A patient with type 2 diabetes has insulin resistance. At the cellular level, which post-receptor defect most commonly accounts for impaired glucose uptake in skeletal muscle?

• A Reduced expression of insulin receptor on the cell surface
• B Defective tyrosine kinase activity of the insulin receptor
• C Increased activity of protein tyrosine phosphatase PTP1B, which degrades phosphorylated insulin receptor
• D Reduced IRS-1/PI3K/PKB (Akt) signaling with impaired GLUT4 translocation to the plasma membrane ✓

Explanation

In type 2 diabetes, the most common post-receptor defect is impairment of the IRS-1 → PI3K → Akt (PKB) signaling cascade, which is required to trigger translocation of GLUT4-containing vesicles from intracellular compartments to the plasma membrane. Reduced GLUT4 translocation is the rate-limiting step for insulin-stimulated glucose uptake in muscle and fat. While PTP1B can contribute, the IRS-1/PI3K/Akt defect is the central established mechanism. Insulin receptor expression and tyrosine kinase activity are often relatively preserved.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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