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To determine whether defects in the insulin signal transduction cascade are present in skeletal muscle from prediabetic individuals, we excised biopsies from eight glucose-intolerant male first-degree relatives of patients with type 2 diabetes (IGT relatives) and nine matched control subjects before and during a euglycemic-hyperinsulinemic clamp. IGT relatives were insulin-resistant in oxidative and nonoxidative pathways for glucose metabolism. In vivo insulin infusion increased skeletal muscle insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation (P = 0.01) and phosphatidylinositide 3-kinase (PI 3-kinase) activity (phosphotyrosine and IRS-1 associated) in control subjects (P < 0.02) but not in IGT relatives (NS). The incremental increase in insulin action on IRS-1 tyrosine phosphorylation was lower in IGT relatives versus control subjects (P < 0.05). The incremental defects in signal transduction noted for IRS-1 and PI 3-kinase may be attributed to elevated basal phosphorylation/activity of these parameters, because absolute phosphorylation/activity under insulin-stimulated conditions was similar between IGT relatives and control subjects. Insulin increased Akt serine phosphorylation in control subjects and IGT relatives, with a tendency for reduced phosphorylation in IGT relatives (P = 0.12). In conclusion, aberrant phosphorylation/activity of IRS-1, PI 3-kinase, and Akt is observed in skeletal muscle from relatives of patients with type 2 diabetes with IGT. However, the elevated basal activity of these signaling intermediates and the lack of a strong correlation between these parameters to glucose metabolism suggests that other defects of insulin signal transduction and/or downstream components of glucose metabolism may play a greater role in the development of insulin resistance in skeletal muscle from relatives of patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Low birth weight (LBW), a surrogate marker of an adverse fetal milieu, is linked to muscle insulin resistance, impaired insulin-stimulated glycolysis and future risk of type 2 diabetes (T2D). Skeletal muscle mass, fiber composition and capillary density are important determinants of muscle function and metabolism, and alterations have been implicated in the pathogenesis of insulin resistance. The aim of this study was to investigate whether an adverse fetal environment (LBW) induces permanent changes in skeletal muscle morphology, which may contribute to the dysmetabolic phenotype associated with LBW. Vastus lateralis muscle was obtained by percutaneous biopsy from 20 healthy 19-yr old men with birth weights ≤ 10th percentile for gestational age (LBW) and 20 normal birth weight controls (NBW), matched for body fat, physical fitness and whole-body glucose disposal. Myofibrillar ATPase staining was used to classify muscle fibers as Type I, IIa and IIx (formerly Type IIb), and double immunostaining was performed to stain capillaries (LBW: N=8, NBW: N=12). LBW was associated with an increased proportion of Type IIx fibers (+66%. P=0.03), at the expense of decreased Type Ha fibers (-22%, P=0.003). No significant change was observed in proportion of Type I fibers (+ 16%, P=0.11). In addition, mean area of Type IIa fibers was increased (+29%, P=0.01), and tended to be increased for Type I fibers as well (+l7%, P=0.08). Capillary density was not significantly different between groups. We speculate that alterations in fiber composition and size may contribute to development of T2D in individuals with LBW. [ABSTRACT FROM AUTHOR]