Anti-diabetic Agents

DR.JAHID Head of Pharmacology MD-AUCMS

The Endocrine Pancreas 1 million islets of Langerhans

The islets are endocrine tissue containing four types of cells. In order of abundance, they are: alpha cells (20 %), which secrete glucagon; beta cells (75 %), which secrete insulin and amylin; delta cells (3-5 %), which secrete somatostatin Gamma cell (1%), which secrete gastrin F cells (1%), which secrete gastrin & polypeptide.

Diabetes Mellitus
Incidence: 171 M worldwide (WHO 2006) Malaysia would have a total number of 2.48 million diabetics compared to 0.94 million in 2000 - a 164% increase.

Greatest prevalence: Asia & Africa

Top 5 of the most significant diseases in developed world ADA: 18.3% (8.6M) of Americans age 60

Diabetes Mellitus
Diabetes mellitus is defined as an elevated blood glucose associated with absent or inadequate pancreatic insulin secretion, with or without concurrent impairment of insulin action.

Diabetes Mellitus
Type 1 Diabetes - cells that produce insulin are destroyed - results in insulin dependence - commonly detected before 30 Type 2 Diabetes - blood glucose levels rise due to 1) Lack of insulin secretion 2) Insufficient insulin action (resistant cells) - commonly detected after 40 - eventually leads to -cell failure (resulting in insulin dependence) Type 3 Diabetes -Refers to multiple other specific causes of an elevated blood glucose Type 4 Diabetes (Gestational Diabetes) 3-5% of pregnant women in the US develop gestational diabetes

Table 24-8. Type 1 Versus Type 2 Diabetes Mellitus (DM) Type 2 DM Clinical Onset: >30 years Obese Increased blood insulin (early);normal to moderate decreased insulin (late) Anti-islet cell antibodies No anti-islet cell antibodies Ketoacidosis common Ketoacidosis rare; nonketotic hyperosmolar coma Genetics 30-70% concordance in twins 50-90% concordance in twins Linkage to MHC Class II HLA No HLA linkage genes Linkage to candidate diabetogenic genes (PPAR, calpain 10) Pathogenesis Autoimmune destruction of - Insulin resistance in cells mediated by T cells and skeletal muscle, adipose humoral mediators (TNF, IL-1, tissue and liver NO) -cell dysfunction and relative insulin deficiency Absolute insulin deficiency Islet cells Insulitis early No insulitis Marked atrophy and fibrosis Focal atrophy and amyloid deposition -cell depletion Mild -cell depletion Type 1 DM Onset: <20 years Normal weight Markedly decreased blood insulin

Diabetes Insulin
(synthesis, storage, secretion) Chemistry: a small protein with molecular weight of 5808 contains 51 amino acids arranged in 2 chains ( A & B ) linked by disulfide bonds/bridges

stored crystals consisting of 2 atoms of zinc & 6 molecules of insulin

contain 8mg of insulin/human pancreas (=200 units)

Diabetes Insulin
(synthesis, storage, secretion)

Proinsulin, a long single-chain protein molecule, it is hydrolyzed into insulin and a residual connecting segment called C-peptide

Diabetes Insulin
(synthesis, storage, secretion)
Insulin is a small protein consisting of an A chain of 21 amino acids linked by two disulfide (SS) bridges to a B chain of 30 amino acids.

Beta cells have channels in their plasma membrane that serve as glucose detectors. Beta cells secrete insulin in response to a rising level of circulating glucose.

Diabetes Insulin
(synthesis, storage, secretion) Glucose upon entering the cells of the pancreas liberates ATP. This ATP blocks the ATP sensitive K+ channel.

So the cell becomes depolarized. Now Ca++ enters through the Ca++ channels. Ca++ binds with the insulin containing granules

Insulin is secreted from the cells by exocytosis.

Diabetes Insulin
(synthesis, storage, secretion)

Regulation of Insulin Release Stimulants of insulin release Glucose, mannose Leucine, arginine Vagal stimulation Sulfonylureas Glucagon-like peptide Gastrin inhibitory peptide Cholecystokinin Secretin, gastrin Inhibitors of insulin release Neural: alpha sympathetic effect of cathecolamines Humoral: somatostatin, amylin, leptin Drugs: diazoxide, phenytoin, vinblastine, colchicine

Diabetes Insulin
Insulin Degradation: - 2 main organs: liver 60%

kidney 35-40% - hydrolysis of the disulfide bonds glutathione insulin transhydrogenase (insulinase )

- half-life: 3-5 minutes

Measurement of Circulating Insulin: - radioimmunoassay permits detection of insulin in picomolar quantities. - basal insulin values: 5-15uU/ml (30-90pmol/L) - peak rise: 60-90uU/ml (360-540pmol/L)

Diabetes - Insulin Receptor

insulin receptors have two units and The unit remains in the outer surface of the cell membrane and the unit crosses the entire length of the membrane and enters cytosol. Insulin combines with the unit and tyrosin kinase enzyme is secreted from the unit. Phosphorylated tyrosin kinase enzyme causes phosphorylation of insulin receptor substrate (IRS) . insulin receptor substrate (IRS) activate other kinasesmost significantly phosphatidylinositol-3-kinase & mitogenactivated protein kinase (MAPK) system.

Resulting increased glycogen formation, activation of transcription factors that enhance DNA synthesis and cell growth and division.

Effects of Insulin on its Targets Transporte rs GLUT 1 Tissues GlucoseK m (Mmo/L) 1-2 Function

All tissues, esp.red cells, brain

GLUT 2

B cells of pancreas; Liver; kidney; gut

Brain, kidney, placenta, other tissues Muscle, adipose

15-20

Basal uptake of glucose; Transport across the BBB Regulation of insulin release, other aspects of glucose homeostasis Uptake into neurons, other tissues Insulin-mediated uptake of glucose Absorption of fructose

GLUT 3

< 1

GLUT 4

GLUT 5

Gut, kidney

1-2

Effect on liver
Inhibits glycogenolysis Inhibits conversion of fatty acids and amino acids to keto acids Inhibits conversion of amino acids to glucose Promotes glucose storage as glycogen (induces glucokinase and glycogen synthase, inhibits phosphorylase) Increases triglyceride synthesis and very-low-density lipoprotein formation

Effect on muscle
Increased protein synthesis Increases amino acid transport Increases ribosomal protein synthesis Increased glycogen synthesis Increases glucose transport nduces glycogen synthase and inhibits phosphorylase

Effect on adipose tissue

Increased triglyceride storage Lipoprotein lipase is induced and activated by insulin to hydrolyze triglycerides from lipoproteins Glucose transport into cell provides glycerol phosphate to permit esterification of fatty acids supplied by lipoprotein transport Intracellular lipase is inhibited by insulin

Principal Types and Duration of Action

1. Rapid-acting insulins:
- Dispensed as clear solutions at neutral pH - Contain small amount of zinc to improve stability & shelf-life - Preferred for use in continuous SC infusion devices
Insulin lispro, Insulin aspart, insulin glulysine,

- Available in powder form for alveolar absorption

human insulin recombinant inhaled

Principal Types and Duration of Action

Pharmacokinetics:
Rapid-acting insulin Insulin lispro Insulin aspart Insulin glulysine Onset Peak Duration

5-15 min 5-15 min 5-15 min

1 hr 1 hr 1hr

3-5 hrs 3-5 hrs 3-5 hrs

HIRI

10-20 min

2 hrs

6-7 hrs

Principal Types and Duration of Action

2. Short-acting insulin Regular insulin
A soluble crystalline zinc Made by recombinant DNA techniques Onset: 30 minutes Peak: 2-3 hours Duration: 5-8 hours Administered intravenously Useful in diabetic ketoacidosis, surgery or during acute infection, and when the insulin requirement is changing rapidly

Principal Types and Duration of Action

3. Intermediate-acting & Long-acting insulins
a. LENTE INSULIN (insulin zinc suspension)
mixture of 30% semilente with 70% ultralente insulin provide a combination of relatively rapid absorption with sustained long action

b. NEUTRAL PROTAMINE HAGEDORN or Isophane Insulin

absorption & onset of action is delayed by combining appropriate amounts of insulin & protamine 6 molecules of insulin per molecule of protamine

Principal Types and Duration of Action

c. INSULIN GLARGINE soluble, peakless, ultra-long-acting insulin analog designed to provide reproducible, convenient, background insulin replacement Onset: 1-1.5 hours maximum effect: 4-5 hours Duration: 11-24 hours or longer given once a day

Principal Types and Duration of Action

d. INSULIN DETEMIR Injected SC Binds to albumin via its fatty acid chain Administered b.i.d. Onset: 1-2 hours Duration: > 24 hours

Species of Insulin
Beef and pork insulin
The beef insulin differs by 3 amino acids, pork differs by 1 amino acid The beef hormone is most antigenic

Human insulin
Less expensive, less immunogenic Production by recombinant DNA techniques

 Purity of Insulin
chromatography

Concentrations:
100 units 500 units

Insulin Delivery Systems

A. Portable Pen Injectors
- to facilitate multiple SQ injections

B. Continuous Subcutaneous Insulin Infusion Devices (CSII, Insulin Pumps)

- encouraged for individuals who are unable to obtain target control while on multiple injection regimens & where excellent glycemic control is desired, such as during pregnancy - velosulin (reg. insulin) & insulin aspart and lispro

C. Inhaled Insulin
- have a rapid route and a relatively short duration of action - used to cover mealtime insulin requirements - to correct high glucose levels

Factors that Affect Insulin Absorption:

site of injection: abdomen, buttock, anterior thigh, or dorsal arm type of insulin

subcutaneous blood flow: massage, hot baths, or exercise

smoking

regional muscular activity at the site of the injection

volume & concentration of injected insulin

depth of injection

Complications of Insulin Therapy

A. Hypoglycemia
Mechanisms and diagnosis
result from a delay in taking a meal unusual physical exertion dosage error

CM: tachycardia, palpitations, sweating, tremulousness, hunger, nausea, convulsion, coma Treatment: glucose administration Glucagons 1 mg SQ or IM Honey or syrup

Complications of Insulin Therapy

B. Immunopathology of Insulin Therapy
1. Insulin allergy

an immediate type of hypersensitivity (IgE-antibodies) Tx: antihistamines, corticosteroids & desensitization

2.

Immune insulin resistance (IgG antibodies) + circulating antibodies that neutralize the action of insulin to a small extent Tx: switching to a lesser antigenic purified insulin

C. Lipodystrophy at injection sites

corrected by avoidance of that specific injection site or with liposuction hypertrophy

 Clinical Features of DM Polyuria Polydipsia Polyphagia Weight loss

DECREASED INSULIN SECRETION

INSULIN RESISTANCE
(*Receptor & post receptor defects *Impaired glucose utilisation)

INCREASED HEPATIC GLUCOSE SYNTHESIS

CONSTITUTIONAL FACTORS
*obesity *hypertension *low physical activity

TYPE 2 DIABETES MELLITUS

Pathophysiology of Type 2 Diabetes

Insulin resistance. Beta cell dysfunction.

Pathophysiology of Type 2 Diabetes

Insulin Resistance
Insulin Resistance starts very early in the course of the disease. insulin resistance alone will not produce diabetes. If beta-cell function is normal, one can compensate for insulin resistance by increasing insulin secretion.

Pathophysiology of Type 2 Diabetes

Beta cell defect

all type 2 patients have at least a relative defect in both beta-cell function and mass. Function: in the (UKPDS), newly diagnosed people with diabetes had, on average, only about 50% of normal beta-cell function. [Diabetes. 1995;44:1249-1258 , Diab Res
Clin Pract. 1998;40(suppl):S21-S25.]

Mass: Autopsy studies comparing the volume of beta cells in non-diabetic individuals with that of people with diabetes found a 41% decrease in beta-cell mass among people with type 2 diabetes

Pathophysiology of Type 2 Diabetes

Other Factors
Two other factors: - Glucagon. - Gastric emptying.

Pathophysiology of Type 2 Diabetes

The Glucagon Factor

In response to a carbohydrate-containing meal, individuals without diabetes not only increase insulin secretion but also simultaneously decrease pancreatic alpha-cell glucagon secretion.
The decrease in glucagon is associated with a decrease in hepatic glucose production, and along with the insulin response, results in a very modest increase in postprandial glucose. N Engl J Med. 1971;285:443-449.

Pathophysiology of Type 2 Diabetes

The Glucagon Factor

In contrast, the glucagon secretion in type 2 diabetics is not decreased, and may even be paradoxically increased. These insulin and glucagon abnormalities produce an excessive postprandial glucose excursion. more than 35 years ago, Roger Unger presciently stated, "One wonders if the development of a pharmacologic means of suppressing glucagon to appropriate levels would increase the effectiveness of available treatments for diabetes.
N Engl J Med. 1971;285:443-449.

Pathophysiology of Type 2 Diabetes

The Gastric Emptying Factor

Many factors can affect the rate of gastric emptying.
studies suggest that all other factors being equal, most people with type 1 and type 2 diabetes have accelerated gastric emptying compared to those without diabetes.Gastroenterology. 1990;98:A378.

Oral Anti-diabetic Agents

4 Categories:
a. Insulin secretagogues (sulfonylureas, meglitinides, D-phenylalanine derivatives)

b.
c.

Biguanides
Meglitinide analogs

c.
d.

Thiazolidinediones
Alpha-glucosidase inhibitors

Insulin Secretagogues: Sulfonylureas are in

A. Sulfonylureas Mechanism of Action: increase insulin release from
sulin secretagogues , triggering insulin release by direct action on the KATP channel of the pancreatic B cells pancreatic beta cells

Sulfonylureas bind to S receptor inhibits efflux of K+ depolarization opens a voltage-gated Ca++ channel results in Ca++ influx and the release of preformed insulin reduction of serum glucagon concentrations

Chronic administration of sulfonylureas to type 2 diabetics reduces serum glucagon levels potentiation of insulin action on target tissues

Insulin Secretagogues:
Chlorpropamide: duration of action: up to 60 hours half-life: 32 hours slowly metabolized in the liver 20-30% is excreted unchanged in the urine SE: hypoglycemia, hyperemic flush, dilutional hyponatremia, transient leukopenia, thrombocytopenia, jaundice CI: hepatic & renal insufficiency Dosage: 250mg daily

Insulin Secretagogues:
Sulfonylureas: 1st generation tolbutamide tolazamide chlorpropamide acetohexamide 2nd generation glipizide glyburide 3rd generation glimepiride

Insulin Secretagogues:
Tolbutamide:
well absorbed but rapidly metabolized in the liver duration of action: 6-12 hours elimination half-life: 4-5 hours toxic reactions: skin rash hypoglycemia drug interactions: dicumarol, phenylbutazone, sulfonamides

Insulin Secretagogues:
Tolazamide:
duration of action: 10-14 hours more slowly absorbed half-life: 7 hours SE: hypoglycemia

Insulin Secretagogues:
Glipizide:
has the shortest half-life: 2-4 hours duration of action: 10-24 hours 90% is metabolized in the liver 10% excreted unchanged in the urine SE: hypoglycemia

Contraindication: renal & hepatic insufficiency

Dosage: 5-20mg as a single dose, 30 minutes before breakfast

Insulin Secretagogues:
Glyburide:
metabolized in the liver
short plasma half-life

duration of action: 10-24 hours

SE: flushing, hypoglycemia

Contraindication: hepatic & renal insufficiency

Dosage: 5-10mg as single morning dose

Insulin Secretagogues:
B. Meglitinides
Repaglinide:
hepatically cleared by CYP3A4 half-life: 1 hour indication: controlling postprandial glucose excursions Dosage: 0.25-4 mg SE: hypoglycemia Caution: hepatic & renal impairment

Insulin Secretagogues:
B. Meglitinides
Repaglinide:
N NH O O O OH

modulate B cell insulin release by regulating K+ efflux through the K+ channels

2-Ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid

no direct effect on insulin exocytosis peak concentration & peak effect: within 1 hour fast onset & duration of action (5-8 hrs.)

Biguanides
Mechanisms of action:
direct stimulation of glycolysis in tissues, with increased glucose removal from blood
reduced hepatic & renal gluconeogenesis

slowing of glucose absorption from the GIT, with increased glucose to lactate conversion by enterocytes Its a euglycaemic agent reduction of plasma glucagon levels

Euglycemia describes a normal level of glucose in the blood.

Biguanides
Metabolism & Excretion: Metformin:
half-life: 1.5-3 hours duration of action: 10-12 hours not bound to plasma proteins not metabolized excreted by the kidneys as active compound may impair the hepatic metabolism of lactic acid
H N H + N H N H H N N

HCl

Biguanides
Clinical Uses: refractory obesity whose BS is due to ineffective insulin action (insulin resistance syndrome) - only anti-diabetic drug that has been proven to
reduce the complications of diabetes, as evidenced in a large study of overweight patients with diabetes (UKPDS 1998).

use as in combination with sulfonylureas or thiazolidinediones in type 2 diabetics in whom oral monotherapy is inadequate dosage: 500mg TID

Biguanides
Toxic Effects: anorexia, nausea, vomiting, abdominal discomfort, diarrhea absorption of B12 appears to be reduced during long-term therapy

Biguanides
Contraindications: renal disease, alcoholism hepatic disease chronic cardiopulmonary dysfunction

Thiazolidinediones
Increase the sensitivity of muscle, fat & liver to endogenous & exogenous insulin (insulin sensitizers) Binds to and activates the gamma isoform of the peroxisome proliferator-activated receptor (PPAR) (PPAR is a member of the
steroid hormone nuclear receptor superfamily, and is found in adipose tissue, cardiac and skeletal muscle, liver and placenta)

Major site of action: adipose tissue promotes glucose uptake and utilization and modulate synthesis of lipid hormones or cytokines and other proteins involved in energy regulation
Considered euglycemics Have a slow onset and offset of activity

Thiazolidinediones
Side Effects:
Hypoglycemia in combination Drop in triglyceride levels

Slight rise in HDL & LDL cholesterol values

Edema fluid retention

Anemia
Dose-related weight gain (1-3 kg)

Thiazolidinediones CI:
pregnancy Significant liver disease Heart failure

Alpha-Glucosidase Inhibitors
are competitive inhibitors of the intestinal alphaglucosidases and reduce the postprandial digestion and absorption of starch and disaccharides--> lowering post-meal glycemic excursion (45-60mg/dl) and creating an insulin-sparing effect.
members: acarbose

miglitol
H

H O O N

H 1-(2-Hydroxy-ethyl)-2-hydroxymethylpiperidine-3,4,5-triol

Alpha-Glucosidase Inhibitors
taken in doses of 25-100 mg just prior to ingesting the first portion of each meal both are absorbed from the gut SE: flatulence, Diarrhea, Abdominal pain CI: Chronic or inflammatory bowel disease, Renal impairment, Hepatic disease (acarbose)

Newer Agent
Pramlintide
Synthetic analog of amylin Suppresses glucagon release, delays gastric emptying & has CNS-mediated anorectic effects An injectable antihyperglycemic, administered in addition to insulin Rapidly absorbed after SC administration, before eating

Newer Agent
Pramlintide
Peak level: 20 minutes Duration: not more than 150 minutes

Metabolized & excreted renally

Modulates postprandial glucose levels in type 1 & 2 DM SE: hypoglycemia, N/V, & anorexia

THANK YOU

 Mafauzy M. Diabetes mellitus in Malaysia. Med J Malaysia. 2006 Oct;61(4):397-8. Katzung B.G. Basic and clinical Pharmacology. Mcgrawhill tata, 11th edition.