Preserving Insulin Secretion in Diabetes by Inhibiting VDAC1 Overexpression and Surface Translocation in β Cells.

Abstract

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.

• Authors: Enming Zhang, Israa Mohammed Al-Amily, Sarheed Mohammed, Cheng Luan, Olof Asplund, Meftun Ahmed, Yingying Ye, Danya Ben-Hail, Arvind Soni, Neelanjan Vishnu, Pradeep Bompada, Yang De Marinis, Leif Groop, Varda Shoshan-Barmatz, Erik Renström, Claes B Wollheim, Albert Salehi
• Journal: Cell metabolism (Cell Metab) Vol. 29 Issue 1 Pg. 64-77.e6 (01 08 2019) ISSN: 1932-7420 [Electronic] United States
• PMID: 30293774 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Insulin
• VDAC1 protein, human
• Vdac1 protein, mouse
• Metformin
• Voltage-Dependent Anion Channel 1
• Glucose

Topics

• Animals
• Cell Line, Tumor
• Diabetes Mellitus, Type 2 (metabolism)
• Glucose (metabolism)
• Humans
• Hyperglycemia (drug therapy, metabolism)
• Insulin (metabolism)
• Insulin Secretion (drug effects)
• Insulin-Secreting Cells (cytology, drug effects, metabolism)
• Metformin (pharmacology)
• Mice
• Voltage-Dependent Anion Channel 1 (metabolism)