adipose: insulin stimulates triglyceride storage
 BETA CELL
Insulin release in non - diabetics Ca2+

Arrest of K+ release Opening of

ATP Ca2+ channel
ATP
K+ K+
Glucokinase Ca2+
Metabolism K+

Glucose
Glucose

Glucose Glucose

GLUT 2

Insulin release
Date :12th Mar 09 Valid: 11th Mar 10
 The non - diabetic peripheral cell
Insulin receptors

Glycogen ATP

Glucose Metabolism
pGLUT4

Intracellular vesicle
Dephosphorylation
GLUT4
Translocation

Date :12th Mar 09 Valid: 11th Mar 10

 Insulin secretion

• Insulin secretion increases almost 10 folds within 5 to 10

minutes of food intake.
• Insulin secretion is stimulated by glucose
The Basal/Bolus Insulin Concept

• Basal insulin
– Continuous, constant, low level secretion for 24 hours

– Suppresses glucose production between meals and overnight

– 40% to 50% of daily needs

• Bolus insulin (mealtime)- 2 phases

– Limits hyperglycemia after meals

– Immediate rise and sharp peak at 1 hour

– 10% to 20% of total daily insulin requirement at each meal

 Meal Meal Meal

50

40
Serum insulin (mU/L)

Bolus insulin needs

30

20

10
Basal Insulin Needs
0
0 2 4 6 8 10 12 14 16 18 20 22 24

Time (Hours)
 Phases of insulin release
• First phase
– Release starts as soon as food comes to the stomach

– Preformed stored insulin is released

– 10-fold increase in levels within 3-5 minutes

– Speeds up the use of glucose

– Within 5-10 minutes, insulin secretion decreases by half

• Second phase
– Rising glucose levels send signals to the beta cell nucleus
 DNA produces mRNA  mRNA produces more insulin
– Causes a less acute rise in insulin levels

– Reaches a plateau in 2-3 hours

Insulin release
 Effects of insulin:
Stimulates Inhibits
 Liver
glycogen synthesis glycogenolysis
triglyceride synthesis ketogenesis
gluconeogenesis
 Skeletal Muscle
glucose uptake
protein synthesis protein degradation
glycogen synthesis glycogenolysis
 Adipose tissue
glucose uptake
triglyceride storage lipolysis

Promotes anabolic Inhibits catabolic

processes processes
Glucose metabolism
&
Diabetes mellitus
 History of Diabetes
• 1500BC – Egyptians recorded diabetes as polyuria

• 1st Century AD – diabetes described as “the melting down of flesh and limbs
into urine”

• 20th Century – children with Type 1 diabetes had life expectancy of 2 years
– Hypothesized that liver and pancreas were involved in some way,
although cause unknown

• 1922 – Frederick Banting & Co. successfully isolate insulin extract for
diabetes Type 1

• 2011 – Type 2 diabetes comprises roughly 90% of all diagnosed cases, likely
due to increased obesity and inactivity levels
 Diabetes Mellitus

Derived from Greek roots

dia – through

bainein – to go

To go through – meaning syphon

Mellitus – Latin ‘mel’ for ‘honey’

Diabetes Mellitus – Sweet syphon

 Diabetes – Definition

Diabetes Mellitus is a metabolic disorder caused

by reduced availability or diminished effectiveness
of insulin, characterized by hyperglycemia with or
without glycosuria.
 Diabetes Mellitus

• Chronic medical condition

• Inability to properly utilize glucose

• Diabetes can cause acute medical emergencies

–Too much glucose (hyperglycemia)

–Too little glucose (hypoglycemia)
 Diabetes

Insulin Insulin
Release Resistance

Diabetes
 Diabetes Mellitus

Types of Diabetes
• Type 1 Diabetes
• Type 2 Diabetes
• Gestational Diabetes
Action of Insulin on the Cell Metabolism
 Type I Diabetes

• Low or absent endogenous insulin

• Dependent on exogenous insulin for life
• Onset generally < 30 years
• 5-10% of cases of diabetes
• Onset sudden
– Symptoms: 3 P’s: polyuria, polydypsia, polyphagia
Type I Diabetes Cell
 Type I Diabetes

• Genetic component to disease

 Type II Diabetes

• Insulin levels may be normal, elevated or depressed

– Characterized by insulin resistance,

– diminished tissue sensitivity to insulin,

– and impaired beta cell function (delayed or inadequate

insulin release)
• Often occurs >40 years
Type II Diabetes
 Type II Diabetes

• Risk factors: family history, sedentary lifestyle, obesity and

aging
• Controlled by weight loss, oral hypoglycemic agents and or
insulin
 TYPE I + TYPE II
Type I Diabetes Type II Diabetes
INSULIN
GLUCOSE

GLUCOSE

CELL
CELL
DM – Type I / II
 Pathogenesis of DM

• Insulin resistance
• Impaired insulin secretion
• Excessive hepatic glucose production
Pathogenesis of DM (Contd.)

Insulin Resistance:
• Decreased ability of insulin to act effectively on
peripheral tissue
• This resistance is relative, since increased levels
of insulin will normalize the Pl. glucose level
Mechanism – exact not known
• Decrease in insulin receptors or post receptor
defect
 Insulin Resistance

• Major defect in individuals with type 2 diabetes1

• Reduced biological response to insulin1–3

• Strong predictor of type 2 diabetes4

IR
• Closely associated with obesity5

American Diabetes Association. Diabetes Care 1998; 21:310–314.

1

2
Beck-Nielsen H & Groop LC. J Clin Invest 1994; 94:1714–1721.
1
American Diabetes Association. Diabetes Care 1998; 21:310–314.
3
Bloomgarden ZT. Clin Ther 1998; 20:216–231.
. J Clin Invest 1994; 94:1714–1721. 3Bloomgarden ZT. Clin Ther 1998; 20:216–231.
4
Haffner SM, et al. Circulation 2000;4 101:975–980.
Boden G. Diabetes 1997; 46:3–10. Haffner SM, et al. Circulation 2000; 101:975–980. Boden G. Diabetes 1997; 46:3–10.
5
5
Insulin Resistance

Click
Pathogenesis of DM (Contd.)

Impair insulin secretion

• Initially insulin secretion increase in response to
insulin resistance to maintain normal blood
glucose levels
• In later stage beta cell failure develops due to
lipo and glucotoxicity - low insulin levels
 Pathogenesis of DM (Contd.)

Increased hepatic glucose production

• Liver maintain Plasma glucose level during fasting

state by glycogenolysis and gluconeogenesis (A.A.,
F.A., glycerol)

• In DM because of insulin resistance, insulin fails to

suppress gluconeogenesis which leads to increased
blood glucose levels.
Diagnosis of Diabetes

 Polyuria – Increased micturition

 Polydipsia – Increased thirst

 Polyphagia – Increased hunger

 Fatigue

 Skin infections

 Impotence

 Tingling, numbness
 Diagnosis of diabetes

Symptoms + Elevated blood glucose level

OR
Elevated blood glucose levels on two occasions
 Diagnostic criteria for type 2 diabetes

Blood Glucose HbA1c FPG PPPG

Parameter

Normal < 6.5% < 100 mg/dl < 140 mg/dl

Pre-diabetes ≥ 6.5 - 7% 100-125 mg/dl (IFG) 140-199 mg/dl

(IGT)

Diabetes ≥ 7% 126 mg/dl or above 200 mg/dl or above

 Definitions
IGT impaired glucose tolerance –
– 2hr plasma glucose is between 7.8mmol/l (140mg/dl) and
11.0mmol/l (200mg/dl)

IFG impaired fasting glucose –

– Fasting plasma glucose is 6.1–6.9mmol/l (100–125mg/dl)

Diabetes-
– Confirmed fasting plasma glucose is ≥7.0mmol/l (126mg/dl)

– 2hr plasma glucose is ≥11.0mmol/l (200mg/dl)

 Prediabetes & Diabetes

Fasting glucose

100mg/dl 125 mg/dl

normoglycemic prediabetes diabetes

140 mg/dl 199 mg/dl

2hr Plasma glucose

Prediabetes is a condition in which the blood sugar level is higher than normal,
but not high enough to be classified as diabetes
 Insulin Resistance – Reduced response to
circulating insulin

Insulin
resistance IR

Liver Muscle Adipose

tissue

 Glucose output  Glucose uptake  Glucose uptake

Hyperglycemia
 Why does the -cell fail?

Over secretion of
insulin to compensate
for insulin resistance1,2
Glucotoxicity2
Lipotoxicity3

Chronic Pancreas High circulating

Hyperglycemia free fatty acids

-cell dysfunction
1
Boden G & Shulman GI. Eur J Clin Invest 2002; 32:14–23.
. Eur J Clin Invest 2002; 32:14–23.,
2
Kaiser N, et2Kaiser N, etEndocrinol
al. J Pediatr al. J Pediatr Endocrinol
Metab Metab 2003; 16:5–
2003; 16:5–22.
22.,3Finegood3Finegood
DT & Topp DT &[Link]
Diabetes ObesObes
B. Diabetes Metab 2001;
Metab 3 (Suppl.
2001; 3 (Suppl.1):S20–S27.
1):S20–S27.
 What is -cell dysfunction?

• Major defect in individuals with type 2 diabetes

• Reduced ability of -cells to secrete insulin in

response to hyperglycemia




DeFronzo RA, et al. Diabetes Care 1992; 15:318–354.

 Core defects in T2DM
Genetic
susceptibility,
Obesity,
Sedentary lifestyle

Insulin b-cell
Resistance IR  dysfunction

Type 2 diabetes

Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13.
 Insulin Resistance & Insulin Deficiency:
2 strongly linked mechanisms

At the time of diagnosis, both defects are already combined

Évolution of diabetes
Insulin
resistance

Fasting
blood glucose

Insulin
secretion

Compensation
Normal Diabetes
phase

DeFronzo R.A. et al., Diabetes Care (1998)

 Natural History of Type 2 Diabetes

Years from -10 -5 0 5 10 15

diagnosis
Onset Diagnosis

Insulin resistance
Insulin secretion

Postprandial glucose
Fasting glucose Microvascular complications
Macrovascular complications
Pre-diabetes Type 2 diabetes
Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789;
Nathan DM. N Engl J Med. 2002;347:1342-1349
 Role of IR and -cell dysfunction in T2DM

Normal IGT* Type 2 diabetes

Insulin Increased insulin

resistance resistance

Insulin Hyperinsulinemia,
secretion then -cell failure

PPPG
Abnormal
glucose tolerance

FPG
Hyperglycemia

*IGT = impaired glucose tolerance

International Diabetes Center (IDC), Minneapolis, 2000.

Progressive -cell Failure in Type 2 Diabetes

100
Diagnosis
-cell function (%)

80

60

40

20

0
-12 -6 0 6 12
Years

UKPDS 16 diabetes 1995, 44:1249-1258

 More IR patients are progressing to T2DM

Insulin sensitive;
low insulin secretion (16%)

Insulin sensitive;
good insulin Insulin resistant;
secretion (1%) low insulin secretion (54%)

83%
Insulin resistant;
good insulin secretion (29%)

Haffner SM, et al. Circulation 2000; 101:975–980.

Insulin release in non-diabetics Ca2+

Arrest of K+ release Opening of

ATP
ATP Ca2+ channel
K+ K+
Glucokinase Ca2+
Metabolism K+

Glucose
Glucose

Glucose Glucose

GLUT 2

Insulin release
Date :12th Mar 09 Valid: 11th Mar 10
 K+
Insulin release in diabetics
Partial Arrest of K+ release Opening of
ATP
ATP Ca2+ channel
K+ K+ Ca2+
Glucokinase K+
Metabolism
Glucose

Glucose Less Glucose

Glucose

GLUT 2

Insulin release
Date :12th Mar 09 Valid: 11th Mar 10
 The non-diabetic peripheral cell
Insulin receptors

Glycogen ATP

Glucose Metabolism pGLUT4

Intracellular vesicle
Dephosphorylation
GLUT4
Translocation

Date :12th Mar 09 Valid: 11th Mar 10

 The diabetic peripheral cell
Insulin receptors

Glycogen ATP

Glucose Metabolism pGLUT4

Intracellular vesicle
Dephosphorylation
GLUT4
Translocation

Date :12th Mar 09 Valid: 11th Mar 10

What goes wrong in diabetes?

Absolute Insulin Deficiency Relative Insulin Deficiency

No Glucose oxidation
(lack of energy)

More Glucose production (from glycogen,

Excessive Hunger
amino acids and Glycerol)
(polyphagia)
Kidney retains (up to 160-180 mg%)
Above 160-180 mg %

Glycosuria
Osmosis
Polyuria
Water loss
Polydipsia
 Symptoms of Diabetes

Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,
World Health Organization, Geneva 1999. Available at: [Link]
 Diagnosis of Diabetes

 Polyuria – Increased micturition

 Polydipsia – Increased thirst

 Polyphagia – Increased hunger

 Fatigue

 Skin infections

 Impotence

 Tingling, numbness

Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,
World Health Organization, Geneva 1999. Available at: [Link]
Diagnosis: Long Term Control

Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,
World Health Organization, Geneva 1999. Available at: [Link]
 Glycated Hb (Hb A1c)

• Increased blood glucose level leads to an increase

in non enzymatic glycation of Hb.

• It reflects glycaemic control over past 2-3

months.

• Normal = < 6%

Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,
World Health Organization, Geneva 1999. Available at: [Link]
Chronic Complication of Diabetes Mellitus

Microvascular Macrovascular

Eye Disease Coronary artery disease

Retinopathy Peripheral vascular disease

(nonproliferative/proliferative) Cerebrovascular disease
Macular edema Other
Cataracts Gastrointestinal
Glaucoma (gastroparesis, diarrhea)

Neuropathy Genitourinary

Sensory ,motor & Autonomic (uropathy/sexual

Nephropathy dysfunction)

Dermatologic
Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,
World Health Organization, Geneva 1999. Available at: [Link]
Diabetes – Chronic complications

Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,
World Health Organization, Geneva 1999. Available at: [Link]
Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,
World Health Organization, Geneva 1999. Available at: [Link]
Diabetes Complications
Diabetes Complications

[Link]
 DIABETIC
MICROVASCULAR
COMPLICATIONS
Diabetic Retinopathy

Underlying cause:
 AGE formation
 Increased Free Radicals
 Lipid Peroxidation
Diabetic Nephropathy

Underlying cause:
 AGE formation inside Arterioles of Glomerulus
 Diabetic Neuropathy

Underlying cause
 Insufficient blood supply to nerves connecting peripheral parts.
 Microvascular AGE
 DIABETIC
MACROVASCULAR
COMPLICATIONS
Stroke
Peripheral Vascular Disease
Coronary Artery Disease

Underlying cause:
 Plaque formation and Thrombogenesis.
 LDL oxidation and Lipid imbalance
 Hypertension

Underlying cause:

 Disturbed or altered Systolic and Diastolic Blood-Pressure

Insulin Resistance is as strong a risk factor for
Cardio Vascular Disease.

1.8

1.6
Odds ratio for incident CVD

1.4

1.2

1.0

0.8

0.6
Age Smoking Total cholesterol: Insulin
HDL cholesterol resistance

Hanley AJ, et al. Diabetes Care 2002; 25:1177–1184.

Bonora E, et al. Diabetes Care 2002; 25:1135–1141.
Bonora E, et al. Diabetes Care 2002; 25:1135–1141.
 Insulin Resistance is closely linked to Cardio
Vascular Disease

Present in > 80% of people

with type 2 diabetes1

Approximately doubles the

Insulin
Resistance IR risk of a cardiac event2

Implicated in almost half of

CHD events in individuals with
type 2 diabetes2

1
1
Haffner
Haffner SM, et al. Circulation 2000; SM, et al. Circulation
101:975–980., 2
Strutton D, 2000;
et al. Am101:975–980.
J Man Care 2001; 7:765–773.
2
Strutton D, et al. Am J Manag Care 2001; 7:765–773.
 Insulin Resistance is linked to a range of
Cardio Vascular risk factors

Hyperglycemia

Dyslipidemia

Insulin
IR Hypertension

Resistance Damage to blood vessels

Clotting abnormalities

Inflammation Atherosclerosis

Zimmet P. Trends Cardiovasc Med 2002; 12:354–362.

 Obesity as a risk factor

~90% of people with

type 2 diabetes are
overweight or obese

World Health Organization, 2005. [Link]

 Goals of Therapy

 TO MAINTAIN BLOOD GLUCOSE AT NEAR-NORMAL LEVELS

(70-120MG/DL)

 REDUCE THE RISK OF COMPLICATIONS

Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease
Surveillance,
World Health Organization, Geneva 1999. Available at: [Link]
 Management Strategies

N EX
O E
TI RC
T RI IS
U E
N
MEDICATIONS

MONITORING
SELF

EDUCATION
Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,
World Health Organization, Geneva 1999. Available at: [Link]
 Management of Diabetes

 Diet
 Exercise
 Weight Management
 OHA
 Insulin

Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,
World Health Organization, Geneva 1999. Available at: [Link]
 Treatment of Type 2 Diabetes

• Monotherapy with oral agent

• Combination therapy with oral agents

• Insulin +/- oral agent

–insulin required in 20-30% of patients

With duration of the disease, more intensive therapy is required

to maintain glycemic goals

Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance,
World Health Organization, Geneva 1999. Available at: [Link]
Diabetes : Pathogenesis

Liver
Adipose Muscle

Gl

se
uc

ke co
os

ta lu
e

up d g
Re

ire
FFA

le

pa
as

Im
e Circulatory System
Circulatory System
Glucose
FFA

Secretion
Defective
Insulin

Pancreas
 How can diabetes care and outcomes
be improved?

Address the underlying

pathophysiology,

including treatment of
insulin resistance and
Beta cell function

Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355.

 India Diabetes Fast Facts

• By 2030, India will become the Diabetic Capital of

the World

• DM is the leading cause of blindness, End Stage

Renal Disease and Amputations

• Over 60% of ESRD is due to Diabetes

• 70 % Diabetics die of – CHD, CVD

• Leading cause of non traumatic LL amputation

• So, screen all for Diabetes and for risk factors

 Diabetes Medications

• Biguanides Ex:Metformin

• Sulfonylureas Ex:Tolbutamide, Glipizide, Glimepiride

• Meglitinides Ex:Repaglinide, Nateglinide

• Alpha Glucosidase Inhibitors Ex:Acarbose, Miglitol, Voglibose

• Thiazolidinediones Ex:Pioglitazone

• DPP4 inhibitors Ex:Sitagliptin, Vildagliptin, Saxagliptin

• GLP-1 analogs Ex:Exanatide, Liraglutide

• Insulin
 Primary sites of action of
Oral Anti-diabetic agents

-glucosidase Sulfonylureas/
inhibitors meglitinides Biguanides Thiazolidinediones

 Carbohydrate  Insulin  Glucose output  Insulin

breakdown/ secretion  Insulin resistance resistance
absorption

Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40.

1

Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endo. Metab 1999; 13:309–329.
2
Biguanides:(Glyciphage-Metformin)

• Biguanides (Metformin) lowers the production of glucose

made in the liver

• Well accepted as the drug of first choice in Type II

• Major side effects are GI

• Lactic acidosis rare but serious side effect

Metformin MOA
Decreasing Insulin Resistance Decrease Macro
Vascular complications

Sulfonylureas/Insulin Metformin

Myocardial All-cause mortality Myocardial All-cause

infarction infarction mortality

21% 8% 39% 36%

Significant Significant

UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:854–865.

UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:854–865.
Insulin sensitizers reduce CV events in T2DM

12-month combined event rate (%) 60

50

40

30

20

10

0
Non-sensitizers Sensitizers

J Am Coll
Kao JA, et [Link]
J Am Coll 2004; 43:37A.
Cardiol 2004; 43:37A.
 Sulfonylureas

• Oldest of oral medecine

• Until 1995 the only meds available

• 1st gen- Tolbutamide

• 2nd gen-Glipizide, Glibenclamide, Gliclazide

• 3rd gen- Glimeperide

• Stimulate the pancreas to release more insulin, hypoglycemia

can be side effect
 Glimepiride MOA
Glucose entry into
cells

Glucose metabolism &

Increase in ATP

Closes ATP-dep.
K Channel

Forced closure of
Decreased K efflux
K+ATP Channel
by Glimepiride
Depolarization of
Membrane

Voltage-gated Ca
Channels open

Translocation of
Granules and Exocytosis

Insulin release
 Meglitinides

• Ex: Repaglinide, Nateglitinide

• Stimulate insulin secretion when there is glucose present in

the blood stream
• Used with meals
 Alpha-Glucosidase Inhibitors

• Example: Acarbose, Miglitol, Voglibose

• Delay the conversion of carbohydrates into glucose during

digestion
• Major side effect gas/bloating limits use
 Voglibose
Ingestion of
food Prolongs glucose absorption
due to reversible inhibition
of enzyme

GI
tract Voglibose

Blood
Alpha Glucosidase Enzyme glucose control

Glucose

Retards sudden
absorption of glucose

Villi of Small Intestine

 Pioglitazone

Class Mechanism Advantages

• PPAR-g activator • No hypoglycemia
TZDs
•  insulin sensitivity • Durability
(Pioglitazone)
•  TGs,  HDL-C,  CVD
Pioglitazone MOA
Thiazolidinedione

Improved Insulin Sensitivity

 The dual action of TZDs

Insulin
Resistance IR
+ 
-cell
function

HbA1c

Lebovitz HE, et al. J Clin Endocrinol Metab 2001; 86:280–288.

1
Lebovitz HE, et al. J Clin Endocrinol Metab 2001; 86:280–288.
2
Rosenblatt S, et al. Coron Artery Dis 2001; 12:413–423.
 DPP-4 Inhibitors

• Dipepityl Peptidase 4 inhibitor-slows the inactivation of

GLP-1 and GIP (glucose-dependent insulinotropic
polypeptide)

• Example: Sitagliptin, Saxagliptin, Vildagliptin

• Very minimal side effects, weight neutral

• Most effective when used with metformin

 Incretin Mimetics

• Exenatide-originally isolated from the saliva of Gila monster Lizard

• Shares several of the coregulatory effects of the incretin glucagon-

like peptide-1(GLP-1)

• Improves glucose dependent insulin secretion

• Restores first phase insulin response

• Suppresses inappropriate glucagon secretion

• Slows rate of gastric emptying

• Increases satiety

• BID injection, main side effect nausea/weight loss

 Insulin

• Rapid Acting

• Intermediate Acting
• Long Acting

• Premixed Insulin
 What does the
ADA / EASD
guidelines say?

PG = plasma glucose Diabetes Care, Diabetologia. 19 April 2012

 ADA-EASD Position Statement:
Management of Hyperglycemia in T2DM
ANTI-HYPERGLYCEMIC THERAPY

Glycemic targets

- HbA1c < 7.0% (mean PG 150-160 mg/dl [8.3-8.9 mmol/l])

- Pre-prandial PG <130 mg/dl (7.2 mmol/l)

- Post-prandial PG <180 mg/dl (10.0 mmol/l)

- Individualization is key:

 Tighter targets (6.0 - 6.5%) - younger, healthier

 Looser targets (7.5 - 8.0%+) - older, comorbidities, hypoglycemia

prone, etc.

PG = plasma glucose Diabetes Care, Diabetologia. 19 April 2012

Diabetes Care, Diabetologia., 19 April 2012 [Epub ahead of print]
 Guidelines for Glycemic, BP, & Lipid
Control American Diabetes Assoc. Goals

HbA1C < 7.0% (individualization)

Preprandial glucose 70-130 mg/dL (3.9-7.2 mmol/l)

Postprandial glucose < 180 mg/dL

Blood pressure < 130/80 mmHg

LDL: < 100 mg/dL (2.59 mmol/l)

< 70 mg/dL (1.81 mmol/l) (with overt CVD)

Lipids HDL: > 40 mg/dL (1.04 mmol/l)

> 50 mg/dL (1.30 mmol/l)

TG: < 150 mg/dL (1.69 mmol/l)

HDL = high-density lipoprotein; LDL = low-density lipoprotein;
ADA. Diabetes Care. 2012;35:S11-63
PG = plasma glucose; TG = triglycerides.
Thank You
 Insulin Actions

Figure – Normal insulin action pathway 126