Pancreatic Hormones & Antidiabetic Drugs By S. Bohlooli, PhD Pharmacology Department School of Medicine, Ardabil University of Medical Sciences

Pancreatic islet cells and their secretory products Cell Types Approximate Percent of Islet Mass Secretory Products A cell (alpha)20Glucagon, proglucagon B cell (beta)75 Insulin, C-peptide, proinsulin, amylin D cell (delta)3-5Somatostatin F cell (PP cell) 1 < 2Pancreatic polypeptide (PP) 1 Within 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 A 1c,

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. TransporterTissues Glucose K m (mmol/ L) Function GLUT 1 All tissues, especially red cells, brain 1-2 Basal uptake of glucose; transport across the blood- brain barrier GLUT 2 B cells of pancreas; liver, kidney; gut Regulation of insulin release, other aspects of glucose homeostasis GLUT 3 Brain, kidney, placenta, other tissues < 1 Uptake into neurons, other tissues GLUT 4Muscle, adipose  5 Insulin-mediated uptake of glucose GLUT 5Gut, kidney1-2Absorption 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

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