糖尿病伴随着肥胖人骨骼肌中参与内体 GLUT4 运输的蛋白质水平的变化。
Diabetes is accompanied by changes in the levels of proteins involved in endosomal GLUT4 trafficking in obese human skeletal muscle.
机构信息
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
Institute of Molecular Cell and Systems Biology, University of Glasgow, Glasgow, UK.
出版信息
Endocrinol Diabetes Metab. 2022 Sep;5(5):e361. doi: 10.1002/edm2.361. Epub 2022 Aug 14.
INTRODUCTION
The regulated delivery of the glucose transporter GLUT4 from intracellular stores to the plasma membrane underpins insulin-stimulated glucose transport. Insulin-stimulated glucose transport is impaired in skeletal muscle of patients with type-2 diabetes, and this may arise because of impaired intracellular trafficking of GLUT4. However, molecular details of any such impairment have not been described. We hypothesized that GLUT4 and/or levels of proteins involved in intracellular GLUT4 trafficking may be impaired in skeletal muscle in type-2 diabetes and tested this in obese individuals without and without type-2 diabetes.
METHODS
We recruited 12 participants with type-2 diabetes and 12 control participants. All were overweight or obese with BMI of 25-45 kg/m . Insulin sensitivity was measured using an insulin suppression test (IST), and vastus lateralis biopsies were taken in the fasted state. Cell extracts were immunoblotted to quantify levels of a range of proteins known to be involved in intracellular GLUT4 trafficking.
RESULTS
Obese participants with type-2 diabetes exhibited elevated fasting blood glucose and increased steady state glucose infusion rates in the IST compared with controls. Consistent with this, skeletal muscle from those with type-2 diabetes expressed lower levels of GLUT4 (30%, p = .014). Levels of Syntaxin4, a key protein involved in GLUT4 vesicle fusion with the plasma membrane, were similar between groups. By contrast, we observed reductions in levels of Syntaxin16 (33.7%, p = 0.05), Sortilin (44%, p = .006) and Sorting Nexin-1 (21.5%, p = .039) and -27 (60%, p = .001), key proteins involved in the intracellular sorting of GLUT4, in participants with type-2 diabetes.
CONCLUSIONS
We report significant reductions of proteins involved in the endosomal trafficking of GLUT4 in skeletal muscle in obese people with type 2 diabetes compared with age- and weight-matched controls. These abnormalities of intracellular GLUT4 trafficking may contribute to reduced whole body insulin sensitivity.
简介
葡萄糖转运蛋白 GLUT4 从细胞内储存到质膜的调节释放是胰岛素刺激葡萄糖转运的基础。2 型糖尿病患者的骨骼肌胰岛素刺激葡萄糖转运受损，这可能是由于 GLUT4 的细胞内转运受损所致。然而，尚未描述任何此类损伤的分子细节。我们假设 2 型糖尿病患者的骨骼肌中 GLUT4 及其/或参与细胞内 GLUT4 转运的蛋白质水平可能受损，并在超重或肥胖且 BMI 为 25-45kg/m 的非 2 型糖尿病患者和 2 型糖尿病患者中对此进行了测试。
方法
我们招募了 12 名 2 型糖尿病患者和 12 名对照参与者。所有参与者的 BMI 均在 25-45kg/m 之间，超重或肥胖。使用胰岛素抑制试验（IST）测量胰岛素敏感性，并在空腹状态下取股外侧肌活检。细胞提取物通过免疫印迹进行定量，以定量测定已知参与细胞内 GLUT4 转运的一系列蛋白质的水平。
结果
与对照组相比，患有 2 型糖尿病的肥胖参与者的空腹血糖升高，IST 中的稳态葡萄糖输注率增加。与此一致的是，2 型糖尿病患者的骨骼肌中 GLUT4 表达水平较低（30%，p=0.014）。网格蛋白 4（一种参与 GLUT4 囊泡与质膜融合的关键蛋白）的水平在两组之间相似。相比之下，我们观察到Syntaxin16 的水平降低（33.7%，p=0.05），Sortilin（44%，p=0.006）和 Sorting Nexin-1（21.5%，p=0.039）和-27（60%，p=0.001），这些是参与 GLUT4 细胞内分拣的关键蛋白，在 2 型糖尿病患者中。
结论
我们报告了与年龄和体重匹配的对照组相比，肥胖的 2 型糖尿病患者的骨骼肌中 GLUT4 内体转运所涉及的蛋白质显著减少。这些细胞内 GLUT4 转运异常可能导致全身胰岛素敏感性降低。
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