Lecture Notes on Gluconeogenesis

Introduction to Gluconeogenesis

• Gluconeogenesis: Formation of new glucose molecules from non-carbohydrate sources.
  • Non-carbohydrate sources: Amino acids, glycerol, lactic acid.

Location of Gluconeogenesis

• Occurs primarily in:
  • Liver
  • Kidneys (specifically the proximal convoluted tubule)

Purpose of Gluconeogenesis

• Occurs when blood glucose levels are low (hypoglycemia).
• Essential for the brain:
  • The brain relies predominantly on glucose as its main fuel.
  • Ketone bodies are a secondary and less preferred fuel source during prolonged fasting, but they may lead to ketoacidosis.

Gluconeogenic Pathway Overview

• Reverse process of glycolysis with some modifications:
  • Glucose enters cells via GLUT transporters (e.g., GLUT 2 in liver, GLUT 3 in kidneys).
  • Converts to various intermediates such as glucose 6-phosphate, fructose 6-phosphate, and ultimately pyruvate.
  • Important control steps in glycolysis are irreversible, requiring alternative pathways in gluconeogenesis.

Key Steps of Gluconeogenesis

1. Lactic Acid to Pyruvate
   • Lactic acid from muscles is converted to pyruvate.
   • Pyruvate enters mitochondria, converts to oxaloacetate (via pyruvate carboxylase), then to malate, exits mitochondria, reconverts to oxaloacetate.
   • Oxaloacetate transforms to PEP (phosphoenolpyruvate) via PEPCK.
2. Fructose 1,6-bisphosphate Conversion
   • Fructose 1,6-bisphosphatase converts fructose 1,6-bisphosphate to fructose 6-phosphate.
3. Glycerol Conversion
   • Glycerol (from triglycerides) converts directly to dihydroxyacetone phosphate, bypassing earlier glycolysis steps.
4. Endoplasmic Reticulum Role
   • Glucose 6-phosphate enters smooth ER, is dephosphorylated by glucose 6-phosphatase, becomes glucose, exits into bloodstream.

Additional Pathways

• Protein Catabolism
  • Proteins are broken down to amino acids which can be converted to glucose intermediates.
• Fatty Acids
  • Odd-chain fatty acids can minimally contribute via succinyl-CoA.

Hormonal Regulation

• Several hormones stimulate gluconeogenesis:
  • Glucagon
  • Norepinephrine & Epinephrine
  • Cortisol (key regulator)
  • Thyroid Hormone
  • Growth Hormone

Summary

• Contributors to Gluconeogenesis:
  • Lactic acid, glycerol, amino acids, and insignificantly, odd-chain fatty acids.

Importance

• Vital for maintaining blood glucose levels, especially during fasting or low carbohydrate intake.
• Prevents hypoglycemia and supports brain function.

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Ensure to review each step of the gluconeogenic pathway and understand the significance of each hormonal regulator in facilitating this metabolic process.