Pancreatic Hormones & Antidiabetic Drugs

ByS. Bohlooli, PhDPharmacology Department

School of Medicine, Ardabil University of Medical Sciences

Pancreatic islet cells and their secretory products

Cell TypesApproximate Percent of Islet

MassSecretory Products

A cell (alpha) 20 Glucagon, proglucagon

B cell (beta) 75 Insulin, C-peptide, proinsulin, amylin

D cell (delta) 3-5 Somatostatin

F cell (PP cell)1 < 2 Pancreatic polypeptide (PP)1Within pancreatic polypeptide-rich lobules of adult islets, located only in

the posterior portion of the head of the human pancreas, glucagon cells are scarce (< 0.5%) and F cells make up as much as 80% of the cells.

Diabeted mellitus Two major type of diabetes mellitus

Type I Type II

Both require careful monitoring of: Diet, fasting, postprandial blood

glucose Hemoglobin A1c,

Insulin Physiology

Proinsulin: 86 amino acid C-peptide: 31 amino acid

Effects Liver Skeletal muscle Adipose tissue

Structure of human proinsulin

One model of control of insulin release from the pancreatic B cell

Glucose transporters.

Transporter TissuesGlucose Km

(mmol/L)

Function

GLUT 1All tissues,

especially red cells, brain

1-2Basal uptake of glucose;

transport across the blood-brain barrier

GLUT 2B cells of pancreas;

liver, kidney; gut

15-20Regulation of insulin release,

other aspects of glucose homeostasis

GLUT 3Brain, kidney,

placenta, other tissues

< 1 Uptake into neurons, other tissues

GLUT 4 Muscle, adipose  5 Insulin-mediated uptake of glucose

GLUT 5 Gut, kidney 1-2 Absorption of fructose

Schematic diagram of the insulin receptor

Insulin promotes synthesis

Endocrine effects of insulin (1)

Effect on liver:      Reversal of catabolic features of insulin deficiency 

    Inhibits glycogenolysis

    Inhibits conversion of fatty acids and amino acids to keto acids

    Inhibits conversion of amino acids to glucose

  Anabolic action 

Promotes glucose storage as glycogen (induces glucokinase and glycogen synthase, inhibits phosphorylase)

Increases triglyceride synthesis and very-low-density lipoprotein formation

Endocrine effects of insulin (2)

Effect on muscle:   

  Increased protein synthesis 

    Increases amino acid transport

    Increases ribosomal protein synthesis

  Increased glycogen synthesis 

    Increases glucose transport

    Induces glycogen synthase and inhibits phosphorylase

Endocrine effects of insulin (3)

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

Insulin preparation Rapid-acting Short-acting Intermediate-acting Long-acting Insulin delivery systems

Extent and duration of action of various types of insulin

Hazards of insulin use Hypoglycemia Insulin induced immunologic

complication

Non Insulin antidiabetic drugs Insulin secretagogues Biguanide metformin Thiazolidinediones Alpha-glucosidase inhibitors

Stimulants of insulin release   

  Glucose, mannose 

  Leucine 

  Vagal stimulation 

  Sulfonylureas 

Amplifiers of glucose-induced insulin release  Enteric hormones: 

    Glucagon-like peptide 1(7-37)

    Gastrin inhibitory peptide

    Cholecystokinin

    Secretin, gastrin

  Neural amplifiers: 

    -Adrenoceptor stimulation  Amino acids: 

    Arginine

Inhibitors of insulin release   

  Neural: -Sympathomimetic effect of catecholamines  Humoral: Somatostatin, amylin 

  Drugs: Diazoxide, phenytoin, vinblastine, colchicine 

Regulation of insulin release

Insulin secretagogues Group drugs:

Sulfunylureas: tolbutamide, chlorpropamide, glyburide, glipizide, glimepride

Mechanism of action Closure of potassium channel

Toxicity Hypoglycemia, allergic reactions Weight gain

Insulin secretagogues: Sulfonylureas

Insulin secretagogues: Sulfonylureas First-Generation Sulfonylureas

Tolbutamide, Chlorpropamide, Tolazamide

Second-Generation Sulfonylureas Glyburide, Glipizide, Glimepiride

Insulin secretagogues: Meglitinides

Biguanides: metformin Mechanism of action

Inhibit gluconeogenesis Induction of glucose uptake in periphery Slowing the absorption of glucose Reduction of glucagon level

Toxicity Gastrointestinal distress Lactic acid in some patiets

Thiazolidinediones Group drugs:

rosiglitazone, pioglitazone Mechanism of action

Increase target tissue sensivity Activating: peroxisome proliferator-

activated receptor-gamma nuclear receptor (PPAR- receptor)

Toxicity Fluid retention, MI, bone fracture Liver enzyme inducers

Thiazolidinediones

Alpha glucosidase inhibitors:acarbose, miglitol Mechanism of action

Inhibit -glucosidase

Toxicity Flatulence, diarrhea, abdominal pain

Alpha glucosidase inhibitors

Miscellaneous Paramlitide Exenatide Sitagliptin