BL4 Glucose Homeostasis

• Glucose homeostasis

  The balance of insulin and glucagon to maintain blood glucose

  
• Blood glucose levels in different states

  • Post-absorptive state: 4.5 to 5.5 mmol/L
  • Fed state: 6.5 to 7.2 mmol/L
  • Starvation: 3.3 to 3.9 mmol/L

  
• Glucose flux in different stages of feeding

  1. Absorptive/fed state

  2. Post-absorptive state

  3. Fasting state

  4. Starvation
• Well-Fed State (Phase I)


  • Increased plasma glucose promotes the release of insulin
  • Excess fuel converted to glycogen and fat
  • Glucose can be converted into glycogen, pyruvate or pentoses
  • Pyruvate used for lipogenesis
  • Much of the absorbed glucose circulates to other tissues
  • Liver utilizes glucose and is not engage in gluconeogenesis

  
• Post-absorptive Phase (Phase II)

  • Liver glycogenolysis provides the most glucose (75%)
  • Gluconeogenesis provides the remainder (alanine 5-10%; lactate 10-15%)
  • Glucose-alanine cycle becomes active

  
• Fasting State (Phase III)


  • Body switches emphasis to free fatty acids as fuel
  • Dietary fuel unavailable and no liver glycogen remains
  • Complete dependence upon hepatic gluconeogenesis
  • Fatty acids cannot be used for net synthesis of glucose
  • Protein catabolism within muscle produces amino acids for glucose synthesis in liver

  
• Prolonged Starvation (Phase IV)


  • Ketones play a central role
  • Replaces glucose as the primary fuel for the brain
  • Signals a reduction in protein catabolism and alanine output from muscle
  • Protein conservation is achieved and glucose homeostasis is maintained

  
• Gluconeogenesis

  The formation of glucose from non-carbohydrate precursors

  
• Insulin


  Important when glucose is in excess

  
• Excessive gluconeogenesis


  • Occurs in critically ill patients in response to injury and infection
  • Contributes to hyperglycemia which impairs endothelial and immune system function, blood coagulation
  • Leads to hyperglycemia in type 2 diabetes
• Compounds that undergo gluconeogenesis


  • Those involving direct net conversion to glucose (most amino acids, propionate)
  • Products of glucose metabolism (lactate, glycerol)

  
• Regulation of glucose homeostasis

  1. Enzymatic regulation (changes in enzyme synthesis, covalent modification, allosteric effects)

  2. Hormonal regulation (insulin, glucagon, growth hormone, ACTH, cytokines, epinephrine)

  
• Regulation by insulin

  • Produced by pancreatic β-cells in response to hyperglycemia
  • Enhances glucose transport into adipose tissue and muscle
  • Enhances synthesis of key enzymes in glycolysis
  • Indirectly inhibits synthesis of key enzymes of gluconeogenesis

  
• Regulation by glucagon

  • Produced by pancreatic α-cells in response to hypoglycemia
  • Stimulates glycogenolysis in the liver
  • Enhances gluconeogenesis from amino acids and lactate

  
• Glucosuria occurs when the renal threshold for glucose is exceeded

  
• Glucose is continuously filtered by the glomeruli but normally completely reabsorbed in the renal tubules

  
• In hyperglycemia, the glomerular filtrate may contain more glucose than can be reabsorbed, resulting in glucosuria

  
• Failure of gluconeogenesis causes

  hypoglycaemia = brain dysfunction, coma, death
• gluconeogenesis helps to

  clear lactate produces by muscle & erythrocyts and glycerol produces by adipose tissue