Insulin-stimulated protein kinase C λ/ζ activity is reduced in skeletal muscle of humans with obesity and type 2 diabetes -: Reversal with weight reduction
Insulin-stimulated protein kinase C λ/ζ activity is reduced in skeletal muscle of humans with obesity and type 2 diabetes -: Reversal with weight reduction
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DOI：
10.2337/diabetes.52.8.1935
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发表时间：
2003-08-01
期刊：
影响因子：
7.7
通讯作者：
Kahn, BB
中科院分区：
文献类型：
--
作者：
Kim, YB;Kotani, K;Kahn, BB
在患有肥胖症或2型糖尿病的人中，胰岛素靶组织对胰岛素的许多作用具有抵抗力。非典型蛋白激酶C(PKC)亚型lambda和zeta位于磷脂酰肌醇-3激酶(PI3K)的下游，是最大限度地刺激胰岛素对葡萄糖摄取所必需的。磷脂酰肌醇依赖的蛋白激酶-1(PDK-1)也位于PI3K下游，介导非典型的PKC亚型和Akt的激活。为了确定PKClambda/Zeta或PDK-1激活受损是否在胰岛素抵抗的发病机制中起作用，我们检测了瘦身、肥胖和肥胖/2型糖尿病人股外侧肌中PKClambda/Zeta和PDK-1的活性。在隔夜禁食和高胰岛素-正常血糖钳夹3小时后进行活组织检查。肥胖的受试者也在减肥后接受了低卡路里饮食的研究。肥胖受试者的胰岛素刺激葡萄糖处理率降低26%，糖尿病受试者减少62%(这两项比较P<；0.001)。与瘦体或肥胖者相比，糖尿病患者胰岛素刺激的胰岛素受体底物(IRS)-1酪氨酸磷酸化和PI3K活性受损40%-50%。在瘦的受试者中，胰岛素刺激PKClambda/Zeta的活性类似于2.3倍；肥胖者和糖尿病受试者基础上的增加量分别减少了57%和65%。糖尿病患者PKClambda/Zeta蛋白含量减少46%，而肥胖非糖尿病患者PKClambda/Zeta蛋白含量正常，表明胰岛素对PKClambda/Zeta的作用受损。重要的是，肥胖受试者的体重减轻使PKClambda/Zeta激活正常化，并增加了IRS-1磷酸化和PI3K活性。在肥胖或糖尿病受试者中，胰岛素还可以刺激PDK-1活性大约两倍，而不会造成损害。与我们之前关于Akt的数据不同，胰岛素刺激的PKClambda/Zeta活性降低可能在肥胖和2型糖尿病受试者肌肉中胰岛素抵抗的发病机制中发挥作用。
In humans with obesity or type 2 diabetes, insulin target tissues are resistant to many actions of insulin. The atypical protein kinase C (PKC) isoforms lambda and zeta are downstream of phosphatidylinositol-3 kinase (PI3K) and are required for maximal insulin stimulation of glucose uptake. Phosphoinositide-dependent protein kinase-1 (PDK-1), also downstream of PI3K, mediates activation of atypical PKC isoforms and Akt. To determine whether impaired PKClambda/zeta or PDK-1 activation plays a role in the pathogenesis of insulin resistance, we measured the activities of PKClambda/zeta and PDK-1 in vastus lateralis muscle of lean, obese, and obese/type 2 diabetic humans. Biopsies were taken after an overnight fast and after a 3-h hyperinsulinemic-euglycemic clamp. Obese subjects were also studied after weight loss on a very-low-calorie diet. Insulin-stimulated glucose disposal rate is reduced 26% in obese subjects and 62% in diabetic subjects (both comparisons P < 0.001). Insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation and PI3K activity are impaired 40-50% in diabetic subjects compared with lean or obese subjects. Insulin stimulates PKClambda/zeta activity similar to2.3-fold in lean subjects; the increment above basal is reduced 57% in obese and 65% in diabetic subjects. PKClambda/zeta protein amount is decreased 46% in diabetic subjects but is normal in obese nondiabetic subjects, indicating impaired insulin action on PKClambda/zeta. Importantly, weight loss in obese subjects normalizes PKClambda/zeta activation and increases IRS-1 phosphorylation and PI3K activity. Insulin also stimulates PDK-1 activity approximately twofold with no impairment in obese or diabetic subjects. In contrast to our previous data on Akt, reduced insulin-stimulated PKClambda/zeta activity could play a role in the pathogenesis of insulin resistance in muscle of obese and type 2 diabetic subjects.