BC ADM Diabetes Pathophysiology 2 — Questions and Answers
Question 1: Which mechanism best explains the progressive beta-cell decline seen in type 2 diabetes over time?
- Autoimmune destruction of islet cells
- Glucotoxicity and lipotoxicity causing oxidative stress and apoptosis (Correct answer)
- Amyloid deposition in the liver reducing glycogen synthesis
- Downregulation of GLUT4 receptors in pancreatic tissue
Correct answer: Glucotoxicity and lipotoxicity causing oxidative stress and apoptosis
Chronic hyperglycemia (glucotoxicity) and elevated free fatty acids (lipotoxicity) generate reactive oxygen species that drive beta-cell apoptosis and functional decline.
Question 2: In type 1 diabetes, which HLA haplotypes confer the highest genetic risk?
- HLA-A and HLA-B antigens
- HLA-DR3/DR4 and DQ2/DQ8 alleles (Correct answer)
- HLA-C and HLA-DP antigens
- HLA-DRB1*15 and DQ6 alleles
Correct answer: HLA-DR3/DR4 and DQ2/DQ8 alleles
HLA-DR3/DR4 and DQ2/DQ8 haplotypes account for the majority of genetic susceptibility to type 1 diabetes by influencing autoreactive T-cell responses.
Question 3: What is the primary defect in maturity-onset diabetes of the young type 2 (MODY2)?
- Mutations in the insulin receptor gene
- Loss-of-function mutations in the glucokinase gene (Correct answer)
- Gain-of-function mutations in the sulfonylurea receptor
- Mitochondrial DNA deletions reducing ATP synthesis
Correct answer: Loss-of-function mutations in the glucokinase gene
MODY2 results from heterozygous glucokinase mutations that raise the glucose threshold for insulin secretion, causing mild stable fasting hyperglycemia.
Question 4: How does insulin resistance in skeletal muscle contribute to postprandial hyperglycemia?
- Skeletal muscle secretes counter-regulatory hormones after meals
- Impaired GLUT4 translocation reduces glucose uptake in the largest glucose-disposal organ (Correct answer)
- Muscle glycogenolysis is accelerated due to glucagon excess
- Skeletal muscle increases hepatic glucose output via myokine signaling
Correct answer: Impaired GLUT4 translocation reduces glucose uptake in the largest glucose-disposal organ
Skeletal muscle accounts for ~80% of postprandial glucose disposal; defective insulin-stimulated GLUT4 translocation here is a major driver of postprandial hyperglycemia.
Question 5: Which phenomenon describes the worsening of fasting hyperglycemia due to early-morning rises in cortisol and growth hormone?
- Whipple's triad
- Dawn phenomenon (Correct answer)
- Somogyi effect
- Staub-Traugott effect
Correct answer: Dawn phenomenon
The dawn phenomenon is caused by pre-dawn surges in cortisol and growth hormone that increase hepatic glucose output and reduce peripheral insulin sensitivity.
Question 6: In the pathogenesis of diabetic ketoacidosis, which hormonal ratio is most critical?
- High cortisol-to-epinephrine ratio
- Low insulin-to-glucagon ratio (Correct answer)
- High aldosterone-to-renin ratio
- Low growth hormone-to-IGF-1 ratio
Correct answer: Low insulin-to-glucagon ratio
An absolute or relative insulin deficiency combined with glucagon excess (low insulin-to-glucagon ratio) drives unchecked lipolysis, ketogenesis, and hepatic glucose output in DKA.
Question 7: Which cellular process links chronic hyperglycemia to the development of diabetic nephropathy via the polyol pathway?
- Excess glucose is converted to sorbitol by aldose reductase, depleting NADPH and glutathione (Correct answer)
- Glucose drives mTOR activation, increasing mesangial cell proliferation directly
- Hyperglycemia inhibits AMPK, reducing fatty acid oxidation in podocytes
- Glucose activates caspase-3 in tubular cells via the hexosamine pathway
Correct answer: Excess glucose is converted to sorbitol by aldose reductase, depleting NADPH and glutathione
Aldose reductase converts excess glucose to sorbitol, consuming NADPH and depleting glutathione, which increases oxidative stress and contributes to nephropathy.
BC ADM Diabetes Pathophysiology 2
Which mechanism best explains the progressive beta-cell decline seen in type 2 diabetes over time?