1. WHY REGULATE PLASMA GLUCOSE? Set Point: 80-100 mg/100 ml plasma Glucose is virtually the only fuel the brain can use to make ATP (also ketones) If plasma glucose falls too low, brain activity declines If plasma glucose rises too high, there are both acute and longterm complications – diabetes mellitus

2. Absorptive state

3. Post absorptive state

4. HOW IS ALL THIS REGULATED? HORMONES!

5. Hormones that decrease glucoseHormones that increase glucose InsulinGlucagon Epinephrine Growth hormone Cortisol How come so many backup systems to prevent low plasma glucose?

6. Pancreas – insulin staining in brown

7. EFFECTS OF INSULIN Increased numbers of glucose transporters on cell surface Activation of enzymes involved in synthesis of glycogen, glycerol, fatty acids, activation of lipoprotein lipase Inhibition of enzymes involved in gluconeogenesis, glycogenolysis, conversion of triacylglycerides to fatty acids and glycerol, synthesis of ketones Net effect = decreased plasma glucose

10. Absorptive state

11. Post absorptive state

12. What causes insulin to be released?

17. Hormones that decrease glucoseHormones that increase glucose InsulinGlucagon Epinephrine Growth hormone Cortisol

18. Effects of glucagon that lead to increased plasma glucose Liver: Activation of enzymes that cause gluconeogenesis Activation of enzymes that promote ketone synthesis Inhibition of enzymes that cause synthesis of glycogen

19. What causes glucagon to be released from the pancreas?

22. Hormones that decrease glucoseHormones that increase glucose InsulinGlucagon Epinephrine Growth hormone Cortisol

24. Hormones that decrease glucoseHormones that increase glucose InsulinGlucagon Epinephrine Growth hormone Cortisol

25.  plasma glucose  Hypothalamus  GHRH secretion  Anterior Pituitary  GH secretion  LiverAdipocytesMost cells  Gluconeogenesis  lipolysis  glucose uptake   plasma glucose  fatty acids

26. Hormones that decrease glucoseHormones that increase glucose InsulinGlucagon Epinephrine Growth hormone Cortisol

27. Diabetes Mellitus Juvenile/insulin dependent/Type I –often follows viral illness –autoimmune attack on islets –decreased insulin production –Prevalence: 0.2-0.3% of the US population adult-onset/non-insulin dependent/Type II) –associated with obesity and older age –insulin levels can be normal or elevated, especially early –peripheral insulin resistance –Prevalence: 6-10% of the US population (and rising)

28. Genetics of Diabetes Mellitus Juvenile/insulin dependent/Type 1 –More common in persons of Northern European descent –Sibling relative risk of about 15 adult-onset/non-insulin dependent/Type 2) –Higher in persons of African, Pacific Island, and Native American descent –Sibling relative risk of about 3-4 –Many whole genome wide studies recently reported identifying several risk loci

30. Type 1 diabetes

36. Acute Complications Hyperglycemia –Increased serum glucose leading to loss of water and glucose in the urine –Hyperosmolarity –Hypotension –Hyperkalemia (increased serum potassium) –Ketosis Hypoglycemia –Resulting from overdose of insulin causing excessive uptake of glucose by cells, manifestations include activation of the sympathetic nervous system

38. Insulin deficiency glucose uptake gluconeogenesis plasma glucose lipolysis ketone synthesis plasma ketones plasma H+ Brain dysfunction, coma, death plasma osmolarity Loss of Na + and H 2 O in urine Blood volume Blood pressure Brain blood flow

39. K + Na + K + Na + insulin adrenalin aldosterone K+K+ K+K+ acidosis increased osmolarity cell injury Hyperkalemia in diabetes mellitus

42. Consequences of high plasma glucose Increased glycosylation of proteins –hemoglobin (useful as an index of average blood glucose levels over last 3 months) –collagen in basement membrane

43. Consequences of high plasma glucose Distrubances in polyol pathways in cells that do not require insulin for glucose uptake (nerves, lens of the eye, kidney, blood vessels) Glucose aldose reductase sorbitol Increased osmolarity swelling Impaired ion pumps injury

44. Chronic Complications Atherosclerosis Microvascular disease –nephropathy –retinopathy Peripheral Neuropathy Infections –Leading cause of amputations

45. Diabetes & Atherosclerosis Potential Mechanisms Hypertension Glycosylation of LDL (decreases liver uptake) Decrease in HDL (? via glycosylation) Glycosylation/protein crosslinking as cause of vessel injury Defects in lipoprotein lipase Enhanced platelet aggregation Sorbitol accumulation in vessel wall

46. Diabetic Retinopathy major cause of blindness –10% of type I after 30 yrs –Leading cause of new blindness in the US Nonproliferative lesions –BM thickening, edema, hemorrhage Proliferative lesions –new blood vessels, fibrous tissue –proliferate over retina over time –secondary to ischemia, microvascular disease –most severe seen in type I

48. CAUSES OF END STAGE RENAL DISEASEPERCENT OF CASES Diabetes34.2 Hypertension29.2 Glomerulonephritis14.2 Interstitial nephritis3.4 Cystic kidney disease3.4 Other or unknown15.4

49. Diabetic Nephropathy approx. 1/3 of type I DM will get renal failure Mechanism: basement membrane damage

50. Peripheral Neuropathy Mechanisms: –changes in nerve components (myelin, schwann cells, etc.) –microvascular disease Consequences –pain, abnormal sensation in extremities –touch, pain sensation eventually lost-- allows tissue damage –autonomic nerve dysfunction GI tract motility GU tract dysfunction

51. Foot ulcer

52. INFECTIONS

53. CAUSES OF INFECTIONS Decreased neutrophil function - due to high glucose More frequent skin eruptions - peripheral neuropathies Ischemia - vascular disease Increased plasma glucose - good growth medium for microorganisms

54. TREATMENT Juvenile/insulin dependent/Type I –Insulin injections adult-onset/non-insulin dependent/Type II) –Diet and exercise –Sulfonylureas (increase insulin release) –Thiazolidinediones (PPAR  agonists) –glucophage (metformin) (increases insulin sensitivity) –Insulin (in severe cases when insulin has been depleted)