Kohichi Matsunaga,1,2* Kaori Honda,3 Muneeb Ali1,4 Abdul Hameed,5 Ryota Inoue,1 Takahiro Tsuno,1 Tatsuya Kin,6 A. M. James Shapiro,6 Hideru Obinata,7 Yasumitsu Kondoh,3 Zaheer Ul-Haq,4, 8 Hiroyuki Osada,3,9 Tetsuro Izumi,2* and Jun Shirakawa1* (1. Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 2. Laboratory of Molecular Endocrinology and Metabolism, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3. Chemical Resource Development Research Unit, RIKEN Center for Sustainable Resource Science, 4. H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, 5. College of Molecular Medicine, Ziauddin University, 6. Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, 7. Core Facility Management and Technical Collaboration Center, Life Science Hub, Gunma University, 8. Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, 9. Institute of Microbial Chemistry (BIKAKEN), *Corresponding Author)
About
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.
Paper information
Kohichi Matsunaga, Kaori Honda, Muneeb Ali1, Abdul Hameed, Ryota Inoue, Takahiro Tsuno, Tatsuya Kin, A. M. James Shapiro, Hideru Obinata, Yasumitsu Kondoh, Zaheer Ul-Haq, Hiroyuki Osada, Tetsuro Izumi, and Jun Shirakawa. Small-molecule modulation of VDAC enhances glucose-stimulated insulin secretion by promoting ATP flux Cell Chem Biol. in press.
Online URL
https://www.cell.com/cell-chemical-biology/abstract/S2451-9456(26)00368-5
