Question 9

College Answer

This question was mainly about the metabolic consequences of an intravenous load of 25 grams of glucose. For a good pass the main areas that required description included: 

• The transient glycosuria.
• The mechanism and time course of the biphasic release of insulin from pancreatic β cells.
• The mechanism of the trapping of glucose within liver cells.
• The multiple actions of insulin which include inhibiting glycogenolysis and promoting
• glycgogen synthesis in the liver, promoting the uptake of glucose by muscle, fat and other cells, increasing the metabolism of glucose to fatty acids and triglycerides, inhibiting triglyceride breakdown and promoting protein synthesis.

Additional marks were awarded for details of where these actions of insulin occurred and the enzymes that were stimulated or inhibited by insulin.
Some candidates stated that this bolus of hypertonic glucose would produce a significant and prolonged increase in plasma osmolarity and then went on to produce detailed descriptions of the thirst and ADH mechanisms. In fact with a normal insulin response glucose is rapidly cleared from the blood.

Reference Text: Guyton Chp 67

Discussion

• Immediate biochemical effects:
  • BSL would increase ( up to 13-15 mmol/L after 5 minutes)
  • This would be transient (~ 30 minutes)
  • Serum osmolality would increase (below osmoreceptor threshold)
  • Blood volume would increase (slightly)
  • Osmotic effects of the excess glucose in the renal tubule fluid produce an osmotic diuresis and glycosuria
• Glucose sensing by pancreatic β-cells and α-cells
  • Glucose diffusion and conversion by glucokinase would result in ATP generation which influences ATP-sensitive potassium channels
  • This depolarises the cells and leads to increased insulin degranulation and decreased glucagon degranulation
• Insulin is released in a biphasic pattern
  • Insulin binds to its receptors (tyrosine kinase intracellular domain)
  • Multiple metabolic 
• Immediate effects of insulin on the liver:
  • Reduced gluconeogenesis, urea synthesis, glycogenolysis, free fatty acid oxidation and ketone production
  • Increased glycogen synthesis and VLDL synthesis
  • This decreases glucose release by the liver, and increases glucose uptake
• Effects of insulin on insulin-sensitive tissues:
  • On binding of insulin to its receptor in these tissues, GLUT4 transport proteins are translocated to the surface, increasing the permeability of the cell membrane to glucose
  • Effect of insulin on the skeletal muscle
    • Increased glycogen synthesis
    • Increased protein synthesis and decreased protein catabolism
  • Effect of insulin on adipose tissue
    • Increased synthesis of triglycerides and decreased lipolysis
    • Increased lipoprotein lipase activity
    • Increased uptake of free fatty acids

Gerich, John E. "Physiology of glucose homeostasis." Diabetes, Obesity and Metabolism 2.6 (2000): 345-350.

Herman, Mark A., and Barbara B. Kahn. "Glucose transport and sensing in the maintenance of glucose homeostasis and metabolic harmony." The Journal of clinical investigation 116.7 (2006): 1767-1775.

Regittnig, Werner, et al. "Assessment of transcapillary glucose exchange in human skeletal muscle and adipose tissue." American Journal of Physiology-Endocrinology and Metabolism 285.2 (2003): E241-E251.

Balentine, Jerry R., et al. "Effect of 50 milliliters of 50% dextrose in water administration on the blood sugar of euglycemic volunteers." Academic emergency medicine 5.7 (1998): 691-694.