1. PATHOPHYSIOLOGY OF DIABETES MELLITUS By Prarit Arora By Prarit Arora

2. Introduction ► tes Mellitus is a metabolic disorder characterized by persistent hyperglycemia (high blood sugar level). ► Diabetes Mellitus is a metabolic disorder characterized by persistent hyperglycemia (high blood sugar level). ► Resulting either from inadequate secretion of hormone insulin, an inadequate response of target cell to insulin or combination of these factors. ► Glucose level in the blood is controlled by several hormone. ► Insulin is the major hormone which controls the level of glucose in blood. ► Insulin is secreted by beta-cells of Islet of langerhans of pancreas. ► tes Mellitus is a metabolic disorder characterized by persistent hyperglycemia (high blood sugar level). ► Diabetes Mellitus is a metabolic disorder characterized by persistent hyperglycemia (high blood sugar level). ► Resulting either from inadequate secretion of hormone insulin, an inadequate response of target cell to insulin or combination of these factors. ► Glucose level in the blood is controlled by several hormone. ► Insulin is the major hormone which controls the level of glucose in blood. ► Insulin is secreted by beta-cells of Islet of langerhans of pancreas.

3. A PATHWAY OF NORMAL INSULIN SYNTHESIS

4. Diagnostic values for Diabetes Mellitus and other categories of hyperglycaemia. Venous plasma glucose mmol/Lmg/dL Diabetes Mellitus≥7.0≥126 fasting or 2hr -post 75g glucose level.≥11.01≥200 IGT (Impaired Glucose Regulation) fasting (if measured)<70<126 2hr. Post 75g glucdose load. ≥7.8 &<11.0≥140 &<200 IFG (Impaired Fasting Glucose) fasting& (if measured )≥5.6 & <7.0≥100 & <126 2hr-post 75g glucose load.<7.8<140

5. DIAGONISTIC TESTS,Cont’d Test for: Tests/Goals: Frequency (or more often if needed to achieve goals): Glycemic control (short-term) Preprandial PG*: 90–130 mg/dL Peak postprandial PG*: <180 mg/Dl3 or more times daily for patients. Glycemic control (long-term) Glycosylated hemoglobin A1C: <7.0% Every 3 months if not meeting glycemic goals otherwise every 6 months. Gum disease Dental examEvery 6 months Hypertension Blood pressure: <130/80 mmHgEvery 3-6 months and at every routine visit Albuminuria/Nephp athyUrinalysis for protein, albuminEvery 12 months Hyperlipidemia LDL: 40 mg/dL ( ♂ ), >50 mg/dL ( ♀ )Every 12 months Peripheral neuropathyNeurological examEvery 12 months Foot disordersThorough foot examEvery 12 months RetinopathyDilated retinal eye examEvery 12 months

6. Diabetes Mellitus is of three types: TYPE-1 –IDDM (Insulin Dependent Diabetes Mellitus) TYPE-2 –NIDDM (Non-Insulin Dependent Diabetes Mellitus) TYPE-3 –Gestational Diabetes

7. TYPE-1 –IDDM ► It is characterized by loss of the insulin producing beta-cells of islet of langerhans of the pancreas. ► Sensitivity and responsiveness to insulin are usually normal. ► This type of Diabetes Mellitus comprises up to 10%. ► Type-1 IDDM can affect childrens or adults. ► Common causes: ► Loss of beta-cells leading to Type-1 IDDM is autoimmune destruction or by antibodies directed against insulin and Islet proteins.

8. TYPE-2 - NIDDM ► Type-2-NIDDM is due to combination of defective insulin secretion and defective responsiveness to insulin or reduced insulin sensitivity. ► It is quite common ; comprising 90% or more of cases in many population.

9. TYPE-3 GESTATIONAL DIABETES ► secretion and responsiveness. ► It involves combination of inadequate insulin secretion and responsiveness. ► It develops during pregnancy and improve or disappear after delivery. ► Individuals at higher risk for Gestational Diabetes include : I. Obese woman. II. Those with previous history of glucose intolerance. III. Any pregnant woman who has elevated fasting, or casual, blood glucose level. IV. Those with a history of gestational diabetes mellitus. V. Those with a history of large for gestational –age-babies. VI. Strong family history of diabetes mellitus.

10. OTHER SPECIFIC TYPES OF DIABETES Genetic defects of β-cell function Chromosome 20,HNF-4α. Chromosome 20,HNF-4α. Chromosome 7,Glucokinase. Chromosome 7,Glucokinase. Chromosome 12,HNF-1 α. Chromosome 12,HNF-1 α. Chromosome 13, Chromosome 13, Chromosome 13, IPF-1. Mitochondrial DNA 3243 mutation Others ► ► Genetic defects in insulin action Type A insulin resistance Leprechaunism Others Rabson-Mendenhall syndrome Lipoatrophic diabetes ► Endocrinopathies Cushing's syndrome Acromegaly Phaeochromocytoma Glucagonoma Hyperthyroidism Somatostatinoma Others ► Diseases of the exocrine pancreas Fibrocalculous pancreatopathy Pancreatitis Trauma / pancreatectomy Neoplasia Cystic fibrosis Haemochromatosis Others

11. PATHOGENESIS OF TYPE-1-IDDM ► Three main factors are involved:- a) Genetic b) Environmental c) Auto-Immunity

12. Discussion of TYPE-1 IDDM ► Genetic Factors : i. It accounts for about 1/3 rd of the susceptibility. ii. In a genetic susceptibility person ; there is a development of Auto-antigen receptors lead to destruction of beta-cells. iii. Susceptibility gene on HLA region in Chromosome-6. iv. It concordance with identical twins 50%. Environmental Factors : Environmental Factors : i. Such as viruses ; are mainly involved. ii. Geographical and seasonal variations are also occurred. iii. The environmental factors changes structure features with beta-cell and leads to destruction of beta-cell. Auto-Immunity Factors : Auto-Immunity Factors : i. Type-1 IDDM is a slow T-cell mediated Auto-immune disease. ii. Destruction of the insulin secretion cell in the pancreatic islets takes place over many years. iii. The pathological changes in the pre-diabetic pancreas in Type-1 IDDM is characterized by Insulinitis. iv. It is the infiltration of Islet with mono-nuclear cells containing activated macrophages,helper cytotoxic T-lymphocytes, Natural Killer cells, B- lymphocytes.

13. Characteristics of Type 1 Diabetes ► ► Diabetes-Hypoinsulinemia ( ↓ insulin levels) ► ► 10% of Diabetic cases ► ► Patient require Insulin ► ► Age of Onset – Childhood ► ► Ketoacidosis –( ↑ ketones in blood)

14. PATHOGENESIS OF TYPE -2 NIDDM ► It is more common than Type-1 IDDM. ► There is no evidence of immune activation ► It results mainly due to two defects -: I. Insulin resistance. II. Pancreatic beta-cell failure.

15. DISCUSSION OF TYPE-2 NIDDM ► Insulin resistance : Increased hepatic production of glucose and resistance to action of insulin. Insulin resistance may be any one of three general causes :- Out of these three; target tissue defect is the most common cause of Insulin resistance is Type-2 –NIDDM. Pancreatic beta-cell failure :- Pancreatic beta-cell failure :- I. There is only moderate reduction in the total mass of pancreatic Islet tissues. II. Which inconsistent with a measurable fall in plasma insulin concentration. III. When related to blood glucose level; beta-cell number is reduced and glucagon secretion is increased which may contribute to hyperglycemia and caused Type-2-NIDDM. IV. Possible mechanism for beta-cell decomposition include genotoxicity, Intrinsic failure of Insulin production and degranulation of beta-cells.

16. TYPE-2 NIDDM

17. Characteristics of Type 2 Diabetes ► ► Impaired insulin action ► ► Insulin secretion is normal or increased-90% of diabetic cases ► ► Age of onset: adulthood ► ► Associated with obesity ► ► Ketoacidosis: rare ► ► Most patients don’t require insulin

18. ACUTE COMPLICATION OF DIABETES MELLITUS ► HYPOGLYCAEMIA ► HYPERGLYCAEMIC CRISIS ► INFECTIONS

19. DISCUSSION OF ACUTE COMPLICATIONS ► Hypoglycaemia: Hypoglycaemia in patient of diabetes mellitus is an abnormally low concentration of glucose in the blood caused by insufficient food intake, excessive exercise or overdose with hypoglycaemic agents or insulin. They may include patient of: They may include patient of: a. Advance retinopathy b. Unstable Angina pectoris. c. History of Generalized seizures. Hyperglycaemic crisis Hyperglycaemic crisis a. Diabetic Ketoacidosis : It affect people suffering from Type-1 Diabetes mellitus.Ketoacidosis occurs when body breakdowns Fatty acids and produced them.Ketoacidosis occurs when body breakdowns Fatty acids and produced them into ketone bodies;which are acidic in nature.Some of them are lost through into ketone bodies;which are acidic in nature.Some of them are lost through urine, but those that will remain in the blood and leads to ketoacidosis. urine, but those that will remain in the blood and leads to ketoacidosis. Sign of ketoacidosis: a.Nausea b.Vomiting c.Dry skin and mouth d.Low blood pressure. to be contd………

20. ► ► b. Hyperglycaemic hyperosmolar state: It is much common for people with Type-2 diabetes mellitus to develop the hyperglycaemic hyperosmolar state in face of severe infections or other major incurrent illness. They usually present with dehydration,circulatory compromise and a change in mental state. Acidosis is more uncommon,except when related to lactic acidosis due to hypoperfusion. ► ► Infections : People with poorly controlled Diabetes are more prone to develop bacterial (anaerobic), myobacterial and fungal infections. Urinary tract infections result from obstruction or neurogenic bladder. Pyelitis and Pyelonephritis aggravate diabetic neuropathy. Chronic painless infections may destroy a neuropathic and / or ischemic foot. Tuberculosis of respiratory and other organ systems, fungal infections of skin, bacterial infections of urinary tract and anaerobic of deep tissues poses serious health threats, particularly in poor hygenic surroundings.

21. HYPERGLYCEMIA CRISES CONT’D

22. LATE COMPLICATION OF DIABETES MELLITUS / SECONDARY COMPLICATION ► RETINOPATHY ► NEPHROPATHY ► NEUROPATHY ► ATHEROSCLEROSIS

23. DISCUSSION OF SECONDARY COMPLICATIONS OF DIABETES MELLITUS ► RETINOPATHY : It is characterized by retinal damage such as bleeding in retina due to this retinal damage or retinal detachment occurs from normal position which ultimately leads to cataract or glaucoma. ► DIABETIC NEPHROPATHY : In this renal capillaries become leaky ; due to this proteins appear in the filterate or urine which is known as proteinurea leads to nephron syndrome. It may cause other kidney disorders such as renal atherosclerosis leads to renal failure. Nephropathy occurs due to Advance Glycation End Product (AGE) accumulation. Glycation mainly occur of collagen and other proteins. Initially ; it is reversible, but later on become irreversible,but this deposit on renal capillaries. ► NEUROPATHY : Defect in peripheral Nervous System mainly involves nerves and these become non-functional symptoms include: I. Disturbance in urinary bladder functioning. II. Disturbance in bowel functioning. ATHEROSCLEROSIS : Occurs also due to AGE accumulation in blood vessels. ATHEROSCLEROSIS : Occurs also due to AGE accumulation in blood vessels.

25. MANAGEMENT OF DIABTES MELLITUS INSULIN THERAPY : It is necessary to control hyperglycemia in Type-1 Diabetes Mellitus.Provided hyperglycemia in type-2 diabetes mellitus, patient may given one month trial of diet,exercise and weight management. An anti- hyperglycaemic agent /insulin will be prescribed in this condition. OBJECTIVE OF INSULIN THERAPY : ► ► To eliminate the symptoms of the hyperglycaemia; ► ► To achieve optimum control; ► ► To reduce microvascular or macrovascular complications of the diabetes mellitus. ► ► To treat associated disease. ► ► To allow the patient to achieve normal lifestyle as possible. OTHER TREATMENT OPTION :The backbone of the management of the diabetes mellitus is proper diet and regular exercise. Patient with type-2 diabetes may require oral hyperglycaemic agents and/or insulin, while type-1 will need insulin therapy to survive. to be contd…….

26. The treatment plan for diabetes mellitus may include: ► Diabetes education ► Mealing plan and nutritional recommendation ► Exercise ► Anti-diabetic agent ► Insulin ► Management of associated diseases and complications. Nutritional Recommendation : The goal for medical nutritional therapy that apply to all persons with diabetes mellitus. ► To attain and maintain optimum metabolic outcomes, including:- blood glucose level in the normal range; a lipid and lipoprotein profile that reduces the risk for microvascular disease; blood pressure level that reduces the risk for vascular diseases. ► To prevent and treat the chronic complications of the diabetes i.e. modify nutrient intake and lifestyle as appropriate for prevention and treatment of obesity, dyslipidaemia, cardiovascular disease and hypertension or nephropathy. ► To address individual nutritional needs, taking into considerations personal cultural preference and lifestyle. ► To improve health through healthy food choices and physical activity. to be contd………….. to be contd…………..

27. Recommended distribution for nutrient for diabetics Carbohydrates 45% 45% Total Fats 35% Mono unsaturated fatty acids 20% Poly unsaturated fatty acids <8% Saturated and trans-fatty acids <7% Protein15-20% Cholesterol<200mg/day EXERCISE : Exercise is an extremely important in the management of diabetes because of its effects on blood glucose and free fatty acids. Exercise burn calories and help to control weight,eases stress ad tension and maintain feeling of well- being. In addition, regular exercise improves the body’s response to insulin and may make oral anti-diabetic drugs and insulin more effective. It also promotes circulation and lower cholesterol and triglycerides levels, thus reducing the level of cardiovascular diseases. Persons with Diabetic should be encouraged to lead a normal life and participate in sports and exercise programmes.

28. PHARMACOLOGICAL THERAPHY ► The Pharmacological therapeutic methods should be consists of following options: 1. Insulin sensitizers 2. Insulin secretagogues 3. α – glucosidase inhibitor 4. Insulin  Oral agent may counteract insulin resistance,improving β – cell sensing and insulin secretion or control the rate of intestinal glucose absorption.  Combination of agents, particularly sulfonylurea plus metformin,thiazolinidinediones plus metformin have improved the care of diabetic patients and may be used when monotheraphy is ineffective.

29. GroupName Recommend daily dose Mode of Action Insulin secretagogues Sulfonylureas Glibenclamide 5-20 mg/day Stimulate Insulin secretion Glyburide 2.5-20 mg/day Stimulate Insulin secretion Glipizide 2.5-20 mg/day Stimulate Insulin secretion Glimepride 1-8 mg/day Stimulate Insulin secretion Gliclazide 40-160 mg/day Stimulate Insulin secretion Gliclazide LA 30 mg Stimulate Insulin secretion Insulin sensitizers BiguanideMetformin 0.5-2 mg/day Decrease hepatic glucose production Increase Insulin sensitivity ThiazolidinedionesRosiglitazone 2-8 mg/day Increase Insulin sensitivity and decrease hepatic glucose production Pioglitazone 15-45 mg/day Increase Insulin sensitivity and decrease hepatic glucose production α – glucosidase inhibitor Acarbose 100-300 mg/day Delays carbohydrate absorption Miglitol 100-300 mg/day Delays carbohydrate absorption TYPES AND MECHANISM OF ACTION OF ORAL ANTI-DIABETIC AGENTS