3 Insulin and Glucagon Regulation Notes

Insulin and Glucagon Overview

  • Insulin and glucagon are key hormones involved in the regulation of blood glucose levels.
Reciprocal Regulation
  • Phosphorylation and Dephosphorylation:
    • Insulin stimulates dephosphorylation of enzymes.
    • Glucagon stimulates phosphorylation of enzymes.
Glycogen Metabolism
  • High Blood Glucose:
    • Insulin activates glycogen synthesis and blocks glycogen breakdown.
  • Low Blood Glucose:
    • Glucagon blocks glycogen synthesis and activates glycogen breakdown.

Hormonal Regulation in Skeletal Muscle

  • Catecholamines: Adrenalin (epinephrine) and noradrenalin (norepinephrine)
    • Stimulates phosphorylation of enzymes, blocking glycogen synthesis and enhancing breakdown.
    • Increases levels of fructose 2,6-bisphosphate, stimulating glycolysis.

Genetic Deficiencies and Glycogen Storage Diseases

  • Glycogen storage diseases:
    • Result from deficiencies in enzymes involved in glycogen degradation.
    • Hepatic forms:
      • Fasting hypoglycemia, liver damage.
    • Myopathic forms:
      • Muscle weakness and wasting.
Specific Diseases
  • Von Gierke Disease:
    • Deficiency in glucose-6-phosphatase leading to inability to convert glucose-6-phosphate to glucose in the liver.
  • McArdle Disease:
    • Deficiency of glycogen phosphorylase in muscle tissue.

Fasting State and Blood Glucose

  • Prolonged fasting (approx. 24 hours) leads to depletion of liver glycogen stores.
  • Following depletion, gluconeogenesis becomes the primary method to maintain blood glucose levels.

Gluconeogenesis and Glycolysis Comparison

  • Gluconeogenesis employs 7 of the 10 enzyme-catalyzed reactions of glycolysis.
  • Specific 'by-pass' reactions occur at the 3 regulatory steps of glycolysis.
  • ATP Consumption:
    • $6 ext{ ATP}$ are consumed in gluconeogenesis.
Substrates Used
  • Gluconeogenesis:
    • Lactate, alanine (AAs via TCA cycle), glycerol.

Glucose-6-Phosphate to Glucose

  • The final reaction in gluconeogenesis and glycogen breakdown in the liver.
  • The enzyme involved is embedded in the ER membrane, facilitating glucose secretion out of the cell.
  • Glucose 6-phosphatase is mainly expressed in the liver and kidney.

Von Gierke Disease (Type I)

  • Characterized by a deficiency in glucose-6-phosphatase.
  • Results in no glucose release from the liver to replenish blood glucose levels.
  • Patients experience profound fasting hypoglycemia and require regular carbohydrate feeding, including nocturnal gastric infusions of glucose or uncooked corn starch.

Hormonal Regulation in the Liver

Glycolysis and Gluconeogenesis
  • Fructose 2,6-bisphosphate:
    • The molecule through which insulin and glucagon influence glycolysis and gluconeogenesis in the liver.
    • Levels Effect:
      • High cellular levels = glycolysis “on” and gluconeogenesis “off.”
      • Low cellular levels = gluconeogenesis “on.”
    • Levels are determined by the activity of a bifunctional enzyme that has two enzymatic activities.

Fructose 2,6-Bisphosphate Levels

  • Increased F2,6BP levels turn glycolysis “on.”
  • Decreased F2,6BP levels turn gluconeogenesis “on.”
  • Hormonal influence:
    • Glucagon: Decreases F2,6BP levels.
    • Insulin: Increases F2,6BP levels.
  • Fructose-6-P serves as the precursor and is regulated by these mechanisms.