Gluconeogenesis (1)

Gluconeogenesis Overview

  • Definition: Group of metabolic reactions in cytosol and mitochondria to maintain blood glucose levels during fasting.

  • Regulation: Local and global regulation through hormones such as insulin, glucagon, and cortisol. Some reactions are highly exergonic and irreversible.

  • Key Organs: Liver is the primary organ for blood glucose supply; kidneys play a secondary role during prolonged fasting.

Importance of Glucose Supply

  • Continuous glucose supply is essential for several tissues:

    • Brain: Primarily relies on glucose, using 70% of the total glucose produced during fasting.

    • Erythrocytes, Renal Medulla, Lens and Cornea, Testes, Skeletal Muscles: Also require glucose.

  • Initial Energy Sources: Hepatic glycogenolysis (up to 190 g of glucose available) covers energy needs for roughly one day. The daily requirement is approximately 160 g.

Shift to Gluconeogenesis

  • After several hours of fasting, gluconeogenesis starts contributing significantly to glucose production:

    • 54% from gluconeogenesis after 14 hours of starvation.

    • 64% after 22 hours and up to 84% after 42 hours.

Alternative Glucose Sources

  • With depleted glycogen storage, alternative sources for gluconeogenesis include:

    • Lactate

    • Glycerol: Derived from triglyceride catabolism.

    • Glucogenic Amino Acids: Such as alanine, methionine, and valine.

    • Odd-chain Fatty Acids: Converted during beta-oxidation to propionyl CoA, then to succinyl CoA, an intermediate in the TCA cycle that can enter gluconeogenesis.

Mechanism and Reactions

  • Initiation: Pyruvate carboxylase converts pyruvate to oxaloacetate, which is then phosphorylated to phosphoenolpyruvate (PEP) through PEP carboxykinase.

  • Key Enzymes:

    • Pyruvate Carboxylase (PC): Requires ATP and biotin, found in mitochondria.

    • Phosphoenolpyruvate Carboxykinase (PEPCK): Uses GTP as a phosphate donor, induced by glucocorticoids.

  • Subsequent Steps:

    • Enolase converts PEP to 2-phosphoglycerate, followed by a series of reversible reactions leading to fructose-1,6 bisphosphate.

    • Rate-Limiting Step: Conversion of fructose-1,6 bisphosphate to fructose-6 phosphate via fructose-1,6 bisphosphatase, regulated by ATP, citrate, AMP, and fructose-2,6 bisphosphate.

Final Conversion to Glucose

  • The last irreversible step is catalyzed by glucose-6 phosphatase, converting glucose-6 phosphate to glucose, primarily in the liver and kidneys.

  • Muscle cells do not express this enzyme, as their glucose use is primarily for energy needs.

Clinical Significance

Glycogen Storage Disease Type 1 - Von Gierke Disease

  • Characteristics: Inherited metabolic disorder with poor fasting tolerance due to lack of glucose-6 phosphatase.

  • Symptoms:

    • Hepatomegaly and kidney enlargement.

    • Severe fasting hypoglycemia.

    • Lactic acidosis due to accumulation of glucose-6 phosphate.

    • Hypertriglyceridemia and hyperuricemia due to disrupted metabolic pathways.

Pyruvate Carboxylase Deficiency

  • Implications: Lack of pyruvate carboxylase leads to lactic acidosis, hyperammonemia, and hypoglycemia.

  • Hyperammonemia caused by reduced oxaloacetate levels affecting the urea cycle.