INSULIN &

ORAL HYPOGLYCEMICAGENTS

INTRODUCTIONDiabetes or Diabetes Mellitus

Chronic Metabolic Disorder Vascular Abnormalities

Characterized by• Hyperglycemia• Glycosuria• Polydipsia• Polyphagia • Ketoacidosis

5

Characteristic Type 1 ( 10% ) Type 2

Onset (Age) Usually < 30 Usually > 40 Type of onset Abrupt GradualNutritional status Usually thin Usually obese

Diet Mandatory with insulin Mandatory with or without drug

Hypoglycemic drugs Should not be used Clinically indicated

Clinical symptoms Polydipsia, polyphagia, polyurea, Wt loss

Often asymptomatic

Ketosis Frequent Usually absentEndogenous insulin Absent Present, but relatively

ineffective

Related lipid abnormalities

Hypercholesterolemia frequent, all lipid fractions elevated in ketosis

Cholesterol & triglycerides often elevated; carbohydrate- induced hypertriglyceridemia common

Insulin therapy Required Required in only 20 - 30% of patients

BLOOD GLUCOSE LEVELScategory Fasting values

(mg/dL)Post prandial

(mg/dL)Minimum

valueMaximum

value2 hrs after

consuming glucose

Normal 70 100 <140

Early diabetes

101 126 140-200

Established diabetes

>126 - >200

6

Pancreatic Hormone

REGULATION

Regulation of Insulin and Glucagon

Action of Insulin on Various Tissues

Liver Muscle Adipose↓ glucose production ↑ Glucose transport ↑ glucose transport

↑ glycolysis ↑ glycolysis ↑ lipogenesis& lipoprotein lipase activity

↑ TG synthesis ↑ glycogen deposition ↓ intracellular lipolysis

↑ Protein synthesis ↑ protein synthesis

INSULIN

Degradation of Insulin

Liver and Kidney are two organ remove insulin from circulation by hydrolysis of disulfide connection between A & B chains.

Liver remove 60% of insulin.

Kidney remove 35-40% of insulin.

INSULIN RECEPTORBinding sites

Cellmembrane

Tyrosin kinase

Intracellularspace

Amino Acid SubstitutonsA-

chain

Position

B- chain Position

Source/Type

A21 B3 B28 B29 B30 B31 AndB32

Human Asn Asn Pro Lys Thr

Aspart Asn Asparticacid

Lys Thr

Lispro Asn Lys Pro ThrGlulisin

eAsn Lys Pro Glu Thr

Glargine Gly Pro Lys Thr Arg

Detemir Lys Myristicacid

rapid-acting

long-acting

16

Ultra-short-acting (Rapid acting)

Short-acting (Regular)

Intermediate-acting

Long-acting

TYPES OF INSULIN PREPARATIONS

17

Short-acting (regular) insulins e.g. Humulin R, Novolin R

Uses Designed to control postprandial hyperglycemia & to treat emergency diabetic ketoacidosis

Physical characteristics

Clear solution at neutral pH

Chemical structure

Hexameric analogue

Route & time of administration

S.C. 30 – 45 min before mealI.V. in emergency (e.g. diabetic ketoacidosis)

Onset of action 30 – 45 min ( S.C )Peak serum levels 2 – 4 hr

Duration of action 6 – 8 hr

Usual administration

2 – 3 times/day or more

Ultra-Short acting insulins e.g. Lispro, aspart, glulisine

Similar to regular insulin but designed to overcome the limitations of regular insulin

Clear solution at neutral pH

Monomeric analogue

S.C. 5 min (no more than 15 min) before mealI.V. in emergency (e.g. diabetic ketoacidosis)

0 – 15 min ( S.C )30 – 90 min

3 – 4 hr

2 – 3 times / day or more

18

3. Intermediate - acting insulins

e.g. Isophane (NPH) Turbid suspension Injected S.C.(Only) Onset of action 1 - 2 hr Peak serum level 5 - 7 hr Duration of action 13 - 18 hr

Insulin mixtures

75/25 70/30 50/50 ( NPH / Regular )

19

Lente insulin Turbid suspension Mixture of 30% semilente insulin 70% ultralente insulin Injected S.C. (only) Onset of action 1 - 3 hr Peak serum level 4 - 8 hr Duration of action 13 - 20 hr

20

4. Long – acting insulins e.g. Insulin glargine

• Onset of action 2 hr• Absorbed less rapidly than NPH & Lente insulins.• Duration of action - 24 hr

Designed to overcome the deficiencies of intermediate acting insulins

Advantages over intermediate-acting insulins:

More safe than NPH & Lente insulins due to reduced risk of hypoglycemia(esp.nocturnal hypoglycemia).

Clear solution that does not require resuspension before administration.

21

Glargine

ORAL HYPOGLYCAEMIC AGENTS

Sulfonylurea drugs Meglitinide analogues Biguanides α -glucosidase inhibitors. Thiazolidinediones. Dipeptidyl peptidase-4 inhibitors e.g. Sitagliptin, vildagliptin

Classification

Insulin secretagogues

Sulfonylurea drugs Meglitinide analogues D-phenylalanine derivatives

Insulin sensitizers

Biguanides Thiazolidinediones or glitazones

Classification based on MOA

SULFONYLUREAS :

First generation Second generation

Tolbutamide Glipizide Tolazamide Glyburide Acetohexamide (Glibenclamide) Chlorpropamide Glimepiride

MEGLITINIDE ANALOGUES

Rapidly acting insulin secretagogues

Repaglinide (Prandin) Nateglinide (Starlix)

Mechanism of Action

Stimulate insulin release from functioning B cells by modulating K efflux via blocking ATP-sensitive K channels resulting in depolarization and calcium influx.

30

BIGUANIDES

MECHANISM OF ACTION

1. Increase peripheral glucose utilization

2. Inhibits gluconeogenesis

3. Impaired absorption of glucose from the gut

Metformin Phenformin

Thiazolidinediones (Glitazones)• Insulin Sensitizers

• Activation of Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ).

• Do not promote Insulin secretion from β-cells

• Two agents are :

Pioglitazone

Rosiglitazone

Mechanism of Action

α-Glucosidase Inhibitors

• Competitive inhibitor of Intestinal α- Glucosidase .

• Delays carbohydrate absorption .

• Agents are :

- Acarbose

- Miglitol

Acarbose

Acarbose

Acarbose

Mechanism of Action

Incretin Therapy or Dipeptidyl-Peptidase 4 Inhibitors

Glance at Diabetes 2 therapy