Pancreatic Hormones & Antidiabetic Drugs By S. Bohlooli, PhD Pharmacology Department Faculty of Pharmacy, 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

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 Sulfonylureas, meglitinides, D-phenylalanine derivatives Biguanide metformin Thiazo-lidine-diones Alpha-glucosidase inhibitors Incretin-based therapies An amylin analog bile acid binding sequestrant

Insulin secretagogues: Sulfunylureas 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: Sulfonylureas: Side Effects Hypoglycemia Contraindicated in significant hepatic or renal impairment Sulfonylurea allergy

Insulin secretagogues: Megli-tinides

Insulin Secretagogue: Megli-tinides Mechanism: Regulate potassium efflux through the potassium channels Have two binding sites One in share with sulfonylureas Other is unique Should be taken just before each meal

INSULIN SECRETAGOGUE: D-PHENYLALANINE DERIVATIVE Nate-glinide Acts through closure of the ATP- sensitive K + channel Ingested just before meals

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 acidosis in some patients

Biguanides: Metformin Recommended as first-line therapy Has a half-life of 1.5–3 hours No protein bound No metabolism Excreted by the kidneys

Thiazo-lidine-diones Group drugs: Rosi-glitazone, Pio-glitazone Mechanism of action Increase target tissue sensitivity Activating: peroxisome proliferator-activated receptor-gamma nuclear receptor (PPAR-  receptor) Major site of Tzd action is adipose tissue Toxicity Fluid retention, MI, bone fracture, congestive heart failure Liver enzyme inducers Loss of bone mineral density

Thiazo-lidine-diones

Alpha glucosidase inhibitors: acarbose, miglitol Mechanism of action Inhibit  -glucosidase Delaying the digestion and absorption of starch and disaccharides Toxicity Flatulence, diarrhea, abdominal pain Contraindicated in patients with inflammatory bowel disease

Alpha glucosidase inhibitors

BILE ACID SEQUESTRANTS Cole-seve-lam Decrease in farnesoid X receptor (FXR) activation Interruption of the enterohepatic circulation Impair glucose absorption Side Effects: gastrointestinal complaints

AMYLIN ANALOG Pram-lin-tide Suppresses glucagon release Has anorectic effects Should injected immediately before eating

GLUCAGON-LIKE POLYPEPTIDE-1 (GLP-1) RECEPTOR AGONISTS Exena-tide, Liraglu-tide Increase insulin secretion Suppression of postprandial glucagon release Loss of appetite Slowed gastric emptying Side Effects: Nausea, vomiting and diarrhea Necrotizing and hemorrhagic pancreatitis

DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS Sita-gliptin, saxa-gliptin, and lina-gliptin Increase circulating levels of native GLP-1 Increase glucose-dependent insulinotropic polypeptide (GIP) Adverse effects: Nasopharyngitis, upper respiratory infections Acute pancreatitis