Ketone Metabolism

Overview

• Ketone metabolism occurs under specific conditions:
  • Low blood glucose levels
  • Prolonged starvation
  • Uncontrolled diabetes mellitus (mainly Type 1)
  • Carbohydrate-restricting diets (e.g., Atkins diet)

Stimuli for Ketone Metabolism

• Low Blood Glucose Levels: Brain and muscles require an alternative energy source.
• Prolonged Starvation: Depletion of glucose stores.
• Uncontrolled Diabetes: Insulin deficiency leads to low glucose availability inside cells.
• Special Diets: Restrictions on carbohydrates force body to seek alternate energy sources.

Organ Utilization

• Brain: Switches to ketone bodies when glucose is not available.
• Muscles: Uses ketone bodies when fatty acids and glucose are low.

Ketogenesis Location

• Liver: Main site of ketone body production.
• Muscles and Brain: Main sites of ketone body utilization.

Biochemical Pathways

Normal Glucose Metabolism

1. Glucose → Pyruvate → Acetyl-CoA
2. Acetyl-CoA + Oxaloacetate (OAA) → Citrate (Krebs Cycle)
3. Produces: NADH, FADH2, ATP

Conditions with Low Blood Glucose

• Low pyruvate & acetyl-CoA → Reduced Krebs cycle activity
• Gluconeogenesis: OAA → Malate → OAA → Phosphoenolpyruvate (PEP) → Glucose
• Beta-Oxidation: Fatty acids → Acetyl-CoA (Excess)

Shift in Metabolic Pathway

• Primary Fuel: Carbohydrates
• Secondary Fuel: Fatty acids (via beta-oxidation)

Ketogenesis Process

1. Beta-Oxidation: Fatty acids → Acetyl-CoA
2. Excess Acetyl-CoA: Conversion to ketone bodies in the liver
   • Two Acetyl-CoA (via acetoacetyl-CoA transferase) → Acetoacetyl-CoA
   • Acetoacetyl-CoA + Acetyl-CoA → HMG-CoA (via HMG-CoA synthase)
   • HMG-CoA (via HMG-CoA lyase) → Acetoacetate + Acetyl-CoA
   • Acetoacetate can convert to Beta-hydroxybutyrate (via beta-hydroxybutyrate dehydrogenase)

Ketosis & Associated Conditions

• Ketone Bodies: Acetoacetate & Beta-hydroxybutyrate travel in blood to brain/muscle
• Ketoacidosis: High levels of ketone bodies make blood acidic
  • Symptoms:
    • Acetone breath
    • Acidosis (Low blood pH)
    • Elevated anion gap
    • Vomiting
    • Hypovolemia
    • Coma (Severe cases)
    • Kussmaul breathing (Deep, rapid breaths)
    • Ketonuria (Ketones in urine)

Utilization in Muscles and Brain

1. Beta-hydroxybutyrate: Converted back to acetoacetate
   • Beta-hydroxybutyrate dehydrogenase: Converts Beta-hydroxybutyrate → Acetoacetate
2. Acetoacetate: Converted to Acetoacetyl-CoA
   • SCOT enzyme: Transfers CoA from succinyl-CoA to acetoacetate
3. Acetoacetyl-CoA → 2 Acetyl-CoA
   • Enters Krebs Cycle → Produces NADH, FADH2, and ATP

Clinical Symptoms of Ketosis

• Acetone Breath: Fruity smell due to acetone production.
• Ketoacidosis Lab Findings: Elevated anion gap, ketones in urine.
• Vomiting & Hypovolemia: Excess vomit leads to dehydration.
• Kussmaul Breathing: Deep, rapid breaths to expel CO2 and reduce acidosis.

Conclusion

• Ketones serve as an essential alternative energy source under specific conditions.
• Active metabolic management is crucial in conditions like uncontrolled diabetes.
• Recognizing the symptoms and biochemical changes in ketosis is critical in medical settings.