## Pathophysiology of Type 2 Diabetes Mellitus ### The Correct Answer: Glucagon Suppression Remains Normal **Key Point:** In Type 2 DM, glucagon secretion is INAPPROPRIATELY elevated despite hyperglycemia. This is a critical pathophysiologic defect — the alpha cells lose their sensitivity to glucose-mediated suppression. **High-Yield:** The "triumvirate" of Type 2 DM pathophysiology includes: 1. Insulin resistance (skeletal muscle, liver, adipose tissue) 2. Beta cell dysfunction (progressive loss of insulin secretion) 3. **Excessive glucagon secretion** (loss of glucose-mediated suppression) This inappropriate glucagon secretion drives hepatic glucose overproduction, worsening fasting hyperglycemia even when insulin levels are adequate. ### Why the Other Options Are Correct | Feature | Mechanism | Evidence | |---------|-----------|----------| | **Insulin resistance in muscle** | Defects in IRS-1/PI3K signaling and GLUT4 translocation; some evidence of tyrosine kinase domain dysfunction | Well-established in pathology | | **Beta cell dysfunction** | Progressive loss of glucose-sensing capacity; loss of first-phase (acute) insulin response to glucose | Occurs over years; precedes overt hyperglycemia | | **Hepatic glucose overproduction** | Increased gluconeogenesis and glycogenolysis due to insulin resistance and elevated glucagon | Major contributor to fasting hyperglycemia | **Clinical Pearl:** The loss of first-phase insulin secretion is one of the earliest detectable abnormalities in Type 2 DM — it occurs before fasting glucose becomes elevated and is a marker of impaired glucose tolerance. [cite:Robbins 10e Ch 24]
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