2. Academic Validation
  3. VDAC1 is a target for pharmacologically induced insulin hypersecretion in β cells

VDAC1 is a target for pharmacologically induced insulin hypersecretion in β cells

  • Cell Rep. 2025 Jun 24;44(6):115834. doi: 10.1016/j.celrep.2025.115834.
Gitanjali Roy 1,  Andrea Ordóñez 1,  Derk D Binns 2,  Karina Rodrigues-Dos-Santos 1,  Michael B Kwakye 1,  George C King 1,  Rachel L Kuntz 1,  Noyonika Mukherjee 3,  Andrew T Templin 4,  Zhiyong Tan 5,  Timothy I Richardson 6,  Emma H Doud 7,  Amber L Mosley 8,  Kathryn L Schueler 9,  Christopher H Emfinger 9,  Alan D Attie 9,  Mark P Keller 9,  Travis S Johnson 10,  Michael A Kalwat 11
Affiliations

Affiliations

  • 1 Indiana Biosciences Research Institute, Indianapolis, IN, USA.
  • 2 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 3 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 4 Indiana Biosciences Research Institute, Indianapolis, IN, USA; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; Roudebush VA Medical Center, Indianapolis, IN, USA.
  • 5 Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 6 Indiana Biosciences Research Institute, Indianapolis, IN, USA; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 7 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA; Center for Proteome Analysis, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 8 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA; Center for Proteome Analysis, Indiana University School of Medicine, Indianapolis, IN, USA; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 9 Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA.
  • 10 Indiana Biosciences Research Institute, Indianapolis, IN, USA; Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 11 Indiana Biosciences Research Institute, Indianapolis, IN, USA; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: mkalwat@indianabiosciences.org.
PMID: 40512624 DOI: 10.1016/j.celrep.2025.115834
Abstract

β cells are dysfunctional in type 2 diabetes (T2D) and congenital hyperinsulinism (HI), but the mechanisms linking hypersecretion to β cell failure are poorly understood. Here, we use proteomics and functional assays in human and mouse β cell lines to identify VDAC1 as a target for the small molecule hypersecretion inducer SW016789. By enhancing membrane depolarization, SW016789 acutely increases CA2+ influx, eventually driving β cell dysfunction. Time-course transcriptomics analysis reveals a distinct hypersecretory response signature compared to classical endoplasmic reticulum (ER) stress, highlighting ER-associated degradation (ERAD) as a key adaptive pathway. While SW016789 reduces ERAD substrate OS-9 levels, broader ERAD component changes are limited in cell lines. However, immunostaining of the T2D human pancreas shows altered distributions of the ratios of the core ERAD components SEL1L, HRD1, and DERL3 in β cells. This work provides a detailed mechanistic characterization of a hypersecretion-specific stress response, revealing potential therapeutic targets, including VDAC1 and ERAD, for modulating β cell function and survival in disease.

Keywords

CP: Cell biology; CP: Metabolism; ER stress; ER-associated degradation; congenital hyperinsulinism; diabetes; hypersecretion; insulin secretion; pancreatic islets; target identification; transcriptomics; β cells.

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