“Diabetes” That which passes through…

1. “Diabetes”That which passes through… • Diabetes • Diabetes Insipidus(“…tasteless”) • Diabetes Mellitus (“…honey”) • Type 1 : Early Onset : IDDM • Type 2 : Late Onset : NIDDM • Atypical diabetes • Metabolic Syndrome

2. Diabetes Insipidus (DI) • Disorder arising from deficiency of anti-diuretic hormone (ADH) or its action •  copious amounts of dilute urine • Rare, 0.01% of hospitalisations in US • Central DI : failure of posterior pituitary gland to secrete adequate ADH • Nephrogenic DI : renal tubules fail to respond to circulating ADH • Inability of CT/CD to reabsorb water • Lack of ADH-induced aquaporin 2 (‘water pores’) • Osmotic gradient between medullary interstitium and filtrate still there, but cells of CD impermeable •  large volumes of dilute urine •  cellular and extracellular dehydration and hypernatremia

3. Water (and solute) balance

4. Bad Bad Less Water More Water Good

5. ECF Osm

6. Posterior Pituitary • Composed of nerve fibres • cell bodies in hypothalamic supraoptic & paraventricular nuclei • These neurosecretory cells synthesize Oxytocin & Vasopressin (ADH) • pass down nerve fibres & stored in/released from the posterior pituitary • both nine-AA peptides • ADH release stimulated by... • Plasma osmolarity >280 mOsm/L • Fall in plasma volume • Emotional factors/stress • Sleep

8. Effect of ADH on nephron water permeability No ADH 100,000 + ADH 10,000 Water Permeability 1,000 100 10 PCT tdL TAL DCT CCD IMCD Nephron Segment

9. Osmotic gradients and Urine Conc Always 100!

11. Effects/Causes/Treatment • Effects • polyuria, polydipsia, nocturia/enuresis, hypernatraemic dehydration • Causes (central) • Idiopathic (30%) • Tumours (30%) • Infection, trauma, thyroiditis, leukaemia, genetic (AD, X-link) • Treatment (central) • Desmopressin (DDAVP) • Synthetic analogue • Longer half-life • More potent, more specific for renal effects • Causes (nephrogenic) • familial: X-linked recessive • Renal disease (chronic renal failure, polycystic) • Treatment (nephrogenic) • Adequate fluid intake, low sodium diet, diuretics

12. Diabetes Mellitus (DM) • Group of metabolic diseases characterized by hyperglycemia • Results from defects in insulin secretion and/or action • Chronic hyperglycemialong-term damage/dysfunction/failure • eyes, kidneys, nerves, heart, and blood vessels • Main players… • glucose • glucose transporter • insulin • insulin receptor • Increasing prevalence/burden  ‘epidemic’

13. diasoce1.ppt

14. Diabetes: Complications Macrovascular Microvascular Diabetic eye disease (retinopathy and cataracts) Stroke Heart disease and hypertension Renal disease Erectile Dysfunction Peripheral vascular disease Peripheral Neuropathy Foot problems Meltzer et al. CMAJ 1998;20(Suppl 8):S1-S29.

15. Diabetes: Burden • Leading cause of blindness (12.5% of cases) • Leading cause of End-Stage Renal Disease, ESRD (42% of cases) • 50% of all non-traumatic amputations • 2.5x increase risk of stroke • 2-4x increase in cardiovascular mortality • DM ‘responsible’ for 25% of cardiac surgery • Mortality in DM: 70% due to Cardiovascular Disease

16. Haffner et al, NEJM, 339(4):229-34, 1998.

17. Diabetes: Brief History • 2nd Cent AD: “diarrhoea of the urine”... “the thirsty disease” Galen. “Diabetes is a wonderful affection, not very frequent among men, being a melting down of the flesh and limbs into urine” Aretaeus the Cappadocian • 1850s autopsies suggest link with pancreas (patients with damaged pancreases almost always had DM) • 1869: Paul Langerhans discovered existence of pancreatic acinar cells (pancreatic juice) and islets floating among the acini with an unknown function • 1889: Minkowski & Von Mering depancreatized a dog  polyuria as in diabetes. Ligating ducts did not  DM (so not pancreatic juice) • 1916: Paulescu normalized a diabetic dog with aqueous pancreatic extract • 1955: Sanger’s group sequences bovine insulin

18. Islet of Langerhans with acinar cells

19. Insulin and Glucose Homeostasis • Part of a larger picture… • Glucose, Lipoprotein, Protein, Ketone metabolism • Organs… • Endocrine pancreas • Adipose tissue, Liver, Gut, Skeletal muscle, Kidneys • Hormones… • Pancreatic hormones • Insulin (β-cell) • Glucagon (α-cell) • Amylin (β -cell) • Intestinal Hormones (Incretins) • GLP-1 (L-cells) • Glucagon-like Peptide • GIP (K-cells) • Glucose-dependent Insulin-releasing Peptide

20. Insulin and Glucose Homeostasis • Terms… • Glycogenolysis • Catabolism of glycogen • Gluconeogenesis • Production of glucose from non-carbohydrates or proteins • Ketogenesis • Production of ketone bodies • ‘emergency’ fuel for heart/skeletal muscle • Insulin Sensitivity • Ability of insulin to lower circulating glucose concentrations • Insulin Resistance • Condition of low insulin sensitivity • Honeymooning • The ability of the failing β -cells to become hyper-productive and compensate for failing insulin response

21. Simple Homeostasis

22. Homeostasis: Norm vs DM (Type 1?)

23. Glycosuria/Diuresis in DM • Renal Filtered Load = [Plasma Gluc] x GFR • Reabsorption is via facilitated transport • Finite number of sites • therefore Transport Maximum • Hyperglycaemia increased Filtered Load • When nears/exceeds Transport Max •  glucose remains in tubule • Osmotic effects of glucose ‘trap’ water in tubule • Get glucose in urine plusosmotic diuresis

24. DM and Glycosuria

25. Glucose Metabolism

26. Insulin Overview Hepatic glucose output _ INSULIN + Blood glucose Peripheral Tissue Uptake diet

27. Lipoprotein Metabolism

28. Ketone Metabolism

29. fat cell TG DKA: Pathophysiology Insulin - Ketoacids Glucose HSL FFA Insulin + PFK Liver Cell Pyruvate Fatty Acyl-CoA Acetyl-CoA + Kreb’s Glucagon Insulin + VLDL (TG)

30. fat cell TG DKA: Pathophysiology Insulin - Ketoacids Glucose HSL FFA Insulin + PFK Liver Cell Pyruvate Fatty Acyl-CoA Acetyl-CoA + Kreb’s Glucagon Insulin + VLDL (TG)

31. Protein Metabolism

32. Insulin Secretion: Constitutive/Regulated • Constitutive secretion maintains sensitivity of islets to glucose?

33. Insulin Secretion: Regulation by Glucose

34. Insulin causes receptor autophosphorylation Insulin Action: Glucose Transport

35. Insulin Action: Glucose Transport Activated insulin receptor phosphorylates IRS-1

36. Phosphorylated IRS-1 activates PI-3 kinase Insulin Action: Glucose Transport

37. PI-3 kinase converts PIP2 => PIP3 (activates PDK1) Insulin Action: Glucose Transport

38. PDK1 activates protein kinase B (PKB) Insulin Action: Glucose Transport

39. PKB stimulates GLUT-4 translocation Insulin Action: Glucose Transport

40. Bigger Picture: More than Insulin… • Glucagon – glycogen breakdown, gluconeogenesis • Adrenaline, noradrenaline – glycogen breakdown and gluconeogenesis in muscles, lactate  glucose in liver • Growth hormone (anabolic hormone), lipolysis, protesynthesis • Glucocorticoids– gluconeogenesis, block of proteosynthesis • Thyroid hormones and oestrogens • Amylin – Co-secreted with insulin; anorectic (acts on brain  ‘sated’ feeling) • GLP-1 - “Incretin” hormone secreted by GI cells in response to a meal; +ve insulin secretion/sensitivity