Gluconeogenesis: Reactions and Regulation

Gluconeogenesis Overview - Sweet Rebirth

• Definition: Metabolic pathway generating new glucose from diverse non-carbohydrate precursors like lactate, pyruvate, glycerol, and specific amino acids.
• Primary Function: Maintains blood glucose during fasting, starvation, or prolonged exercise.
• Major Sites:
  • Liver (primary, ~90%)
  • Kidney cortex (secondary, ~10%)
• Cellular Location:
  • Mitochondria
  • Cytosol
  • Endoplasmic Reticulum (ER - final step)

⭐ Gluconeogenesis is NOT a simple reversal of glycolysis; it bypasses three irreversible glycolytic reactions using distinct enzymes.

Gluconeogenesis Substrates - Fueling Glucose Up

• Lactate: From anaerobic glycolysis (muscle, RBCs); via Cori cycle. $Lactate \rightarrow Pyruvate$.
• Pyruvate: Central entry point.
• Glycerol: From triglyceride breakdown (adipose); forms Dihydroxyacetone Phosphate (DHAP).
• Glucogenic Amino Acids: All except Leucine & Lysine (📌 "L"ovely "L"adies are ketogenic). Enter as pyruvate or TCA intermediates.

  ⭐ Alanine (muscle; Glucose-Alanine cycle) is a key gluconeogenic amino acid.

• Propionyl CoA: From odd-chain fatty acids, some AAs; forms succinyl CoA.

Gluconeogenesis Reactions - The Uphill Sugar Path

Error generating content for this concept group: Failed to process successful response

Gluconeogenesis Regulation - Glucose Traffic Cops

Gluconeogenesis (GNG) is precisely regulated by hormones and allosteric molecules, with $F-2,6-BP$ as a key reciprocal switch.

Gluconeogenesis Clinicals - Sweetness Gone Sour

• Impaired GNG causes Hypoglycemia:
  • Alcohol intoxication: ↑NADH/NAD+ ratio diverts pyruvate $\rightarrow$ lactate & oxaloacetate (OAA) $\rightarrow$ malate.
  • Enzyme deficiencies: Glucose-6-phosphatase (Von Gierke's), PEPCK, Fructose-1,6-bisphosphatase.
• Type 2 Diabetes: Excessive gluconeogenesis contributes to hyperglycemia.

⭐ Alcohol-induced hypoglycemia is primarily due to the increased NADH/NAD+ ratio, which inhibits the conversion of lactate to pyruvate and malate to oxaloacetate, thus limiting gluconeogenic precursors.

High‑Yield Points - ⚡ Biggest Takeaways

• Gluconeogenesis is the synthesis of new glucose from non-carbohydrate precursors like lactate, glycerol, and amino acids.
• Primarily occurs in the liver; minor extent in the kidney cortex.
• Bypasses irreversible steps of glycolysis using pyruvate carboxylase, PEPCK, fructose-1,6-bisphosphatase, and glucose-6-phosphatase.
• Fructose-1,6-bisphosphatase is a key regulatory enzyme; inhibited by AMP and fructose-2,6-bisphosphate.
• Acetyl-CoA allosterically activates pyruvate carboxylase.
• Stimulated by glucagon and cortisol; inhibited by insulin.
• Glucose-6-phosphatase, present only in liver and kidney, releases free glucose into blood.