BC ADM Diabetes Pathophysiology 3 — Questions and Answers
Question 1: Which incretin hormone is deficient or has a blunted response in type 2 diabetes and normally stimulates insulin secretion in a glucose-dependent manner?
- Cholecystokinin (CCK)
- Glucagon-like peptide-1 (GLP-1) (Correct answer)
- Gastric inhibitory polypeptide (GIP) — and it remains fully intact in T2D
- Peptide YY (PYY)
Correct answer: Glucagon-like peptide-1 (GLP-1)
GLP-1 secretion is reduced and its insulinotropic effect is blunted in type 2 diabetes, while GIP secretion is relatively preserved but its response is also diminished.
Question 2: In latent autoimmune diabetes in adults (LADA), which antibody is most commonly detected at diagnosis?
- Anti-thyroid peroxidase antibody
- Glutamic acid decarboxylase antibody (GADA) (Correct answer)
- Anti-smooth muscle antibody
- Islet amyloid polypeptide antibody
Correct answer: Glutamic acid decarboxylase antibody (GADA)
GADA (anti-GAD65) is the most sensitive and specific autoantibody for LADA, distinguishing it from type 2 diabetes in adults who initially appear non-insulin-dependent.
Question 3: What role does islet amyloid polypeptide (IAPP/amylin) play in the pathophysiology of type 2 diabetes?
- IAPP stimulates glucagon secretion to maintain fasting glucose
- Aggregated IAPP fibrils are cytotoxic to beta cells and contribute to islet destruction (Correct answer)
- IAPP promotes GLUT4 translocation in adipose tissue
- IAPP inhibits renal glucose reabsorption via SGLT2 suppression
Correct answer: Aggregated IAPP fibrils are cytotoxic to beta cells and contribute to islet destruction
IAPP co-secreted with insulin forms toxic oligomeric and fibrillar aggregates within islets that impair beta-cell function and promote apoptosis in type 2 diabetes.
Question 4: Which mechanism explains why patients with type 2 diabetes have elevated fasting hepatic glucose output despite elevated insulin levels?
- Insulin-receptor mutations prevent any hepatic insulin signaling
- Selective hepatic insulin resistance impairs suppression of gluconeogenesis while lipogenesis remains intact (Correct answer)
- The liver lacks glycogen synthase in type 2 diabetes
- Portal insulin is cleared by the kidney before reaching hepatocytes
Correct answer: Selective hepatic insulin resistance impairs suppression of gluconeogenesis while lipogenesis remains intact
In T2D, selective hepatic insulin resistance dissociates pathways: gluconeogenesis suppression fails (raising fasting glucose) while lipogenic pathways remain insulin-sensitive, worsening dyslipidemia.
Question 5: Which adipokine is decreased in obesity and type 2 diabetes and normally improves insulin sensitivity?
- Leptin
- Resistin
- Adiponectin (Correct answer)
- Visfatin
Correct answer: Adiponectin
Adiponectin activates AMPK in muscle and liver to improve insulin sensitivity; its levels are paradoxically low in obese and type 2 diabetic individuals.
Question 6: In neonatal diabetes mellitus, which genetic mutation most commonly causes a permanently open KATP channel, preventing insulin secretion?
- Mutations in the glucokinase gene (GCK)
- Activating mutations in KCNJ11 (Kir6.2) or ABCC8 (SUR1) (Correct answer)
- Loss-of-function mutations in the PDX1 transcription factor
- Mutations in the mitochondrial tRNA-Leu gene
Correct answer: Activating mutations in KCNJ11 (Kir6.2) or ABCC8 (SUR1)
Gain-of-function mutations in KCNJ11 or ABCC8 keep the KATP channel open regardless of intracellular ATP levels, preventing membrane depolarization and insulin secretion.
Question 7: Which mechanism best explains how chronic hyperglycemia causes endothelial dysfunction and accelerated atherosclerosis in diabetes?
- Hyperglycemia directly lyses endothelial cells via osmotic pressure
- Advanced glycation end-products (AGEs) cross-link proteins and activate RAGE, promoting inflammation and oxidative stress (Correct answer)
- Elevated glucose suppresses VEGF, reducing vascular repair capacity
- Glucose competes with arginine for eNOS binding, reducing vasodilation
Correct answer: Advanced glycation end-products (AGEs) cross-link proteins and activate RAGE, promoting inflammation and oxidative stress
AGEs accumulate on long-lived proteins and activate the receptor RAGE, triggering NF-κB–driven inflammatory cascades and oxidative stress that impair endothelial function and accelerate plaque formation.
BC ADM Diabetes Pathophysiology 3
Which incretin hormone is deficient or has a blunted response in type 2 diabetes and normally stimulates insulin secretion in a glucose-dependent manner?