Insulin & Glucose Transport
A 36-year-old obese man has impaired fasting glucose. Which transporter in skeletal muscle is upregulated after insulin receptor activation, and what intracellular signaling pathway mediates this?
GLUT-4; PI3K → Akt → translocation.
In which mitochondrial compartment do the TCA cycle and fatty acid β-oxidation occur?
Mitochondrial matrix.
Differentiate type I from type II diabetes in terms of C-peptide level.
Type I = low/absent C-peptide; Type II = normal/high C-peptide.
A test for pre-diabetes has sensitivity of 95% and specificity of 60%. Explain the trade-off in terms of false negatives vs. false positives.
Few false negatives (good for screening) but many false positives.
What is the most important allosteric activator of phosphofructokinase-1 (PFK-1), and how is it regulated by insulin vs. glucagon?
Fructose-2,6-bisphosphate. Synthesized by PFK-2 (stimulated by insulin), degraded by FBPase-2 (stimulated by glucagon)
A researcher knocks out IRS-1 in mice. What effect will this have on serum glucose and why?
Hyperglycemia, because IRS-1 is essential for insulin receptor signaling → GLUT-4 activation.
A drug inhibits Complex IV of the ETC. Predict the effect on ATP synthesis and oxygen consumption.
Both ↓; oxygen is final electron acceptor, so blocked ETC halts ATP generation.
Which GLUT transporter allows bidirectional glucose flow in the liver and why is this clinically important in diabetes?
GLUT-2; allows hepatic glucose release in fasting → hyperglycemia in diabetes.
This level of disease prevention aims to prevent complications and improve quality of life in patients with established type 2 diabetes, through interventions like foot exams and glycemic control.
Tertiary Prevention
Which ETC complexes pump protons to generate the proton motive force, and how many total ATP are made per glucose molecule in aerobic metabolism?
Proton pumping = Complexes I, III, IV.
Total yield = 30–32 ATP per glucose
A patient with fasting glucose 114 mg/dL has high C-peptide. Explain the mechanistic reason for this finding in pre-diabetes.
Insulin resistance → β-cells increase insulin secretion → elevated C-peptide
A patient has lactic acidosis. Explain how impaired oxidative phosphorylation contributes to this finding.
ETC dysfunction → pyruvate shunted to lactate via LDH → lactic acidosis.
Explain the biochemical basis of diabetic ketoacidosis in type I diabetes.
Absolute insulin deficiency → ↑ lipolysis → ↑ ketone body production (β-hydroxybutyrate, acetoacetate).
Which level of prevention is diet/exercise counseling in pre-diabetes?
Primary prevention.
A 60-year-old diabetic patient has elevated free fatty acids and fasting hyperglycemia. Which enzyme is inhibited by acetyl-CoA and NADH, and why does this worsen his glucose intolerance?
Pyruvate Dehydrogenase Complex (PDC). Inhibition prevents pyruvate → acetyl-CoA conversion, limiting glucose oxidation.
Differentiate between GLUT-2 in the pancreas and GLUT-4 in muscle in terms of insulin dependence and physiologic role.
GLUT-2 = insulin-independent, glucose sensor in β-cells; GLUT-4 = insulin-dependent, mediates glucose uptake in muscle/fat.
How many NADH and FADH₂ molecules are generated per acetyl-CoA in the TCA cycle?
3 NADH, 1 FADH₂, 1 GTP.
Non-enzymatic glycosylation of hemoglobin produces what molecule, and why is this clinically useful?
HbA1c; reflects average glucose over ~3 months.
This type of prevention targets asymptomatic individuals with risk factors for type 2 diabetes—such as obesity—through interventions like dietary counseling and metformin use.
Secondary Prevention
A patient with poorly controlled diabetes develops exercise intolerance and muscle weakness. Why does reliance on anaerobic glycolysis lead to fatigue more quickly than aerobic metabolism?
Anaerobic glycolysis yields only 2 ATP/glucose, vs 30–32 ATP in aerobic metabolism. Rapid ATP depletion causes fatigue in diabetic myopathy.
Why is brain glucose uptake unaffected in type I diabetes, even without insulin?
Brain uses GLUT-1 and GLUT-3 (insulin-independent).
Explain how mitochondrial dysfunction contributes to insulin resistance at the molecular level.
Impaired fatty acid oxidation, increasing lipid metabolite accumulation, and disrupting insulin signaling via abnormal IRS-1 phosphorylation—ultimately decreasing GLUT4-mediated glucose uptake.
Advanced glycation end products (AGEs) damage which vessels first, and what are the resulting complications?
Small vessels (microangiopathy) → retinopathy, nephropathy, neuropathy.
Explain how food deserts contribute to diabetes incidence using the concept of social determinants of health.
Limited access to fresh food → reliance on processed/high-calorie diets → ↑ obesity/diabetes risk.
A patient with type I diabetes in DKA presents with polyuria, dehydration, and fruity breath. Explain how altered insulin signaling shifts metabolism toward ketone body production.
Low insulin, high glucagon → ↓ F2,6-BP → ↓ glycolysis, ↑ gluconeogenesis.
Fatty acid oxidation → ↑ NADH, acetyl-CoA → inhibits PDC.
Excess acetyl-CoA shunted to ketogenesis → DKA.