Department of Clinical Sciences, Malmö, Lund University, Jan Waldenströms Gata 35, Malmö 214 28, Sweden.
Academic Hospital Uppsala University, Uppsala, Sweden.
Cell Metab. 2019 Jan 8;29(1):64-77.e6. doi: 10.1016/j.cmet.2018.09.008. Epub 2018 Oct 4.
Type 2 diabetes (T2D) develops after years of prediabetes during which high glucose (glucotoxicity) impairs insulin secretion. We report that the ATP-conducting mitochondrial outer membrane voltage-dependent anion channel-1 (VDAC1) is upregulated in islets from T2D and non-diabetic organ donors under glucotoxic conditions. This is caused by a glucotoxicity-induced transcriptional program, triggered during years of prediabetes with suboptimal blood glucose control. Metformin counteracts VDAC1 induction. VDAC1 overexpression causes its mistargeting to the plasma membrane of the insulin-secreting β cells with loss of the crucial metabolic coupling factor ATP. VDAC1 antibodies and inhibitors prevent ATP loss. Through direct inhibition of VDAC1 conductance, metformin, like specific VDAC1 inhibitors and antibodies, restores the impaired generation of ATP and glucose-stimulated insulin secretion in T2D islets. Treatment of db/db mice with VDAC1 inhibitor prevents hyperglycemia, and maintains normal glucose tolerance and physiological regulation of insulin secretion. Thus, β cell function is preserved by targeting the novel diabetes executer protein VDAC1.
2 型糖尿病（T2D）在多年的糖尿病前期后发展，在此期间，高葡萄糖（糖毒性）损害胰岛素分泌。我们报告称，在葡萄糖毒性条件下，来自 T2D 和非糖尿病供体的胰岛中，ATP 传导的线粒体外膜电压依赖性阴离子通道 1（VDAC1）上调。这是由葡萄糖毒性诱导的转录程序引起的，该程序在多年的血糖控制不佳的糖尿病前期触发。二甲双胍可拮抗 VDAC1 的诱导。VDAC1 的过表达导致其靶向错误到胰岛素分泌β细胞的质膜，丧失关键的代谢偶联因子 ATP。VDAC1 抗体和抑制剂可防止 ATP 丢失。通过直接抑制 VDAC1 电导，二甲双胍与特异性 VDAC1 抑制剂和抗体一样，可恢复 T2D 胰岛中受损的 ATP 生成和葡萄糖刺激的胰岛素分泌。用 VDAC1 抑制剂治疗 db/db 小鼠可预防高血糖，并维持正常的葡萄糖耐量和胰岛素分泌的生理调节。因此，通过靶向新型糖尿病执行蛋白 VDAC1 可保留β细胞功能。
