Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany;German Center for Diabetes Research, Partner Düsseldorf, Düsseldorf, Germany;Department of Endocrinology and Diabetology, University Hospital Düsseldorf, 40225 Düsseldorf, Germany; and.
Howard Hughes Medical Institute andDepartment of Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06536.
Proc Natl Acad Sci U S A. 2014 Jul 1;111(26):9597-602. doi: 10.1073/pnas.1409229111. Epub 2014 Jun 16.
Muscle insulin resistance is a key feature of obesity and type 2 diabetes and is strongly associated with increased intramyocellular lipid content and inflammation. However, the cellular and molecular mechanisms responsible for causing muscle insulin resistance in humans are still unclear. To address this question, we performed serial muscle biopsies in healthy, lean subjects before and during a lipid infusion to induce acute muscle insulin resistance and assessed lipid and inflammatory parameters that have been previously implicated in causing muscle insulin resistance. We found that acute induction of muscle insulin resistance was associated with a transient increase in total and cytosolic diacylglycerol (DAG) content that was temporally associated with protein kinase (PKC)θ activation, increased insulin receptor substrate (IRS)-1 serine 1101 phosphorylation, and inhibition of insulin-stimulated IRS-1 tyrosine phosphorylation and AKT2 phosphorylation. In contrast, there were no associations between insulin resistance and alterations in muscle ceramide, acylcarnitine content, or adipocytokines (interleukin-6, adiponectin, retinol-binding protein 4) or soluble intercellular adhesion molecule-1. Similar associations between muscle DAG content, PKCθ activation, and muscle insulin resistance were observed in healthy insulin-resistant obese subjects and obese type 2 diabetic subjects. Taken together, these data support a key role for DAG activation of PKCθ in the pathogenesis of lipid-induced muscle insulin resistance in obese and type 2 diabetic individuals.
肌肉胰岛素抵抗是肥胖和 2 型糖尿病的一个主要特征，与细胞内脂质含量增加和炎症密切相关。然而，导致人类肌肉胰岛素抵抗的确切细胞和分子机制仍不清楚。为了解决这个问题，我们在健康、瘦的受试者中进行了一系列肌肉活检，在脂质输注过程中诱导急性肌肉胰岛素抵抗，并评估了先前与肌肉胰岛素抵抗有关的脂质和炎症参数。我们发现，急性诱导的肌肉胰岛素抵抗与总和胞质二酰基甘油 (DAG) 含量的短暂增加有关，这种增加与蛋白激酶 (PKC)θ 的激活、胰岛素受体底物 (IRS)-1 丝氨酸 1101 磷酸化的增加以及胰岛素刺激的 IRS-1 酪氨酸磷酸化和 AKT2 磷酸化的抑制有关。相比之下，肌肉神经酰胺、酰基辅酶 A 含量或细胞因子（白细胞介素-6、脂联素、视黄醇结合蛋白 4）或可溶性细胞间黏附分子-1 的变化与胰岛素抵抗之间没有关联。在健康的胰岛素抵抗肥胖受试者和肥胖 2 型糖尿病受试者中，肌肉 DAG 含量、PKCθ 激活与肌肉胰岛素抵抗之间也存在类似的关联。这些数据表明，在肥胖和 2 型糖尿病个体中，DAG 激活 PKCθ 在脂质诱导的肌肉胰岛素抵抗的发病机制中起关键作用。
