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Diabetes mellitus type 2(biochemistry)

  2. WHAT IS DIABETES MELLITUS ? • Diabetes mellitus is a chronic disease characterized by derangement in carbohydrates, fat and protein metabolism
  3. DIABETES TYPE-2 Type 2 diabetes mellitus comprises an array of dysfunctions resulting from: 1. the combination of resistance to insulin action 2. inadequate insulin secretion.  It is disorders are characterized by hyperglycemia and associated with microvascular (ie, retinal, renal, possibly neuropathic), macrovascular (ie, coronary, peripheral vascular), and neuropathic (ie, autonomic, peripheral) complications.
  4. COMPONENTS OF DM-II Type 2 diabetes Insulin resistance -cell dysfunction
  5. METABOLICABNORMALITIES IN DM-II Obesity Insulin resistance Abnormal insulin secretion Excess glucose production Beta-cell failure
  6. INSULIN RESISTANCE-IR • Insulin resistance is a condition in which the body produces insulin but does not use it properly.
  7. CAUSES OF IR The circulating free fatty acids associated with obesity also responsible for insulin resistance of the muscle and liver.
  8. WHATDOES IR DOES TO OUR BODY METABOLISM? • Decreased glucose uptake by skeletal muscle and adipose tissue. • Increased glucose output by Liver- Gluconeogenesis. • In the early stages of obesity the pancreas compensates for the IR by overproducing insulin so that glucose homeostasis is maintained. • This leads to HYPERGLYCEMIA & HYPER INSULINEMIA
  9. BETA CELL -DYSFUNCTION Chronic hyperglycemia Glucotoxicity2 Lipotoxicity3 Oversecretion of insulin to compensate for insulin resistance1,2 -cell dysfunction
  10. Beta –cell failure • The elevated levels of free fatty acids and or cytokines lead to gradual loss of the ability of the pancreas to overproduce insulin , a process called decompensation-Lipotoxity • Glucose, the main regulator of insulin secretion and production, exerts negative effects on beta-cell function when present in excessive amounts over a prolonged period- glucotoxicity.
  11. INSULINRESISTANCE & BETACELL-DYSFUNCTION IR Insulin resistance Liver Muscle Adipose tissue  Glucose output  Glucose uptake  Glucose uptake Hyperglycemia
  12. KETOACIDOSIS • It rarely develops in DM-II • Insulin present in DM-II is enough to prevent uncontrollable release of fatty acids from adipocytes and fattyacids reaching the liver or synthesized de novo are directed to triacyglycerol.
  13. KETOACIDOSIS  If it is develops: Insulin Deficiency Increased Glycogenolysis Increased Gluconeogenesis Increased Hepatic glucose output Decreased Peripheral glucose uptake Elevates blood glucose Increased Lipolysis Increased Release of FFA in liver Increased VLDL & ketones Ketonemia and hyperTG Acidosis & Diuresis
  14. HYPERTRIACYLGLYCEROLEMIA It is a characteristics of DM-II Results from an increase in VLDL without hyperchylomicronemia. This happens by hepatic synthesis of fatty acids and diversion of free fatty acids reaching the liver in to triacylglycerol and VLDL.
  15. Hepatic Insulin Resistance Leads to Hypertriglyceridaemia Normal Normal TG Type 2 diabetes High TG Low HDL cholesterol Small dense LDL (diabetic dyslipidaemia) Normal insulin level Impaired insulin action to inhibit VLDL production Increased liver fat Insulin deficiency exacerbates hypertriglyceridaemia
  16. COMPLICATIONS OF DM 2 • Chronic complications –  Microvascular- retinopathy, nephropathy, neuropathy.  Macrovascular - cardiovascular, cerebrovascular, peripheral vascular diseases.  Acute complications – diabetic ketoacidosis, hyperosmalor coma.
  17. POLYOL FORMATION AND RETINOPATHY • Hyperglycaemia in insulin independent tissues (nerve, lens, retina) gives rise to polyol formation. • The enzyme aldose reductase catalyses the reduction of glucose to sorbitol, which is converted to fructose. • Sorbitol does not easily easily cross cell membranes and its accumulation may cause damage by osmotic effect (e.g. in the lens). • Sorbitol trapped in retinal cells, the cells of the lens, and the Schwann cells that myelinate peripheral nerves can damage these cells, leading to retinopathy, cataracts and peripheral neuropathy.
  18. TREATMENT OF DM-II Carbohydrate (I)-Insulin Carbohydrate Acarbose Reduces absorption Sulphonylurea Repaglinide Stimulates pancreas Metformin Reduces hepatic glucose output (??muscle/fat effects) Thiazolidinediones Reduce Insulin Resistance