pancreatic hormones & antidiabetic drugs by s. bohlooli, phd pharmacology department school of...
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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,TRANSCRIPT
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