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

October 21, 2026

A research group at Gunma University, in collaboration with the RIKEN CSRS, has discovered a novel compound, DPEU, that acts on pancreatic β-cells, which produce insulin, to enhance insulin secretion in response to elevated blood glucose levels.

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.

Original article: Cell Chemical Biology　DOI: 10.1016/j.chembiol.2026.09.019; K. Matsunaga, K. Honda, M. Ali, A. Hameed, R. Inoue, T. Tsuno, T. Kin, A. M. J. Shapiro, H. Obinata, Y. Kondoh, Z. Ul-Haq, H. Osada, T. Izumi, J. Shirakawa,; "Small-molecule modulation of VDAC enhances glucose-stimulated insulin secretion by promoting ATP flux".
Contact: Hiroyuki Osada; Group Director (at the time), Senior Visiting Scientist
Yasumitsu Kondoh; Senior Research Scientist (at the time)
Kaori Honda; Technical Staff I
Chemical Biology Research Group (at the time)