Gluconeogenesis BY MD. Abdullah AL Mamun From BUHS

Gluconeogenesis is the vital metabolic pathway through which the body synthesizes new glucose from non-carbohydrate precursors. Occurring primarily in the liver (and to a lesser extent in the kidneys), this process is essential for maintaining stable blood sugar levels during fasting, strenuous exercise, or low-carbohydrate intake.

The key substrates for gluconeogenesis include lactate (produced by muscles and red blood cells), glycerol (from the breakdown of fats in adipose tissue), and glucogenic amino acids (from dietary protein or muscle breakdown). The pathway is not simply the reverse of glycolysis; it bypasses three irreversible steps of glycolysis using four unique enzymes: pyruvate carboxylase, phosphoenolpyruvate carboxykinase (PEPCK), fructose-1,6-bisphosphatase, and glucose-6-phosphatase.

This energetically expensive process (consuming 6 ATP equivalents to make one glucose molecule) is crucial for supplying glucose to glucose-dependent tissues, most notably the brain and red blood cells. Hormonally, gluconeogenesis is stimulated by glucagon and cortisol, and suppressed by insulin, ensuring glucose is produced precisely when the body needs it most.

1. Gluconeogenesis by AAM

2. Submitted by, MD ABDULLAH AL MAMUN Department : Biochemistry & Cell Biology Id : 0672410003011031 Session : Spring – 24 Submitted to, Prof. Dr. Rahelee Zinnat Head of the Department of Biochemistry & Cell Biology Bangladesh University of Health Sciences

3. Gluconeogenesis: Gluconeogenesis is the metabolic process by which glucose is synthesized from non-carbohydrate precursors , mainly when blood glucose levels are low (e.g., during fasting or intense exercise). It literally means “new formation of glucose .” Sites of Gluconeogenesis : Liver — main site (~90%) Kidney cortex — secondary site (in prolonged fasting~10%) Small intestine — minor role Muscles don’t do gluconeogenesis (lack glucose-6-phosphatase )

4. Why is it important !! Maintains normal blood glucose during fasting, starvation, or intense exercise. Provides glucose for glucose-dependent tissues — brain, RBCs, renal medulla, lens of eye. Removes lactate produced by anaerobic glycolysis in muscles (Cori cycle). Removes alanine from muscle (glucose-alanine cycle) — helps remove ammonia. Provides substrate for glycogen synthesis (indirectly replenishes glycogen stores after fasting). Supports survival during prolonged fasting by ensuring glucose supply. Helps in acid-base balance — kidney gluconeogenesis uses lactate and glutamine, producing ammonia to buffer acid. Important in stress conditions — cortisol stimulates gluconeogenesis to increase blood glucose. Prevents hypoglycemia between meals. Plays a role in metabolic flexibility — shifts body from using carbohydrates to fats/proteins for glucose production .

5. Substrates : Non-carbohydrate precursors: Amino acids (especially alanine & glutamine) Lactate (from anaerobic glycolysis; Cori cycle) Glycerol (from triglyceride breakdown) TCA cycle intermediates (e.g., oxaloacetate) Pyruvate Starting Meterial : Oxaloacetate is the starting meterial for Gluconeogenesis.

6. Regulation of Gluconeogenesis : Stimulated by: Fasting Glucagon (↑ cAMP → activates key enzymes) Cortisol (induces gluconeogenic enzymes) High ATP & Acetyl-CoA (from fat oxidation) Inhibited by: Insulin (promotes glycolysis instead) High ADP (low energy inhibits) High glucose levels 🔑 Key regulatory enzymes: Pyruvate carboxylase (activated by acetyl-CoA) PEP carboxykinase (induced by glucagon, cortisol) Fructose-1,6-bisphosphatase (inhibited by fructose-2,6-bisphosphate & AMP) Glucose-6-phosphatase

7. Gluconeogenesis from Amino acids

8. Gluconeogenesis from Lactate(Cori Cycle)

9. Gluconeogenesis from Glycerol

10. Gluconeogenesis from Intermediates of TCA Cycle

11. Gluconeogenesis from Pyruvate

12. Key Steps & Enzymes: 1) Pyruvate → Oxaloacetate → Phosphoenolpyruvate (PEP) Enzymes: Pyruvate carboxylase (mitochondria; needs biotin; activated by acetyl-CoA) PEP carboxykinase (PEPCK) (cytosol) 2) Fructose-1,6-bisphosphate → Fructose-6-phosphate Enzyme: Fructose-1,6-bisphosphatase (key control point; inhibited by fructose-2,6-bisphosphate & AMP) 3) Glucose-6-phosphate → Glucose Enzyme: Glucose-6-phosphatase (present in liver & kidney; absent in muscle)

13. Hormonal Regulation of Gluconeogenesis Hormones that Stimulate Gluconeogenesi s: Glucagon Increases cAMP → activates PKA → activates key gluconeogenic enzymes. ↓ Fructose-2,6-bisphosphate → less inhibition of Fructose-1,6-bisphosphatase . Cortisol (stress hormone) Increases expression of gluconeogenic enzymes (PEPCK, glucose-6-phosphatase). Mobilizes amino acids from muscle for gluconeogenesis. Epinephrine (Adrenaline) Indirectly supports gluconeogenesis during stress & exercise. Increases lipolysis → more ATP & acetyl-CoA → supports gluconeogenesis .

14. Hormone that Inhibits Gluconeogenesis: Insulin ↓ Gluconeogenic enzyme expression. ↑ Glycolysis & glycogen synthesis instead. ↑ Fructose-2,6-bisphosphate → inhibits Fructose-1,6-bisphosphatase. Decreases PEPCK & glucose-6-phosphatase expression. Clinical Relevance Prevents hypoglycemia in fasting. ↑ Gluconeogenesis → hyperglycemia in diabetes & Cushing’s. ↓ Gluconeogenesis → hypoglycemia in alcohol abuse, enzyme defects (e.g., Von Gierke’s ). Failure to clear lactate → lactic acidosis .

15. Disorders of Gluconeogenesis Von Gierke’s Disease: ↓ Glucose-6-phosphatase → fasting hypoglycemia. Fructose-1,6-bisphosphatase deficiency: Hypoglycemia, lactic acidosis. Alcohol abuse: NADH ↑ → blocks gluconeogenesis → hypoglycemia. Diabetes & Cushing’s: ↑ Gluconeogenesis → hyperglycemia. Kidney failure: ↓ renal gluconeogenesis → hypoglycemia risk.

16. Conclusion on Gluconeogenesis Gluconeogenesis is vital for maintaining blood glucose during fasting or stress. It uses non-carbohydrate sources like amino acids, lactate, and glycerol. Liver and kidney are the main sites. It is tightly regulated by hormones — glucagon & cortisol stimulate , insulin inhibits . Proper function prevents hypoglycemia , while imbalance can cause hypo- or hyperglycemia . Overall, it plays a key role in energy balance & survival during periods without food.