2. Regarding type 1 diabetes mellitus, which one statement is correct: Regarding type 1 diabetes mellitus, which one statement is correct: a. Most commonly develops in old age b. Type 1 diabetes is an autoimmune disease with pancreatic beta islet cell destruction caused by T- lymphocytes c. Usually not associated with genetic susceptibility d. Type 1 diabetes is an autoimmune disease with pancreatic beta islet cell destruction caused by B- lymphocytes

3. Regarding type 1 diabetes mellitus, which one statement is correct: Regarding type 1 diabetes mellitus, which one statement is correct: a. Most commonly develops in old age b. Type 1 diabetes is an autoimmune disease with pancreatic beta islet cell destruction caused by T-lymphocytes c. Usually not associated with genetic susceptibility d. Type 1 diabetes is an autoimmune disease with pancreatic beta islet cell destruction caused by B- lymphocytes

4. Regarding type-2 diabetes mellitus (DM), which one statement is correct: Regarding type-2 diabetes mellitus (DM), which one statement is correct: a. Genetic factors less important than in type 1 DM b. There is no link between obesity and DM c. Insulin resistance is the primary event, followed by progressive pancreatic beta cell destruction d. Regulation of adipokines may lead to insulin resistance

5. Regarding type-2 diabetes mellitus (DM), which one statement is correct: Regarding type-2 diabetes mellitus (DM), which one statement is correct: a. Genetic factors less important than in type 1 DM b. There is no link between obesity and DM c. Insulin resistance is the primary event, followed by progressive pancreatic beta cell destruction d. Regulation of adipokines may lead to insulin resistance

6. Which one of these satisfy the diagnostic criteria for diabetes mellitus using fasting plasma glucose Which one of these satisfy the diagnostic criteria for diabetes mellitus using fasting plasma glucose a. 6.0 mmol/L b. 5.0 mmol/L c. 4.0 mmol/L d. 7.0 mmol/L

7. Which one of these satisfy the diagnostic criteria for diabetes mellitus using fasting plasma glucose levels (FPG): Which one of these satisfy the diagnostic criteria for diabetes mellitus using fasting plasma glucose levels (FPG): a. 6.0 mmol/L b. 5.0 mmol/L c. 4.0 mmol/L d. 7.0 mmol/L

8. Which one of these satisfy the diagnostic criteria for diabetes mellitus using two hour plasma glucose level using 75 gram oral glucose tolerance test (OGTT): Which one of these satisfy the diagnostic criteria for diabetes mellitus using two hour plasma glucose level using 75 gram oral glucose tolerance test (OGTT): a. 10.1 mmol/L b. 11.1 mmol/L c. 9.1 mmol/L d. 8.1 mmol/L

9. Which one of these satisfy the diagnostic criteria for diabetes mellitus using two hour plasma glucose level using 75 gram oral glucose tolerance test (OGTT): a. 10.1 mmol/L b. 11.1 mmol/L c. 9.1 mmol/L d. 8.1 mmol/L

10. Which one of these satisfy the diagnostic criteria for diabetes mellitus using random plasma glucose levels: Which one of these satisfy the diagnostic criteria for diabetes mellitus using random plasma glucose levels: a. 10.1 mmol/L b. 9.1 mmol/L c. 11.1 mmol/L d. 8.1 mmol/L

11. Which one of these satisfy the diagnostic criteria for diabetes mellitus using random plasma glucose levels: Which one of these satisfy the diagnostic criteria for diabetes mellitus using random plasma glucose levels: a. 10.1 mmol/L b. 9.1 mmol/L c. 11.1 mmol/L d. 8.1 mmol/L

12. Which one of these satisfy the diagnostic criteria for diabetes mellitus using blood glycosylated haemoglobin levels in percentages: a. HbA1c < 5.5 % b. HbA1c < 4.5 % c. HbA1c > 6.5 % d. HbA1c < 3.5 %

13. Which one of these satisfy the diagnostic criteria for diabetes mellitus using blood glycosylated haemoglobin levels in percentages: a. HbA1c < 5.5 % b. HbA1c < 4.5 % c. HbA1c > 6.5 % d. HbA1c < 3.5 %

14. Patients with each of the following conditions may manifest with elevated blood glucose levels except: Patients with each of the following conditions may manifest with elevated blood glucose levels except: a. Pheochromocytoma b. Cushing’s syndrome c. Glucagonoma d. Pancreatic beta cell neoplasms e. Elevated Growth hormone

15. Patients with each of the following conditions may manifest with elevated blood glucose levels except: Patients with each of the following conditions may manifest with elevated blood glucose levels except: a. Pheochromocytoma b. Cushing’s syndrome c. Glucagonoma d. Pancreatic beta cell neoplasms e. Elevated Growth hormone

16. Complication of diabetes mellitus (D.M) Brig Rizwan Hashim Pathology dept Army Medical College

18. Diabetes Mellitus vs Impaired Fasting Glucose/Impaired Glucose Tolerance DM – Risk of macrovascular and microvascular complications DM – Risk of macrovascular and microvascular complications IFG/IGT – Risk of macrovascular complications (But not microvascular) IFG/IGT – Risk of macrovascular complications (But not microvascular)

19. D.M Complications D.M Complications Short term Complications: (metabolic) Short term Complications: (metabolic) Hypoglycemia Hypoglycemia Diabetic Ketoacidosis Diabetic Ketoacidosis Non Ketotic hyperosmolar diabetic coma Non Ketotic hyperosmolar diabetic coma Lactic acidosis Lactic acidosis

20. Patho-physiology of DKA Relative or absolute insulin deficiency in the presence of catabolic counter-regulatory stress hormones (particularly glucagon and catecholamines, but also growth hormone and cortisol) leads to hepatic overproduction of glucose and ketones.

21. Patho-physiology of DKA Lack of insulin combined with excess stress hormones promotes lipolysis, with the release of non-esterified fatty acids (NEFA s ) from adipose tissue into the circulation. Lack of insulin combined with excess stress hormones promotes lipolysis, with the release of non-esterified fatty acids (NEFA s ) from adipose tissue into the circulation.

22. Mechanisms of ketoacidosis. NEFA, non-esterifies fatty acids.

23. Clinical features of diabetic ketoacidosis.

24. Complications Long term complications:(microangiopathy) Angiopathy, Angiopathy, Retinopathy, Retinopathy, Nephropathy, Nephropathy, Neuropathy Neuropathy

25. Long term Complications: Angiopathy Angiopathy Atherosclerosis Atherosclerosis Hyaline arteriolosclerosis Hyaline arteriolosclerosis Diabetic microangiopathy Diabetic microangiopathy Nephropathy Nephropathy Nodular glomerulosclerosis Nodular glomerulosclerosis Retinopathy Retinopathy Non Proliferative & Proliferative Non Proliferative & Proliferative Neuropathy Neuropathy Peripheral axonal neuropathy Peripheral axonal neuropathy

26. Pathogenesis of Microangiopathy: Long standing diabetes Long standing diabetes Combination of glucose with proteins - Particularly collagen in blood vessels - Glycosylation. Combination of glucose with proteins - Particularly collagen in blood vessels - Glycosylation. Excess deposition of glycosylated type IV collagen in the basement membrane Excess deposition of glycosylated type IV collagen in the basement membrane Thick and Leaky blood vessels. Thick and Leaky blood vessels. Chronic Ischemia & protein loss into tissues. Chronic Ischemia & protein loss into tissues. Organ damage... Organ damage...

27. Microvascular complications Proposed mechanisms Proposed mechanisms Hyperglycaemia- stimulates aldol reductase enzymes – metabolise glucose to sorbitol (polyol sugar) - tissue accumulation Hyperglycaemia- stimulates aldol reductase enzymes – metabolise glucose to sorbitol (polyol sugar) - tissue accumulation Non-enzymatic glycation of proteins (Amadori products, ‘ advanced glycation endproducts’) Non-enzymatic glycation of proteins (Amadori products, ‘ advanced glycation endproducts’)

28. C (CHOH) 4 | CH 2 OH NH || CH | (CHOH) 4 | CH 2 OH GlucoseProtein Schiff base H0 NH | CH 2 | C=O | (CHOH) 3 | (CH 2 OH) N N Protein cross- link in advanced glycosylation end products Amadori product NH 2 Reversible K1 K-1 (hours) K2 K-2 Reversible (days) KN Irreversible (Weeks) A

30. Ischemic Stage of Diabetic Retinopathy (low magnification) The microphotograph shows multiple capillary aneurysms

31. Pathogenesis of Retinopathy

32. Diabetic Eye Disease

34. Diabetic Retinopathy Cotton wool spots

37. New vessels on the iris (rubeosis iridis). There is also vitreous haemorrhage.

38. Diabetic cataract

39. Diabetic Nephropathy

42. Evolution of diabetic nephropathy

43. Diabetic Glomerulosclerosis

44. End-Stage Lesion of Diabetic Nephropathy The glomerulus in the center of the microphotograph is completely sclerotic. The most common cause of chronic renal failure in the United States is diabetic nephropathy.

45. Renal Tubules (high magnification) The basement membrane of the tubules are markedly thickened leading to tubular atrophy and dysfunction

46. Renal Necrotizing Papillitis Necrotizing papillitis is can occur in diabetics as a renal complication. The papilla extending into the minor calyces become necrotic as demonstrated in the microphotograph (arrows). Necrotizing papillitis can also be caused by sickle cell disease (vaso-occlusive) and indomethicin (toxicity).

47. Diabetic Neuropathy

49. Generalized wasting of the interossei (and hypothenar eminence) caused by bilateral ulnar nerve palsies in a diabetic patient.

51. Neuropathic foot, showing clawed toes, dry skin and prominent veins.

52. Typical neuropathy ulcer. Note the surrounding callus.

53. Distended veins on the dorsum of the foot of a diabetic patient with painful peripheral neuropathy.

54. Neuroischaemic damage caused by tightly fitting shoes.

55. Macro vascular Diseases in Diabetes

56. Diabetic Macrovascular DiseasePathophysiology Multiple metabolic changes Multiple metabolic changes Lipid changes in DM Lipid changes in DM - Raised total cholesterol, LDL and triglycerides - Raised total cholesterol, LDL and triglycerides - Low HDL - Low HDL LDL subfraction profile (small dense LDL) LDL subfraction profile (small dense LDL) Glycation and peroxidation of: Glycation and peroxidation of: - Lipoproteins - Lipoproteins - Thrombotic/thrombolytic factors - Thrombotic/thrombolytic factors

58. Lipid disorder in DM

59. Motility disorders associated with diabetes at various levels of the gastrointestinal tract.

60. Candidiasis

61. Other investigations: Serum Urea. Serum Creatinine Serum Lipid profile: cholesterol; triglyceride; LDL-C; HDL-C. Serum sodium, potassium, 24 hour urine for: protein; creatinine clearance; microalbumin; Spot urine for microalbumin Spot urine for albumin creatinine ratio- ACR

62. Other investigations and evaluations: Blood complete picture Urine routine examination: glucose; protein/, albumin, WBC, sp gravity. Urine for ketone bodies Arterial blood gases-ABG’s Ultra sound liver- Fatty liver Fundoscopy- for diabetic retinopathy; Routine eye exam: diabetic cataract Blood pressure measurement Examination of feet- ulcer; poor sensations/neuropathy

63. Insulin pens Management

64. Monitoring

65. Metabolic abnormalities leading to Microvascular complications in DM

66. Figure 18.4

67. Flowchart for the investigation of diabetic ketoacidosis

68. The stages and determinants of diabetic nephropathy.(AER, albumin excretion rate.) Diabetic nephropathy