A 38-year-old man with uncontrolled type 1 diabetes mellitus presents with diabetic ketoacidosis (DKA). His arterial blood gas shows pH 7.15, HCO~3~^−^ 12 mEq/L, and PaCO~2~ 28 mmHg. Regarding ketone body metabolism in this patient, all of the following are true EXCEPT:

Explanation

## Ketone Body Metabolism in Diabetic Ketoacidosis **Key Point:** DKA is characterized by excessive production of the two metabolically active ketone bodies—acetoacetate and beta-hydroxybutyrate—which are strong organic acids. Acetone, the third ketone body, is metabolically inert and does NOT contribute to the acidosis. ## Analysis of Each Statement ### Statement 1: Elevated Beta-Hydroxybutyrate/Acetoacetate Ratio **Correct.** In DKA, the mitochondrial NADH/NAD^+^ ratio is markedly elevated due to accelerated fatty acid oxidation. This favors the reduction of acetoacetate to beta-hydroxybutyrate via beta-hydroxybutyrate dehydrogenase. The ratio of beta-hydroxybutyrate to acetoacetate can reach 10:1 or higher (compared to 3:1 in the fed state), making beta-hydroxybutyrate the predominant ketone body. [cite:Harrison 21e Ch 397] ### Statement 2: Elevated Acetyl-CoA and Impaired Pyruvate Dehydrogenase **Correct.** In uncontrolled diabetes: - Lipolysis is uncontrolled due to low insulin and high glucagon, releasing free fatty acids. - Fatty acid oxidation generates acetyl-CoA in excess of the TCA cycle's capacity to oxidize it. - Low insulin also impairs pyruvate dehydrogenase activity (via increased acetyl-CoA and NADH, which inhibit the enzyme). - These conditions converge to drive ketogenesis. [cite:KD Tripathi 8e Ch 12] ### Statement 3: Acetone as Primary Cause of Metabolic Acidosis **INCORRECT — This is the answer.** Acetone is NOT an organic acid and does NOT contribute to the metabolic acidosis in DKA. The acidosis is caused by the two active ketone bodies: - **Acetoacetate** (a β-keto acid, pKa ~3.5) - **Beta-hydroxybutyrate** (a β-hydroxy acid, pKa ~4.8) Acetone is a volatile, non-acidic byproduct that is exhaled and has no role in the pH disturbance. The anion gap metabolic acidosis in DKA is due to accumulation of acetoacetate and beta-hydroxybutyrate, not acetone. [cite:Harrison 21e Ch 397] ### Statement 4: Insulin Deficiency and Glucagon Elevation **Correct.** In type 1 DM: - Low insulin removes the inhibition of hormone-sensitive lipase and removes suppression of HMG-CoA synthase-2. - High glucagon (unopposed in the absence of insulin) activates lipolysis and upregulates ketogenic enzymes. - Together, these hormonal changes are the primary drivers of excessive ketogenesis. [cite:KD Tripathi 8e Ch 12] ## Pathophysiology of DKA: Ketone Body Contribution ```mermaid flowchart TD A[Type 1 DM: Insulin Deficiency]:::outcome --> B[Low Insulin + High Glucagon]:::outcome B --> C[Uncontrolled Lipolysis]:::action C --> D[Elevated Free Fatty Acids]:::outcome D --> E[Mitochondrial Beta-Oxidation]:::action E --> F[Excess Acetyl-CoA]:::outcome F --> G[HMG-CoA Synthase-2 Upregulation]:::action G --> H[Ketone Body Synthesis]:::action H --> I[Acetoacetate]:::outcome H --> J[Beta-Hydroxybutyrate]:::outcome H --> K[Acetone]:::outcome I --> L[Strong Organic Acid]:::urgent J --> L K --> M[Volatile, Non-Acidic]:::decision L --> N[Metabolic Acidosis & Low pH]:::urgent M --> O[Exhaled: Fruity Breath Odor]:::outcome ``` ## High-Yield Clinical Pearls **Clinical Pearl:** In DKA, the serum ketone measurement (often reported as "serum beta-hydroxybutyrate" or "total ketones") reflects the two active ketone bodies. Acetone is NOT measured in serum ketone assays and does NOT contribute to the anion gap or pH disturbance. **High-Yield:** The characteristic fruity (acetone-like) odor on the breath of DKA patients is from exhaled acetone, which is metabolically inert and a dead-end product of ketogenesis. **Mnemonic:** **AAB** = **A**cetoacetate (Acid), **A**cetone (Absent from acidosis), **B**eta-hydroxybutyrate (Both active ketones cause acidosis).