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 exclusively under glucose stimulation in β-cells derived from mice, rats, and humans. Furthermore, 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, facilitating ATP efflux from mitochondria into the cytosol during glucose stimulation. To our knowledge, DPEU is the first positive small-molecule modulator of VDAC function that promotes ATP flux in β-cells, acting independently of the classical KATP or cAMP pathways. These findings identify VDAC as a drug target for enhancing insulin secretion.

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