A 58-year-old man with type 2 diabetes mellitus and heart failure with reduced ejection fraction presents to the emergency department with nausea, diffuse abdominal pain, and profound fatigue for the past 24 hours. Two days ago, he underwent a colonoscopy, for which he completed a standard bowel preparation and fasted. His medications include metformin, lisinopril, carvedilol, and a medication that was added one month ago for his heart failure. On physical examination, his blood pressure is 105/65 mm Hg, pulse is 112/min, and respirations are 24/min and deep. Mucous membranes are dry.
Laboratory results:
| Test | Result |
|---|---|
| Serum sodium | 135 mEq/L |
| Serum potassium | 4.8 mEq/L |
| Serum chloride | 98 mEq/L |
| Serum bicarbonate | 12 mEq/L |
| Blood urea nitrogen | 32 mg/dL |
| Serum creatinine | 1.5 mg/dL |
| Serum glucose | 172 mg/dL |
| Arterial pH | 7.24 |
| Arterial pCO2 | 26 mm Hg |
| Urinalysis | 3+ glucose, 4+ ketones |
Which of the following best describes the primary biochemical mechanism responsible for this patient's acid-base disturbance?
- Decreased malonyl-CoA production leading to disinhibition of hepatic carnitine palmitoyltransferase-IAnswer
- BDirect inhibition of hepatic mitochondrial glycerol-3-phosphate dehydrogenase
- CAbsolute deficiency of endogenous insulin leading to unrestricted hormone-sensitive lipase activity
- DAccumulation of organic unmeasured anions secondary to an acute reduction in glomerular filtration rate
- ECytosolic accumulation of NADH and pyruvate due to impaired peripheral tissue perfusion
Answer
Decreased malonyl-CoA production leading to disinhibition of hepatic carnitine palmitoyltransferase-I
This patient's presentation of high anion gap metabolic acidosis, significant ketonuria, and a mildly elevated blood glucose level in the setting of a recent fasting state and a newly added heart failure medication is highly characteristic of euglycemic diabetic ketoacidosis (DKA) induced by a sodium-glucose cotransporter-2 (SGLT2) inhibitor. SGLT2 inhibitors promote renal glycosuria, which artificially lowers blood glucose. This relative carbohydrate deficit triggers a marked decrease in endogenous insulin secretion and an increase in glucagon secretion from the pancreas. In the liver, this low insulin-to-glucagon ratio inhibits the enzyme acetyl-CoA carboxylase, resulting in decreased production of malonyl-CoA. Malonyl-CoA is a potent allosteric inhibitor of carnitine palmitoyltransferase-I (CPT-I). Its reduction effectively disinhibits CPT-I, allowing large amounts of free fatty acids to be transported into the mitochondria for beta-oxidation. This leads to the massive overproduction of ketone bodies (acetoacetate and beta-hydroxybutyrate), generating the severe high anion gap metabolic acidosis.
Step-by-Step Solution
Key Concept
Sodium-glucose cotransporter-2 (SGLT2) inhibitors can cause euglycemic diabetic ketoacidosis, driven by a low insulin-to-glucagon ratio that decreases malonyl-CoA levels, thereby disinhibiting carnitine palmitoyltransferase-I and promoting unregulated ketogenesis.