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Title

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

Authors
Zhang, Enming
Mohammed Al-Amily, Israa
Mohammed, Sarheed
Luan, Cheng
Asplund, Olof
Ahmed, Meftun
Ye, Yingying
Ben-Hail, Danya
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Published in Cell Metabolism. 2019, vol. 29, no. 1, p. 64-77.e6
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.
Keywords ATPEp300(−/−)cellsVDACdb/db micehuman isletsisolated VDAC1 channel conductancemetforminmitochondrial metabolismoxygen consumption ratetype 2 diabetes
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PMID: 30293774
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ZHANG, Enming et al. Preserving Insulin Secretion in Diabetes by Inhibiting VDAC1 Overexpression and Surface Translocation in β Cells. In: Cell Metabolism, 2019, vol. 29, n° 1, p. 64-77.e6. https://archive-ouverte.unige.ch/unige:113163

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Deposited on : 2019-01-22

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