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WHY REGULATE PLASMA GLUCOSE? Set Point : 80-100 mg/100 ml plasma

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

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WHY REGULATE PLASMA GLUCOSE? Set Point : 80-100 mg/100 ml plasma

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  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 Insulin Glucagon 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

  8. Green = insulin promotes Red = insulin inhibits

  9. What causes insulin to be released?

  10. Hormones that decrease glucoseHormones that increase glucose Insulin Glucagon Epinephrine Growth hormone Cortisol

  11. 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

  12. Post absorptive state

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

  14. Factors increasing glucagon release from the pancreas • Decreased plasma glucose • Increased plasma amino acids* • Epinephrine and sympathetic stimulation • Cortisol and growth hormone * Important in preventing meal induced hypoglycemia in carnivores

  15. Factors increasing glucagon release from the pancreas • Decreased plasma glucose • Increased plasma amino acids* • Epinephrine and sympathetic stimulation • Cortisol and growth hormone * Important in preventing meal induced hypoglycemia in carnivores

  16. Hormones that decrease glucoseHormones that increase glucose Insulin Glucagon Epinephrine Growth hormone Cortisol

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

  18. Diabetes Mellitus • Juvenile/insulin dependent/ Type 1 • often follows viral illness (with a latency period) • autoimmune attack on islets • decreased insulin production • Prevalence: 0.2-0.3% of the US population • adult-onset/non-insulin dependent/ Type 2) • 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)

  19. The insulin receptor

  20. 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

  21. Insulin deficiency lipolysis ketone synthesis plasma ketones plasma H+ glucose uptake gluconeogenesis plasma glucose Loss of Na+ and H2O in urine Blood volume Blood pressure Brain blood flow plasma osmolarity Brain dysfunction, coma, death

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

  23. 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

  24. 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

  25. Chronic Complications • Atherosclerosis • Microvascular disease • nephropathy • retinopathy • Peripheral Neuropathy • Infections • Leading cause of amputations

  26. 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

  27. dambrosio-eye-care-boston.com

  28. CAUSES OF END STAGE RENAL DISEASE PERCENT OF CASES Diabetes 34.2 Hypertension 29.2 Glomerulonephritis 14.2 Interstitial nephritis 3.4 Cystic kidney disease 3.4 Other or unknown 15.4

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

  30. 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

  31. 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

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

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