2. Academic Validation
  3. Altered immune and metabolic molecular pathways drive islet cell dysfunction in human type 1 diabetes

Altered immune and metabolic molecular pathways drive islet cell dysfunction in human type 1 diabetes

  • J Clin Invest. 2025 Sep 30:e195267. doi: 10.1172/JCI195267.
Theodore Dos Santos 1,  Xiao-Qing Dai 1,  Robert C Jones 2,  Aliya F Spigelman 1,  Hannah M Mummey 3,  Jessica D Ewald 4,  Cara E Ellis 1,  James G Lyon 5,  Nancy Smith 1,  Austin Bautista 6,  Jocelyn E Manning Fox 1,  Norma F Neff 7,  Angela M Detweiler 7,  Michelle Tan 7,  Rafael Arrojo E Drigo 8,  Jianguo Xia 9,  Joan Camunas-Soler 10,  Kyle J Gaulton 11,  Stephen R Quake 2,  Patrick E MacDonald 6
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of Alberta, Edmonton, Canada.
  • 2 Department of Bioengineering, Stanford University, Stanford, United States of America.
  • 3 Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, United States of America.
  • 4 European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom.
  • 5 Department of Pharmacology, Unviersity of Alberta, Edmonton, Canada.
  • 6 Alberta Diabetes Institute, University of Alberta, Edmonton, Canada.
  • 7 Chan Zuckerberg Biohub, San Francisco, United States of America.
  • 8 Department of Molecular Physiology and Biophysics, Vanderbilt, Nashville, United States of America.
  • 9 Department of Microbiology & Immunology, McGill University, Montreal, Canada.
  • 10 Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, United States of America.
  • 11 Department of Pediatrics, University of California San Diego, La Jolla, United States of America.
PMID: 41026524 DOI: 10.1172/JCI195267
Abstract

Type 1 diabetes (T1D) is characterized by the autoimmune destruction of most insulin-producing β-cells, along with dysregulated glucagon secretion from pancreatic α-cells. We conducted an integrated analysis that combines electrophysiological and transcriptomic profiling, along with machine learning, of islet cells from T1D donors. The few surviving β-cells exhibit altered electrophysiological properties and transcriptomic signatures indicative of increased antigen presentation, metabolic reprogramming, and impaired protein translation. In α-cells, we observed hyper-responsiveness and increased exocytosis, which are associated with upregulated immune signaling, disrupted transcription factor localization and lysosome homeostasis, as well as dysregulation of mTORC1 complex signaling. Notably, key genetic risk signals for T1D were enriched in transcripts related to α-cell dysfunction, including MHC class I, which were closely linked with α-cell dysfunction. Our data provide what we believe are novel insights into the molecular underpinnings of islet cell dysfunction in T1D, highlighting pathways that may be leveraged to preserve residual β-cell function and modulate α-cell activity. These findings underscore the complex interplay between immune signaling, metabolic stress, and cellular identity in shaping islet cell phenotypes in T1D.

Keywords

Autoimmunity; Cell biology; Diabetes; Endocrinology; Islet cells.

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