Diabetes Mellitus

1. Diabetes Mellitus Prof Fawaz Ammari F.R.C.P (London) JUST (University)

2. Diabetes Mellitus DefinitionClassificationEtiologyDiagnosisTreatmentComplication

3. Nobel Prizes Fredrick Banting, John Macleod 1923 Fredrick Sanger 1958 Rosalyn Yalow and Solomon Berson DOROTHY CROWFOOT HODGKIN 1964 Nobel Laureate in Chemistry1978: Human insulin cloned into E. coli by Genentech scientists. Genentech licenses , the human insulin technology to Eli Lilly. In 1982, human insulin, Humulin, becomes the first recombinant DNA drug approved by FDA. [ Nobel Prizes Fredrick Banting, John Macleod 1923 Fredrick Sanger 1958 Rosalyn Yalow and Solomon Berson DOROTHY CROWFOOT HODGKIN 1964 Nobel Laureate in Chemistry1978: Human insulin cloned into E. coli by Genentech scientists. Genentech licenses , the human insulin technology to Eli Lilly. In 1982, human insulin, Humulin, becomes the first recombinant DNA drug approved by FDA. [

4. Insulin release: normal levels Units: 1 U = 36 �g, i.e. 28 U/mg Daily secretion in humans: 40 - 50 U Basal plasma insulin: 12 �U/ml Postprandial insulin: up to 90 �U/ml

5. Insulin metabolism Secreted into portal circulation

6. glycogen synthesis glycogenolysis triglyceride synthesis ketogenesis gluconeogenesis glucose uptake protein synthesis protein degradation glycogen synthesis glycogenolysis glucose uptake triglyceride storage lipolysis Effects of insulin:

7. Abnormalities due to insulin deficiency Hyperglycemia Underutilization of glucose Overproduction of glucose Increased lipolysis Acidosis - Increased conversion of fatty acids to ketoacids (acetoacetic and b-hydroxybutyric) Increased plasma triglycerides and LDL; decreased HDL Osmotic diuresis, plasma hyperosmolarity, dehydration, hypovolemia, polydipsia Depletion of intracellular and whole-body K+

8. Definition of DM D M is a group of metabolic diseases characterized by hyerglycemia resulting from defects in insulin secretion .insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction,and failure of various organ,especially the eye,kidneys,heart,and blood vessels.

9. The worldwide pandemic of type 2 diabetes The next two decades will bring a worldwide pandemic of type 2 diabetes. As many as 300 million people worldwide may have type 2 diabetes by the year 2025. Amos AF, McCarty DJ, Zimmet P. The rising global burden of diabetes and its complications: estimates and projections to the year 2010. Diabet Med 1997;14 (Suppl 5):S1-S85. International Diabetes Federation. Diabetes Atlas 2000. The worldwide pandemic of type 2 diabetes The next two decades will bring a worldwide pandemic of type 2 diabetes. As many as 300 million people worldwide may have type 2 diabetes by the year 2025. Amos AF, McCarty DJ, Zimmet P. The rising global burden of diabetes and its complications: estimates and projections to the year 2010. Diabet Med 1997;14 (Suppl 5):S1-S85. International Diabetes Federation. Diabetes Atlas 2000.

10. Prevalence of type 2 diabetes in selected populations aged 30-64 years There is a wide variation in the prevalence of type 2 diabetes in different populations. As this analysis shows, Pima Indians have a particularly high prevalence of the disease, at 50% whereas in China it is only 2%. This variation in prevalence is also evident in different ethnic groups from the same country. In the United States, for example, the prevalence in the Hispanic population is double that in the white population. Prevalence of type 2 diabetes in selected populations aged 30-64 years There is a wide variation in the prevalence of type 2 diabetes in different populations. As this analysis shows, Pima Indians have a particularly high prevalence of the disease, at 50% whereas in China it is only 2%. This variation in prevalence is also evident in different ethnic groups from the same country. In the United States, for example, the prevalence in the Hispanic population is double that in the white population.

11. Top ten countries for estimated number of adults with diabetes, 1995 and 2025 India has the greatest number of people worldwide with type 2 diabetes, followed by China and the United States, and this ranking is expected to remain the same in 2025. In Pakistan the number of people with diabetes is expected to increase to 14.5 million by 2025, making it the fourth highest in the world, having ranked eighth in 1995. By contrast, Japan, which was ranked fifth highest in 1995 will drop to tenth place by 2025, reflecting relatively slow growth. Top ten countries for estimated number of adults with diabetes, 1995 and 2025 India has the greatest number of people worldwide with type 2 diabetes, followed by China and the United States, and this ranking is expected to remain the same in 2025. In Pakistan the number of people with diabetes is expected to increase to 14.5 million by 2025, making it the fourth highest in the world, having ranked eighth in 1995. By contrast, Japan, which was ranked fifth highest in 1995 will drop to tenth place by 2025, reflecting relatively slow growth.

12. Diabetes Mellitus in the US: Health Impact of the Disease

18. Glucose Tolerance Categories

19. Pathogenesis of Type I DM

20. Pathogenesis of Type II DM

21. Natural History of Type 2 Diabetes

22. Type-I Type-II Age: < 40 Years Duration: Weeks Ketonuria: Common Insulin- Dependent Autoantibody: Yes Family History: No Insulin levels: very low Islets: Insulitis Complications: Acute & Metabolic > 40 Years Months to years Rare Independent * No Yes Normal or high * Normal / Exhaustion Complications Late and vascular.

23. Clinical Feature Polyuria and thirst Weakness or fatigue Polyphagia and weight loss Blurring of vision Vulvovaginitis or pruritus Nocturnal enuresis Asymptomatic May presented with acute complication May presented with late complications

24. Management of Diabetes

25. First international consensus EASD/ADA June 06  Call to action : 3 steps to keep control The following three-step approach to achieving and maintaining glycemic control is recommended. This graphic shows the relative glucose-lowering potential of all commonly used antidiabetes agents. Step 1 � initial therapy should be a combination of lifestyle intervention and metformin therapy. Metformin is the first-choice pharmacological intervention because of its efficacy, absence of weight gain and hypoglycemia, high level of acceptance, and low cost. Step 2 � additional therapy within 2�3 months of the initiation therapy or whenever HbA1c goal is not achieved. Basal insulin therapy should be considered for patients with HbA1c levels > 8.5% because insulin is the most effective glucose-lowering agent and can achieve reductions of up to 2.5%. Hospitalisation is not required to initiate insulin or adjust therapy. The patient is the key player and should be trained and empowered with the guidance of healthcare professionals. Step 3 � further adjustments to achieve glycemic targets. This involves initiation of basal insulin if not previously used or intensification of insulin therapy using prandial insulin to control postprandial glucose excursions. In some cases another oral agent may be added but this is often ineffective and can be relatively expensive. Nathan DM, et al. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2006;49:1711�21. The following three-step approach to achieving and maintaining glycemic control is recommended. This graphic shows the relative glucose-lowering potential of all commonly used antidiabetes agents. Step 1 � initial therapy should be a combination of lifestyle intervention and metformin therapy. Metformin is the first-choice pharmacological intervention because of its efficacy, absence of weight gain and hypoglycemia, high level of acceptance, and low cost. Step 2 � additional therapy within 2�3 months of the initiation therapy or whenever HbA1c goal is not achieved. Basal insulin therapy should be considered for patients with HbA1c levels > 8.5% because insulin is the most effective glucose-lowering agent and can achieve reductions of up to 2.5%. Hospitalisation is not required to initiate insulin or adjust therapy. The patient is the key player and should be trained and empowered with the guidance of healthcare professionals. Step 3 � further adjustments to achieve glycemic targets. This involves initiation of basal insulin if not previously used or intensification of insulin therapy using prandial insulin to control postprandial glucose excursions. In some cases another oral agent may be added but this is often ineffective and can be relatively expensive. Nathan DM, et al. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2006;49:1711�21.

26. DIET Diet is the coroner stone of manag of DM There is no stander diabetic diet Diet must be individualized Flexibility in use ordinary food is important Diet must be of adequate calories for maintaining weight for adult,normal growth for children,increased metabolic needs in pr Diet must contain 10-20% of protein 20-30% fat and 50-60% carbohydrate Fiber intake must be increase

28. Pathophysiology of Type 2 DM Insulin resistance ? insulin receptor number ? insulin receptor kinase activity Post-receptor defects ? GLUT4 translocation from impaired signaling Impaired islet function Loss of first phase insulin secretion ? secretion of proinsulin Defective pulsatile insulin secretion Deposition of islet amyloid polypeptide

29. Treatment of Type 2 Diabetes Diet and exercise 80 % of Type 2 diabetics are obese ? caloric intake ? physical exercise first line of treatment recent clinical trial showed that exercising at least 30 minutes a day reduces Type 2 risk more effectively than medication

30. Treatment of Type 2 Diabetes Monotherapy with oral agent Combination therapy with oral agents Insulin +/- oral agent insulin required in 20-30% of patients With duration of the disease, more intensive therapy is required to maintain glycemic goals

31. Oral Drug Therapy for Type 2 DM Sulfonylureas Repaglinide Nateglinide Biguanides Thiazolidinediones Acarbose Miglitol

32. Sulfonylureas: Metabolism & Excretion

33. Clinical Uses of Sulfonylureas

34. Adverse Effects of Sulfonylureas Severe hypoglycemia Overdose Early in treatment Most common with glyburide Weight gain Erythema, skin reactions Blood dyscrasias (abnormal cellular elements) Hepatic dysfunction and other GI disturbances

35. Contraindications for Sulfonylureas

37. REPAGLINIDE (Profile) Class: Meglitinides Mode of Action: Stimulating release of insulin via distinct beta cell bindings sites a part from sulfonylurea binding site * Benzoic acid derivatives * has greater effect postprandially * Fast onset and offset action Contraindication: DKA - Type 1 diabetes - hypersensitivity Adverse effects: hypoglycemia - hypersensitivity - weight gain

38. ACARBOSE (Profile) Class: alpha -Glucosidase inhibitor Mode of Action: - inhibiting alpha-glucosidase locally in small intestine- Slows intestinal absorption of carbohydrates- reduces postprandial hyperglycemia * As monotherapy or combination with sulfonylurea * Most useful in patients with exaggerated postprandial hyperglycemia Contraindications: IBD, Ulcer, malabsorption, partial intestinal obstraction Adverse Effects: Flatulence - bloating (very common but may subside over the time) * monitoring of transaminase / 3 months

39. ROSIGLITAZONE Class: thiazolindendione Mode of Action: binds to peroxisome profilerator - activated receptor -gamma regulation of glucose and fatty acid metabolism (young et al 1998) * Significantly improved FBS & HbA1C in type 2 diabetics ( clinical investigator news 1998) Adverse effects: Rosiglitazone = placebo However; minor anemia - fluid retention - weight gain

40. New Diabetes Agents Pramlintide Synthetic Amylin Taken as pre-meal subcutaneous injections Insulin is continued Type 2 and Type 1 patients Exenatide Incretin mimetic Possesses the effects of GLP-1 Resistant to breakdown by DPP-4 Twice daily subcutaneous injections with pen device Type 2 DM patients not controlled on sulfonylurea, metformin or TZD Sitagliptin, Vildagliptin DPP-4 inhibitors Once daily oral agent Type 2 DM patients as monotherapy or combination with metformin, glimepiride or TZD

42. Insulin Insulin is a protein hormone consisting of two long-chain peptides (the A-chain containing 21 amino acids and the B-chain containing 30) which are connected by two pairs of sulphur atoms (termed disulphide bridges). Porcine insulin differs from human insulin in only a single amino acid Bovine insulin has only two additional substitutions.

43. Insulin structure The structure (amino-acid sequence) of human insulin. Each small circle refers to an amino acid. The highlighted residues are those that differ in porcine and bovine insulins, as show.

45. Insulin Preparations lispro regular NPH lente ultralente glargine

46. Insulin treatment regimens Conventional insulin treatment 1 or 2 daily subcutaneous injections mixture of short- and intermediate or long-acting insulins Usual dose is 0.4 to 1 U/kg/day for Type 1 DM Mixing Insulin: Short and intermediate mixed in syringe Regular NPH- does not retard action of regular protamine ? 0.4 mg/ 4 mg insulin Premixed insulins Do not allow independent adjustment necessary for intensive treatmentUsual dose is 0.4 to 1 U/kg/day for Type 1 DM Mixing Insulin: Short and intermediate mixed in syringe Regular NPH- does not retard action of regular protamine ? 0.4 mg/ 4 mg insulin Premixed insulins Do not allow independent adjustment necessary for intensive treatment

47. Insulin treatment regimens Intensive insulin treatment Frequent monitoring of blood glucose 3 or more daily injections of insulin Some regular alone, some combined regular and intermediate- or long-acting Adjusted to needs of individual patient

48. Insulin treatment regimens Continuous subcutaneous insulin infusion Insulin pump with lispro or regular insulin Programmed basal delivery allows control of �dawn phenomenon� Patient-triggered bolus before meals

49. Guideline on dosage of insulin The correct dose of insulin is that which achieve the best glycemic control The daily insulin dose is 0.5-0.6 iu/kg /daily The start dose for normal wt patient 15-20iu The start dose for obese patient 25-30 iu 2/3 of the dose in the morning 1/3 in the eve 1/3 rapid acting 2/3 intermediate acting

50. Insulin dosage depends on many factors Age Weight Stage of puberty Duration of diabetes Nutritional intake Exercise patterns Results of BG monit Intercurrent illness

51. Adverse Effects of Insulin Therapy Hypoglycemia Especially dangerous in Type 1 diabetics Glucose or glucagon treatment Allergy and resistance to insulin Local cutaneous reactions or systemic Switch to less antigenic form or desensitization Lipohytertrophy Due to lipogenic effect of insulin when small area used for frequent injections Absorption from such sites is unpredictable Lipoatrophy Due to impurities: switch to highly purified insulin Lipogenic effect of insulin can repair lesion Insulin edema- transient, rare