BCHM 503: Advanced Cellular Biochemistry - Gluconeogenesis and Maintenance of Blood Glucose

Functions of Gluconeogenesis:
- The process of gluconeogenesis serves to synthesize glucose from non-carbohydrate precursors, maintaining blood glucose levels, especially during fasting or intense exercise.
Physiological Conditions for Gluconeogenesis:
- Active primarily in the liver and, to a lesser extent, in the kidneys during fasting.
Enzymes Unique to Gluconeogenesis vs Glycolysis:
- Unique gluconeogenic enzymes include:
- Pyruvate carboxylase
- Phosphoenolpyruvate carboxykinase (PEPCK)
- Fructose-1,6-bisphosphatase
- Glucose-6-phosphatase
- Glycolytic enzymes include:
- Glucokinase
- Phosphofructokinase-1 (PFK-1)
- Pyruvate kinase.
Precursors for Gluconeogenesis:
- Lactate: Produced by anaerobic glycolysis in exercising muscle or red blood cells.
- Glycerol: Released from adipose tissue during triacylglycerol mobilization.
- Alanine: Amino acid produced in muscles, converted to pyruvate in the liver via alanine aminotransferase.
Regulation of Gluconeogenesis:
- Controlled by hormonal signals such as insulin and glucagon and energy status (ATP/ADP and NADH/NAD+ ratios).
Regulation of Blood Glucose Levels:
- After a meal: Insulin is secreted leading to uptake of glucose.
- In fasting state: Glucagon stimulates gluconeogenesis to maintain glucose levels.
- During starvation: Increased gluconeogenesis from fatty acids and proteins.

Lactate:
- Produced in anaerobic conditions in muscles and red blood cells.
- Conversion from lactate to pyruvate involves lactate dehydrogenase and NAD+.
Glycerol:
- Derives from the breakdown of triacylglycerol in adipose tissue.
- Glycerol is phosphorylated to glycerol-3-P by glycerol kinase.
Alanine:
- Produced during protein degradation.
- Converted to pyruvate in the liver via alanine aminotransferase.

Glycolysis:
- Key steps driven by enzymes like glucokinase and phosphofructokinase-1.
- Conversion of glucose to pyruvate leading to generation of ATP.
Gluconeogenesis:
- The reverse pathway requires unique enzymes to bypass irreversible steps in glycolysis:
- Conversion of pyruvate to phosphoenolpyruvate (PEP) is catalyzed by:
  - Pyruvate carboxylase (pyruvate to oxaloacetate) and PEPCK (oxaloacetate to PEP).
- Conversion of fructose-1,6-bisphosphate to fructose-6-phosphate via fructose-1,6-bisphosphatase.
- Conversion of glucose-6-phosphate to glucose via glucose-6-phosphatase.

Inhibitors and Activators:
- Fructose 2,6-bisphosphate:
- Inhibits fructose-1,6-bisphosphatase.
- Stimulated by insulin and inhibited by glucagon.
- Alanine and Acetyl-CoA:
- Activates gluconeogenesis.
- ATP and ADP levels:
- High ATP levels stimulate gluconeogenesis, while low levels of ADP do not.

Postprandial State:
- Blood glucose rises to approximately 120-140 mg/dL after a high-carbohydrate meal and should return to fasting levels within 2-3 hours.
- Insulin release is stimulated by rising glucose levels impacting GLUT2 transport in pancreatic beta cells.
- Insulin facilitates glucose uptake by tissues, converting excess glucose to glycogen in the liver and muscle.
- ATP production from glucose oxidation occurs in every cell, leading to triacylglycerol storage in adipose tissue.

Hyperglycemia:
- Continuously high blood glucose can lead to dehydration (osmotic effect).
- Can culminate in hyperosmolar coma if not regulated.
Hypoglycemia:
- Blood glucose levels dropping below 80-90 mg/dL can lead to lack of energy in glucose-dependent tissues.
- Symptoms include light-headedness, dizziness, drowsiness, and may lead to coma (especially in the brain).

Insulin:
- Secreted in response to elevated blood glucose, promotes uptake and utilization by tissues.
Glucagon:
- Released during low glucose levels to stimulate gluconeogenesis and glycogenolysis in the liver.