期刊
CELL METABOLISM
卷 29, 期 1, 页码 64-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2018.09.008
关键词
-
资金
- Diabetes & Wellness Foundation Sweden
- Oresund Diabetes Academy
- Mats Paulsson Foundation
- Forget foundation
- Bo and Kerstin Hjelt foundation for diabetes type 2
- Lund University innovation board
- Crafoord Foundation
- Swedish Research Council
- ERC Advanced Researcher grant [GA269045]
- Knut and Alice Wallenberg Foundation
- Swedish Diabetes Association
- Diabetes Wellness Sweden Foundation
- ALF
- Swedish Research Council, Linnaeus grant [349-2006-237]
- Strategic Research Area Exodiab [2009-1039]
- Swedish Foundation for Strategic Research LUDC-IRC [IRC15-0067]
- Israel Science Foundation
- Sima and Philip Needleman research funds
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 insulinsecreting beta 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, beta cell function is preserved by targeting the novel diabetes executer protein VDAC1.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据