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ANTIDIABETIC DRUGS
RAYMUND N. TAPAOAN, RPH
Glucose Metabolism
Glucose levels in the blood rise after a
meal. This increase stimulates the β-cell s in the islets of Langerhans to secrete i nsulin. Insulin has effects on several tiss ues: liver, adipose tissue, muscle tissue and other body cells. In general insulin s timulates glucose uptake. In the liver an d in muscle tissue insulin also induces g lycogen synthesis. These events result i n a decrease of the blood glucose levels to normal values. In adipose tissue the s ynthesis of triglyceride is stimulated. Regulation of Glucos e Uptake The physiological regulation of glucose uptake is de picted below. After food intake (1) the complex sugar s are broken down in the small intestine into glucose molecules. L-cells in the distal intestinal wall secrete the incretin GLP-1 upon stimulation by food/glucose (2). This glucagon-like peptide-1 is released proportional to the amount of food post-prandial in the distal intes tine. GLP-1 is key player in many processes after a m eal. It stimulates the release of insulin by the β-cells i n the pancreas (3) Similarly, GLP-1 inhibits the release of glucagon by t he α-cells (4). The rise in insulin will stimulate the glucose uptake f rom the blood into the cells (8). Further, GLP-1 inhibits gastric emptying (5) and indu ces the feeling of satiety (6) in order to reduce furthe r carbohydrate intake. GLP-1 is metabolised by the enzyme dipeptidyl pepti dase 4 (DDP-IV) which is present in the cell wall (7). Diabetes Mellitus Diabetes mellitus (DM) It is a meta bolic disorder characterized by hy perglycaemia, glycosuria and keto naemia. Pathophysiology of DM A widespread pathological change is t hickening of capillary basement mem brane, increase in vessel wall matrix and cellular proliferation resulting in v ascular complications like • lumen narrowing, • early atherosclerosis, • sclerosis of glomerular capillaries, • retinopathy, • neuropathy • peripheral vascular insufficiency. Pathophysiology of DM Enhanced glycosylation of tissue pro teins due to persistent exposure to hi gh glucose concentrations and the a ccumulation of larger quantities of so rbitol (a reduced product of glucose) in tissues are believed to be causativ e in the pathological changes of diab etes. Risk Factors of DM Blood Sugar Level Chart DM Type 1 (IDDM-Insulin-dependent diabetes mellitus In diabetes mellitus type I, there is an absol ute shortage of insulin resulting from autoi mmune destruction of pancreatic β-cells. Due to this insulin deficiency, the mechanis ms that decrease glucose levels in the bloo d do not work. As a result, dangerously high blood glucos e levels occur, whereas glucose levels in c ells are low. Because DM type I patients cannot even pr oduce modest amounts of insulin, dangero us ketone bodies are formed by fat breakd own and ketoacidosis can occur. Symptoms of diabetic patients are polyuria, dehydration, fatigue, muscle weakness and coma. Insulin Insulin, used for the treatment of diabetes is produ ced by recombinant DNA techniques. Insulin affect s glucose-, fat-, and protein metabolism. It binds to a tyrosine kinase receptor at the cell sur face. Activation of the receptor is the beginning of a cascade of phosphorylations of enzymes in the cytoplasm, eventually resulting in changes in cellul ar processes. Insulin stimulates the transport of vesicles containi ng glucose transporters towards the cell membran e. At the level of carbohydrate metabolism, insulin stimulates uptake of glucose in muscle and adipos e tissue. In the liver, insulin inhibits glucose production by i nhibiting glycolysis and gluconeogenesis and by st imulating glycogen synthesis. In adipose tissue, in sulin stimulates triglyceride formation and inhibits r elease of fatty acids. Protein synthesis is induced by insulin. Insulin Insulins with different durations of action are us ed to treat diabetes: short-acting insulin (4-6 hours, in blue): normal i nsulin Actrapid® short-acting insulin analogues (4-6 hours, in blu e): aspart (Novorapid®) and lispro (Humalog®) long-acting insulin (14-28 hours, in purple): glar gin (Lantus®) and detemir (Levemir®) Normal insulin and glucose levels and administ ered insulin levels are compared in the graphs below. Patients must control their own sharp setting of insulin administration. Short-acting insulin needs to be injected 2-3 tim es a day just prior to a meal. In addition, 1-2 inj ections a day with long-acting insulin are neces sary. The arrows represent the injections with short-acting insulin (blue) during the day and the injection with long-a cting insulin (purple) in the evening.ti ons a day with long-acting insulin are necessary. DM Type 2 (NIDDM Noninsulin-dependent diabetes mellitus) Type II diabetes mellitus is caused by a mi sbalance between β-cell function and insul in resistance (1). Insulin levels can be normal or elevated. T ype II patients develop hyperglycemia, be cause insulin secretion does not fully com pensate for insulin resistance (2). They do not show ketoacidosis, because t hey secrete enough insulin to prevent the conversion of fatty acids to ketoacids. Tre atment consists of weight loss and caloric restriction. Usually this does not help appropriately a nd drugs have to be used to decrease glu cose uptake, increase insulin secretion an d to decrease insulin resistance. Pathophysiology of Glucose Uptake In DM type II patients, the physiology by the GLP-1 regulation is clearly disturbed, as sho wn in the graphic below. These patients mos tly have a larger food intake (1). The postprandial incretin GLP-1 response is diminished (2). The insufficient GLP-1 concentration in the blood has several unwanted effects: the β-c ells in the pancreas release less insulin (3), the glucagon release by the α-cells is less in hibited (4), the gastric emptying is not delayed (5), the appetite remains (6) and the dipeptidyl peptidase 4 (DPP-IV) enz yme is overactivated (7). All these events re sults in postprandial hyperglycemia (8). Sulphonylureas Sulphonylurea derivatives enhance the secr etion of insulin from pancreatic tissue (β-cel ls). These drugs can block ATP-dependent pot assium channels in the cell membrane of β- cells. The block of the potassium efflux cau ses a depolarization of the membrane pote ntial, resulting in an influx of calcium ions. The increase of calcium in the cytoplasm e nhances the secretion of insulin. The short-acting tolbutamide, gliclazide, an d glimepiride are the most prominent sulph onylureas. The long-acting glibenclamide is not used very often, because it increases the risk of hypoglycemia. Biguanides The exact mechanism of action of big uanides is not known. It is thought tha t biguanides inhibit the production an d release of glucose by the liver and t hat they increase the sensitivity for in sulin in peripheral tissues. Metformin is the main representant of this group of drugs. The recommended dose for metformi n is 500 mg 3 times a day. Thiazolidinediones Thiazolidinediones are a new group of drug s that improve insulin sensitivity. The precis e mechanism of action is not known. Thiazolidinediones bind to peroxisome proli ferator-activated receptors in the nucleus (PPARs), specifically PPARγ. In that way, thiazolidinediones alter transcri ption of certain genes. They are most effect ive in adipose tissue, muscle tissue and the liver. Rosiglitazon and pioglitazon belong to this group of drugs. When metformin or sulphonylderivatives ar e not effective, addition of thiazolidinedione s to these drugs might obtain better effectiv ity. Insulinoma induced hypoglyc emia Hypoglycemia can occur as a result of i nappropriate insulin use by diabetics. In addition, insulinoma creates a pathol ogical condition of inappropriately high insulin levels and decreased glucose le vels. Hypoglycemia causes nervousness, ta chycardia, tremor, sweating, paleness and ultimately coma. The ultimate treatment of insulinoma is surgical resection. For acute treatment of insulin-induced hypoglycemia, glucagon can be used. Glucagon Glucagon increases plasma glucose le vels by stimulation of glycogenolysis in the liver. After binding to a G-protein co upled receptor, the second messenger cAMP stimulates enzymes of glycogen olysis. The glucose is released by the li ver and glucose blood levels rise. Glucagon is indicated in cases of sever e hypoglycemia after the use of blood glucose lowering drugs. One (1) mg of glucagon should be injected intramusc ularly or intravenously. When the patient is conscious again, h e/she should take carbohydrate rich fo od. THANK YOU RNTER TEXT