INSULIN-RECEPTOR PHOSPHORYLATION, INSULIN-RECEPTOR SUBSTRATE-1 PHOSPHORYLATION, AND PHOSPHATIDYLINOSITOL 3-KINASE ACTIVITY ARE DECREASED IN INTACT SKELETAL-MUSCLE STRIPS FROM OBESE SUBJECTS
INSULIN-RECEPTOR PHOSPHORYLATION, INSULIN-RECEPTOR SUBSTRATE-1 PHOSPHORYLATION, AND PHOSPHATIDYLINOSITOL 3-KINASE ACTIVITY ARE DECREASED IN INTACT SKELETAL-MUSCLE STRIPS FROM OBESE SUBJECTS
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DOI：
10.1172/jci117909
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发表时间：
1995-05-01
影响因子：
15.9
通讯作者：
DOHM, GL
中科院分区：
文献类型：
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作者：
GOODYEAR, LJ;GIORGINO, F;DOHM, GL
为了确定肥胖个体中胰岛素刺激的葡萄糖摄取受损是否与胰岛素受体信号传导改变有关，我们测量了完整的人类骨骼肌条中的葡萄糖摄取和胰岛素作用途径的早期步骤。对接受择期手术的 8 名肥胖受试者和 8 名对照受试者进行腹直肌活检（体重指数 52.9 +/- 3.6 vs 25.7 +/- 0.9）。肥胖受试者的肌肉条中，胰岛素刺激的 2-脱氧葡萄糖摄取降低了 53%。额外的肌肉条在基础状态下或与 10(-7) M 胰岛素一起孵育 2、15 或 30 分钟。通过使用抗磷酸酪氨酸抗体进行免疫印迹检测，在瘦受试者中，胰岛素受体和胰岛素受体底物 1 (IRS-1) 的酪氨酸磷酸化在所有时间点均因胰岛素而显着增加。在肥胖受试者的骨骼肌中，胰岛素刺激酪氨酸磷酸化的效果较差（最大受体和 IRS-1 磷酸化分别降低 35% 和 38%），与对照组相比，肥胖受试者中胰岛素刺激 IRS-1 免疫沉淀磷脂酰肌醇 3-激酶（PI 3-激酶）活性也显着降低（分别是基础值的 10 倍和 35 倍）。此外，肥胖受试者的胰岛素受体、IRS-1 和 PI 3 激酶 p85 亚基丰度较低（分别为非肥胖受试者的 55%、54% 和 64%）。我们得出的结论是，严重肥胖受试者骨骼肌中胰岛素刺激的葡萄糖摄取受损伴随着胰岛素受体信号传导的缺陷，这可能导致胰岛素作用下降。
To determine whether the impaired insulin-stimulated glucose uptake in obese individuals is associated with altered insulin receptor signaling, we measured both glucose uptake and early steps in the insulin action pathway in intact strips of human skeletal muscle. Biopsies of rectus abdominus muscle were taken from eight obese and eight control subjects undergoing elective surgery (body mass index 52.9 +/- 3.6 vs 25.7 +/- 0.9). Insulin-stimulated 2-deoxyglucose uptake was 53% lower in muscle strips from obese subjects, Additional muscle strips were incubated in the basal state or with 10(-7) M insulin for 2, 15, or 30 min. In the lean subjects, tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1), measured by immunoblotting with anti-phosphotyrosine antibodies, was significantly increased by insulin at all time points. In the skeletal muscle from the obese subjects, insulin was less effective in stimulating tyrosine phosphorylation (maximum receptor and IRS-1 phosphorylation decreased by 35 and 38%, respectively), Insulin stimulation of IRS-1 immunoprecipitable phosphatidylinositol 3-kinase (PI 3-kinase) activity also was markedly lower in obese subjects compared with controls (10- vs 35-fold above basal, respectively). In addition, the obese subjects had a lower abundance of the insulin receptor, IRS-1, and the p85 subunit of PI 3-kinase (55, 54, and 64% of nonobese, respectively). We conclude that impaired insulin-stimulated glucose uptake in skeletal muscle from severely obese subjects is accompanied by a deficiency in insulin receptor signaling, which may contribute to decreased insulin action.