FIG. 3.

Tg IRS-1 Ser→Ala mice were protected from high-fat diet–induced muscle insulin resistance. A: After 8 weeks of high-fat feeding (16 ± 1 weeks), age-matched mice were food deprived for 16 h and hyperinsulinemic-euglycemic clamp experiments (2.5 mU · kg⁻¹ · min⁻¹) were performed using Tg IRS-1 Ser→Ala mice and their littermates. Plasma glucose concentration was maintained by an intravenous 20% glucose infusion and glucose infusion rates (GINF) at steady state were assessed. B: Muscle-specific glucose uptake was analyzed by enrichment of [¹⁴C]-2-deoxy-glucose in Musculus gastrocnemius (GAS) (left) and Musclus quadriceps (QD) (right). Results are expressed as means ± SE (WT, n = 12; Tg IRS-1 Ser→Ala, n = 16). C: Insulin-stimulated Akt phosphorylation (Ser⁴⁷³) in GAS was analyzed 15 min after intraperitoneal injection of 0.6 units/kg insulin in control diet–fed mice (WT, n = 6) and high-fat diet–fed mice (WT, n = 16; Tg IRS-1 Ser→Ala, n = 15; Tg IRS-1 WT, n = 3). D: IRS-1–associated PI3-kinase activity in GAS of high-fat–fed mice (WT, n = 12; Tg IRS-1 Ser→Ala, n = 8). E: IRS-1 tyrosine phosphorylation (left) and IRS-1–associated p85 subunit of PI3-kinase (right) were analyzed 15 min after intraperitoneal injection of 0.6 units/kg insulin by immunoprecipitation. Results are expressed as means relative to insulin-stimulated samples of WT high-fat fed mice ± SE.