قناة ثالثة بشري (دفعه 52)

8. Ketosis and Diabetic Ketoacidosis (DKA) Ketosis Occurs when ketone body production exceeds utilization: • Ketonemia • Ketonuria • Acetone smell in breath Diabetic Ketoacidosis (DKA) • Seen in uncontrolled diabetes mellitus • Excess acetoacetate & β-hydroxybutyrate ↓ blood pH • Causes metabolic acidosis Clinical Features • Hyperglycemia & glucosuria • Osmotic diuresis → dehydration • Electrolyte imbalance: • Hyperkalemia (despite total body K depletion) • Na⁺ and phosphate loss • Acidotic breathing • Abdominal pain, vomiting • Acetone breath odor • Coma if untreated 9. Management of DKA 1. Intravenous insulin and glucose 2. Intravenous bicarbonate to correct acidosis 3. Correction of electrolyte imbalance

6. Use of Ketone Bodies by Peripheral Tissues (Ketolysis) Site • Mitochondria of extra-hepatic tissues Steps 1. β-Hydroxybutyrate → Acetoacetate (produces NADH) 2. Acetoacetate → Acetoacetyl-CoA • Enzyme: Thiophorase • CoA donor: Succinyl-CoA 3. Acetoacetyl-CoA → 2 Acetyl-CoA • Enters TCA cycle for ATP production 🔹 Liver lacks thiophorase, so it cannot perform ketolysis. 7. Energetics of Ketone Body Oxidation • Acetoacetate: • Produces 2 acetyl-CoA → 24 ATP • −1 ATP for activation • Net = 23 ATP • β-Hydroxybutyrate: • Produces NADH (+3 ATP) • Net = 26 ATP

5. Regulation of Ketone Body Formation After Meals • ↑ Insulin → ↓ lipolysis → ↓ ketogenesis • Insulin activates acetyl-CoA carboxylase → ↑ malonyl-CoA • Malonyl-CoA inhibits CPT-I → ↓ β-oxidation During Fasting / Diabetes • ↓ Insulin & ↑ counter-regulatory hormones • ↑ Lipolysis → ↑ fatty acid oxidation → ↑ ketogenesis

4. Mechanism of Increased Ketogenesis During Fasting & Diabetes • Increased lipolysis → ↑ free fatty acids • ↑ β-oxidation → ↑ acetyl-CoA • Acetyl-CoA: • Inhibits pyruvate dehydrogenase • Activates pyruvate carboxylase • Oxaloacetate (OAA) is diverted to gluconeogenesis • ↓ OAA for TCA cycle → acetyl-CoA diverted to ketone body synthesis

3. Ketogenesis Ketogenesis is the process by which acetyl-CoA is converted into ketone bodies in the mitochondria of liver cells. Site • Liver mitochondria Precursors • Acetyl-CoA derived from: • Fatty acid β-oxidation • Ketogenic amino acids Key Intermediate • HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) → common intermediate for ketone body and cholesterol synthesis Rate-Limiting Enzyme • HMG-CoA synthase Conditions Increasing Ketogenesis • Starvation • Uncontrolled diabetes mellitus • Low-carbohydrate diet

2. Functions of Ketone Bodies Ketone bodies serve as an alternative source of energy when glucose availability is low. Key Features • Water-soluble → transported freely in blood • Do not require lipoproteins or albumin • Produced when acetyl-CoA exceeds the oxidative capacity of the liver Utilization • Used by extra-hepatic tissues: • Skeletal muscle • Cardiac muscle • Renal cortex • Brain uses ketone bodies after 5–6 days of starvation • Liver cannot oxidize ketone bodies (lacks thiophorase enzyme) • RBCs cannot use ketone bodies (no mitochondria)

🛑🛑 Ketone Bodies 1. Definition of Ketone Bodies Ketone bodies are water-soluble molecules synthesized in the liver mitochondria from excess acetyl-CoA produced mainly during fatty acid oxidation. Types of Ketone Bodies 1. Acetoacetate 2. β-Hydroxybutyrate 3. Acetone (volatile, not used for energy)

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11. α-Oxidation of Fatty Acids • Occurs in brain and nervous tissue • Used for branched-chain fatty acids • Removes one carbon at a time from the α-carbon • Important for metabolism of phytanic acid • Does not produce ATP 12. ω-Oxidation of Fatty Acids • Occurs at the ω-carbon (terminal CH₃ group) • Minor pathway • Takes place mainly in the endoplasmic reticulum • Becomes important when β-oxidation is defective