BC ADM Diabetes Pathophysiology 5 — Questions and Answers
Question 1: Which concept describes the persistent increased risk of diabetic complications even after achieving good glycemic control, due to epigenetic changes from prior hyperglycemia?
- Glycemic variability index
- Metabolic memory (hyperglycemic memory) (Correct answer)
- Post-translational glucose toxicity
- Cumulative glucose burden effect
Correct answer: Metabolic memory (hyperglycemic memory)
Metabolic memory refers to epigenetic modifications — including histone methylation and DNA methylation changes — imprinted during periods of hyperglycemia that sustain vascular damage even after normoglycemia is restored.
Question 2: In the context of diabetic neuropathy, which mechanism specifically drives the pain and allodynia characteristic of small-fiber neuropathy?
- Large myelinated A-beta fiber demyelination reducing vibration sense
- Sensitization and ectopic discharge of damaged C-fibers and A-delta nociceptors due to oxidative stress and AGE accumulation (Correct answer)
- Autonomic ganglion destruction causing paradoxical pain signaling
- Motor neuron apoptosis leading to denervation hypersensitivity
Correct answer: Sensitization and ectopic discharge of damaged C-fibers and A-delta nociceptors due to oxidative stress and AGE accumulation
Small unmyelinated C-fibers and thinly myelinated A-delta nociceptors become hyperexcitable and fire ectopically when damaged by oxidative stress and AGE-mediated pathways in diabetic neuropathy.
Question 3: Which hormonal change during puberty most significantly worsens insulin resistance and increases insulin requirements in adolescents with type 1 diabetes?
- Increased estrogen causing GLUT4 downregulation
- Pubertal rise in growth hormone reducing peripheral insulin sensitivity (Correct answer)
- Elevated testosterone increasing hepatic gluconeogenesis
- FSH surge causing pancreatic alpha-cell hyperplasia
Correct answer: Pubertal rise in growth hormone reducing peripheral insulin sensitivity
The pubertal rise in growth hormone, which peaks nocturnally, substantially reduces insulin sensitivity in peripheral tissues and requires up to 50% more insulin to maintain glycemic targets.
Question 4: What is the pathophysiological basis for the hyperchloremic non-anion gap metabolic acidosis that can occur after treatment of diabetic ketoacidosis?
- Bicarbonate administration causes a rebound chloride shift
- Saline infusion provides a chloride load while ketones are excreted as sodium salts, depleting bicarbonate regeneration capacity (Correct answer)
- Insulin therapy directly inhibits renal bicarbonate reabsorption
- Ketone oxidation produces excess HCl as a metabolic byproduct
Correct answer: Saline infusion provides a chloride load while ketones are excreted as sodium salts, depleting bicarbonate regeneration capacity
During DKA treatment, large-volume normal saline delivers excess chloride, and urinary loss of sodium ketonate salts removes potential bicarbonate; together these produce a dilutional hyperchloremic acidosis.
Question 5: Which pathophysiological mechanism links obesity-induced chronic low-grade inflammation to skeletal muscle insulin resistance?
- Adipose-derived IL-6 directly degrades GLUT4 protein in myocytes
- Excess free fatty acids and inflammatory cytokines (TNF-α, IL-1β) activate IKK-β and JNK, which serine-phosphorylate and inhibit IRS-1 (Correct answer)
- Macrophage-derived leptin competes with insulin at the insulin receptor
- Visceral fat secretes cortisol locally, suppressing AMPK in adjacent muscle
Correct answer: Excess free fatty acids and inflammatory cytokines (TNF-α, IL-1β) activate IKK-β and JNK, which serine-phosphorylate and inhibit IRS-1
FFA and pro-inflammatory cytokines from hypertrophied adipocytes activate IKK-β and JNK serine kinases that phosphorylate IRS-1 at inhibitory serine residues, blocking the insulin signaling cascade.
Question 6: In type 2 diabetes, what explains the paradoxical finding of elevated circulating insulin alongside hyperglycemia in early disease?
- Proinsulin is misidentified as insulin in immunoassays causing artificially high readings
- Peripheral insulin resistance requires compensatory beta-cell hypersecretion, but glucose cannot be effectively utilized (Correct answer)
- Insulin is sequestered in the liver and does not reach peripheral tissues
- Counter-regulatory hormones block insulin-receptor internalization, raising plasma levels
Correct answer: Peripheral insulin resistance requires compensatory beta-cell hypersecretion, but glucose cannot be effectively utilized
Early T2D is characterized by compensatory hyperinsulinemia as beta cells attempt to overcome peripheral insulin resistance; the hyperglycemia reflects ineffective insulin action rather than absolute deficiency.
Question 7: Which form of monogenic diabetes is caused by heterozygous loss-of-function mutations in HNF-1α and is particularly sensitive to sulfonylurea therapy?
- MODY1 (HNF-4α mutation)
- MODY3 (HNF-1α mutation) (Correct answer)
- MODY5 (HNF-1β mutation)
- MODY6 (NeuroD1 mutation)
Correct answer: MODY3 (HNF-1α mutation)
MODY3, caused by HNF-1α mutations, impairs transcriptional regulation of the SUR1 sulfonylurea receptor pathway and paradoxically responds dramatically to low-dose sulfonylureas, often replacing insulin therapy.
BC ADM Diabetes Pathophysiology 5
Which concept describes the persistent increased risk of diabetic complications even after achieving good glycemic control, due to epigenetic changes from prior hyperglycemia?