Welcome to USMLE practice question #143! Today’s topic is biochemistry.
I’m Paul Ciurysek, MD, founder of The USMLE Guys! This daily newsletter aims to provide super high-yield USMLE concepts commonly tested on exam day. All content is FREE! If you’d like more help with your USMLE preparation, please see the options at the bottom of today’s newsletter. Please share the newsletter with a friend if you’d like to support our efforts!
A 21-year-old woman with type 1 diabetes is brought to the hospital by her roommate, who reports that the patient has been drowsy and confused for the past day. She has missed her last two insulin injections because she ran out of medication. Her vital signs reveal a temperature of 37.5°C (99.5°F), pulse of 120/min, respiratory rate of 28/min, and blood pressure of 95/60 mm Hg. Arterial blood gas analysis shows a high anion gap metabolic acidosis with a pH of 7.18. Serum ketones are markedly elevated. Which of the following enzymatic changes in hepatic metabolism most directly contributes to ketogenesis in this scenario?
A) Decreased fructose-1,6-bisphosphatase activity
B) Decreased glucokinase activity
C) Increased glyceraldehyde-3-phosphate dehydrogenase activity
D) Increased activity of carnitine acyltransferase I
E) Upregulation of lactate dehydrogenase
Detailed Breakdown of Answers + Correct Answer Below ⏬
ANSWER + QUESTION BREAKDOWN
It’s important to adopt the correct MENTAL MODEL when answering USMLE questions; it saves time and increases accuracy. The mental model outlined below is a foundational component of our test-taking skills masterclass (check it out if you want to elevate your skills). Here’s how to think through this question:
Step 1. Read the last line to get to the heart of the question: “Which of the following enzymatic changes in hepatic metabolism most directly contributes to ketogenesis in this scenario?”
Step 2: Is this a first-, second-, or third-order question?
Answer: 2nd order. 1st: Diagnose the problem, 2nd: Identify the underlying cause.
Step 3: Read the vignette carefully and ask yourself: “Based on the presence of ketogenesis, the most likely enzymatic cause is ______________.”
Step 4. Look at the answer choices and select the option most closely resembling your final thought from “Step 3” above.
GENERAL ANALYSIS
This 21-year-old woman with type 1 diabetes presents with drowsiness, confusion, and high anion gap metabolic acidosis (pH 7.18), along with markedly elevated serum ketones, consistent with diabetic ketoacidosis (DKA). DKA occurs due to insulin deficiency, which shifts the body’s metabolism toward fat breakdown and ketogenesis. The absence of insulin leads to uncontrolled lipolysis, increased free fatty acid (FFA) release, and subsequent ketone body production in the liver.
ANSWER CHOICES:
CHOICE A: Decreased fructose-1,6-bisphosphatase activity
Explanation: Fructose-1,6-bisphosphatase is a key enzyme in gluconeogenesis that converts fructose-1,6-bisphosphate into fructose-6-phosphate. Decreased activity of this enzyme would impair gluconeogenesis and worsen hypoglycemia.
CHOICE B: Decreased glucokinase activity
Explanation: Glucokinase is a key enzyme in glycolysis that phosphorylates glucose to glucose-6-phosphate in the liver. Decreased glucokinase activity reduces glucose utilization and promotes hyperglycemia.
CHOICE C: Increased glyceraldehyde-3-phosphate dehydrogenase activity
Explanation: Glyceraldehyde-3-phosphate dehydrogenase is an enzyme in glycolysis that converts glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate. Increased activity would enhance glycolysis.
CHOICE D: Increased activity of carnitine acyltransferase I
Explanation: Carnitine acyltransferase I (CPT-1) is a key enzyme in the carnitine shuttle system that transports long-chain fatty acids into the mitochondria for beta-oxidation. In states of insulin deficiency, malonyl-CoA levels decrease due to reduced acetyl-CoA carboxylase activity, relieving inhibition of CPT-1. This allows increased mitochondrial uptake of fatty acids, leading to enhanced beta-oxidation and subsequent ketone body production.
CHOICE E: Upregulation of lactate dehydrogenase
Explanation: Lactate dehydrogenase catalyzes the conversion of pyruvate to lactate under anaerobic conditions. Increased activity leads to lactic acidosis but does not contribute to ketone body production.
FINAL VERDICT…
CORRECT ANSWER: D) Increased activity of carnitine acyltransferase I
In diabetic ketoacidosis, insulin deficiency leads to increased lipolysis and free fatty acid release from adipose tissue. These fatty acids are transported into liver mitochondria via carnitine acyltransferase I (CPT-1), where they undergo beta-oxidation to produce acetyl-CoA, fueling ketogenesis.
KEY CONCEPTS:
Pathophysiology of Diabetic Ketoacidosis (DKA):
Insulin deficiency → Increased lipolysis → Elevated free fatty acids.
Free fatty acids are transported into mitochondria via CPT-1.
Beta-oxidation produces acetyl-CoA → Ketone body synthesis.
Accumulation of acetoacetate and beta-hydroxybutyrate leads to metabolic acidosis.
Role of Carnitine Acyltransferase I (CPT-1):
CPT-1 facilitates mitochondrial uptake of long-chain fatty acids.
Insulin deficiency decreases malonyl-CoA levels (an inhibitor of CPT-1), enhancing CPT-1 activity.
Increased CPT-1 activity drives beta-oxidation and ketogenesis.
Clinical Features of DKA:
Symptoms: Polyuria, polydipsia, abdominal pain, confusion.
Signs: Tachypnea (Kussmaul breathing), fruity breath (acetone), dehydration.
Laboratory findings: High anion gap metabolic acidosis, hyperglycemia, elevated serum ketones.
Management of DKA:
Fluid resuscitation.
Insulin therapy to suppress lipolysis and ketogenesis.
Electrolyte correction (e.g., potassium replacement).