"Never offer the devil a ride. He will always want to be in the driving seat…!"

1. "Never offer the devil a ride. He will always want to be in the driving seat…!"

2. Pathology of Diabetes Dr. Venkatesh M. Shashidhar Associate Professor of Pathology Fiji School of Medicine

3. Diabetes Mellitus • Disorder of metabolism (Carb, Prot & Fat) • Due to Absolute/relative deficiency of insulin. • Characterized by hyperglycemia. • Clinically : Polyuria, Polydypsia, Polyphagia.

4. Introduction • Diabetes mellitus (sweet urine) • 3% of world population, 100 million people • Incidence is increasing alarmingly (40% in the past decade, more in future. 259 m by 2025. • Most Common non communicable disease • High Morbidity & mortality. • DM shortens life span by 15 years. • Leading cause of blindness and Kidney dis. • Pacific Islands – leaders in DM & Obesity…!

5. World Statistics:

6. Normal Pancreatic Islet: ß α ß cells (Insulin)αcells (Glucagon) δ cells (Somatostatin) pp Cells (pan prot)

7. Insulin - Anabolic Steroid • Transmembrane transport of glucose • Liver, muscle & fat  blood glucose • Liver & skeletal muscle -  glycogen • Converts glucose to triglycerides • Nucleic acid & Protein synthesis • Diabetes  Increased catabolism. • Hyperglycemia,  protein synthesis, Liplysis, wasting, weight loss.

8. Hormone Insulin Glucortocoids Glucagon Growth Hormone Epinephrine Action  Glucose  Glucose  Glucose  Glucose  Glucose Blood Glucose & Hormones

9. Insulin Requiring Striated Muscle Cardiac Muscle Fibroblasts FAT Non-Insulin Requiring Blood Vessels Nerves Kidney Eye Lens Cellular Glucose Uptake

10. Low glucose inside cell decreased cell metabolism (muscle, liver) High glucose outside Glycosylation damage (BV) Polyol products – osmotic damage* Pathology in Diabetes:

11. Classification • Primary DM– (primary - no other disease) • Type I – IDDM / Juvenile – 10%. • Type II – NIDDM /Adult onset – 80%. • MODY – 5% maturity onset - Genetic • Gestational Diabetes • Secondary DM – (secondary to other dis.) • Pancreatitis/tumors/Hemochromatosis. • Infectious – congenital rubella, CMV. • Endocrinopathy, downs. • Drugs – Corticosteroids.

12. Pathogenesis of Type I DM Genetic HLA-DR3/4 Environment Viral infe..? Autoimmune Insulitis Ab to ß cells/insulin • PS Glomerulonephritis • Graves, Hashimoto thyroiditis. • Rheumatic heart disease • SLE, Collagen vascular disease • Rheumatoid arthritis. ß cell Destruction Type I / IDDM Insulin deficiency

13. Progression of Type I

14. Pathogenesis of Type II DM Genetic / ß cell defect Obesity / Life style ? Abnor. Secretion Insulin Resistance Relative Insulin Def. IDDM ß cell exhaustion Type II NIDDM

15. “Things may come to those who wait, but only the things left by those who hustle.”– Abraham Lincoln

16. 56 year male obese 30 year female following pregnancy 8 year old boy. 24 year female with Cushing’s sy 68 Year male following Carcinoma of pancreas. 34 year male with extensive tuberculosis. II NIDDM II GDM I IDDM Sec IDDM Sec IDDM Sec IDDM What type?

17. Less common Children < 25 Years Insulin- Dependent Duration: Weeks Acute Metabolic complications Autoantibody: Yes Family History: No Insulin levels: very low Islets: Insulitis 50% in twins More common Adult >25 Years Insulin Independent * Months to years Chronic Vascular complications. No Yes Normal or high * Normal / Exhaustion 60-80% in twins Type-I Type-II

18. Insulitis – Type I Insulinitis

19. Islets in Type II Diabetes: Loss of ß cells, replaced by Amyloid deposits (hyalinization)

20. Islets in Type II Diabetes: Loss of ß cells, replaced by Amyloid deposits (hyalinization)

21. Complications: • Short term Complications: (metabolic) • Hypoglycemia • Diabetic Ketoacidosis • Non Ketotic hyperosmolar diabetic coma • Lactic acidosis • Long term Complications:(Angiopathy) • Microngiopathy - Retinopathy, Nephropathy, Neurophathy, dermatopathy. • Macroangiopathy – Atherosclerosis.

22. Microangiopathy Pathogenesis: • Hyperglycemia chronic. • Glycosylation of basement membrane proteins  Leaky blood vessels. • Excess deposition of proteins – glycosylation cycle. • Thick and Leaky blood vessels. • Narrow lumen • Ischemic Organ damage...

23. Diabetic Microangiopathy Normal • Glucose • Glycosylation • BM damage leak • ‘AGE’ deposition Diabetic

24. Neuropathy • Sensory  Motor (myelin) • Peripheral Neuropathy • Bilateral, symmetric • Progressive, irreversible • Paraesthesia, pain, muscle atrophy • Visceral neuropathy • Cranial nerve – diplopia, Bell palsy • GIT- constipation, diarrhoea • CVS – orthostatic hypotension

25. Neuropathy Myelin loss in nerve

26. Chronic Polyneuropathy Claw foot – Dermopathy & Neuropathy

27. Diabetic Amyotrophy Painful muscle wasting

28. Diabetic Neuropathic ulcer

29. Neuropathic ulcer Etiology: • peripheral sensory neuropathy, Trauma & deformity. Factors: • Ischemia, callus formation, and edema.

30. Neuropathic ulcers FEATURES: Painless, surrounded by callus At pressure points. associated with good foot pulses May not be associated with gangrene

31. Nephropathy • Nodular Glomerulo Sclerosis. • Common morbidity & mortality. • Deposition of ‘AGE’ Advanced Glycosylation End-products as nodules. • Nephrotic syndrome • Pyelonephritis • End stage renal failure

32. Diabetic Nephropathy Microangiopathy, atherosclerosis & infections: • Diffuse or nodular diabetic glomerulosclerosis (Kimmelstiel Wilson Sy) • Renal arteriolosclerosis & atherosclerosis • Necrotizing renal papillitis. • Pyelonephritis. • End stage kidney.

33. Nodular Glomerulosclerosis – KW lesion.

36. Diabetic Glomerulosclerosis Hyaline nodules

37. Diabetic Glomerulosclerosis

38. Normal Retina

39. Non Proliferative Retinopathy • Venous dilation and small red dots posterior retinal pole - capillary micro-aneurysms. • Dot and blot retinal hemorrhages and deep-lying edema and lipid exudates impair macular function. • Late generalized diminution of vision due to ischemia and macularedema - common cause of visual defect (best detected by fluorescein angiography) • Cotton-wool spots (soft exudates) - microinfarcts due to ischemia. They are white and obscure underlying vessels. Hard exudates are caused by chronic edema. They are yellow and generally deep to retinal vessels.

40. Proliferative Retinopathy • Neovascularization - which grows into the vitreous cavity. • In advanced disease, neovascular membranes can occur, resulting in a traction retinal detachment. • Vitreous hemorrhages may result. • sudden severe loss of vision can occur when there is intravitreal hemorrhage. • Poor visual prognosis if severe retinal ischemia, extensive neovascularization, or extensive fibrous tissue formation. • Panretinal photocoagulation may diminish or eliminate proliferative retinopathy

41. Retinopathy • Non Proliferative • Microaneurysms, • Dot blot hemorrhages • Hard and soft exudates • Cotton wool – infarcts • Macular edema. • Proliferative. • Neovascularization • Large hemorrhages • Retinal detachment.

42. Diabetic Retinopathy Neovascularization Cotton wool spots

43. Diabetic Retinopathy Dot blot – Hemorrhages (Microaneurysms)

44. Diabetic Retinopathy Pre retinal Hemorrhage - detachment

45. Diabetic Retinopathy Advanced fibrous plaques

46. “The past cannot be changed, but the future can.. by actions in the present time.” --BK Past is history, Future is mystery Present is the gift…!

47. Label the diagram. 1. 2. 3. 4. 5. Hard dep. Optic disc Macula Blot hem Cotton wool

48. Macroangiopathy Atherosclerosis • Dyslipidemia •  HDL • Non-Enzymatic Glycosylation •  Platelet Adhesiveness •  Thromboxane A2 •  Prostacyclin • Endothelial damage  Atherosclerosis • MI, CVA, Gangrene of Leg (PVD), Renal Insufficiency

49. Atherosclerosis:

50. Slide Show