Small-molecule modulation of VDAC enhances glucose-stimulated insulin secretion by promoting ATP flux.

Abstract

Reduced insulin secretion by β cells is a pivotal factor in diabetes onset and progression. The small molecule NPD976 was identified as a potent insulin secretagogue using high-throughput chemical screening employing an insulin secretion assay system. Even part of the molecular structure of NPD976, designated as DPEU (N-[2-(3,4-dimethoxyphenyl)ethyl]urea), retains insulin secretagogue activity. DPEU enhances insulin secretion specifically under glucose stimulation in β cells derived from mice, rats, and humans. The compound localizes to mitochondria in a manner independent of high glucose stimulation. Biochemical analyses revealed that DPEU directly interacts with voltage-dependent anion channels (VDACs) located in the mitochondrial outer membrane, enhancing ATP efflux from mitochondria into the cytosol during glucose stimulation. To our knowledge, DPEU is a positive small-molecule modulator of VDAC function that promotes ATP flux in β cells through a mechanism distinct from the classical KATP or cAMP pathways. These findings identify VDAC as a potential target for enhancing insulin secretion.