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Peer-reviewedCC BY-NC-NDNature Communications

Heterogeneous endocrine cell composition defines human islet functional phenotypes

  • Carmella Evans‐Molina1,2,3,4,5,6,7,8
  • Yasminye D. Pettway9,10
  • Diane C. Saunders11,12
  • Seth A. Sharp13,14
  • Thomas S. R. Bate11,12
  • Han Sun13,14
  • Heather H. Durai11,12
  • Shaojun Mei11,12
  • Anastasia Coldren11,12
  • Corey Davis11,12
  • Conrad Reihsmann11,12
  • Alexander L. Hopkirk11,12
18 more authors
  • Jay Taylor11,12
  • Amber M. Bradley11,12
  • Radhika Aramandla11,12
  • Greg Poffenberger11,12
  • Adel Eskaros11,12
  • Regina Jenkins11,12
  • Danni Shi15,12
  • Ke Xu15,12
  • Hakmook Kang15,14
  • Varsha Rajesh13,14
  • Swaraj Thaman13,12
  • Fan Feng11,16
  • Jean‐Philippe Cartailler17,12
  • Alvin C. Powers9,11,18,19
  • Kristin M. Abraham20,14
  • Anna L. Gloyn21,22,23,24
  • Joyce C. Niland25,12
  • Marcela Briššová26
26 affiliations
  1. 1Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA. [email protected]
  2. 2Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA. [email protected]
  3. 3Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. [email protected]
  4. 4Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA. [email protected]
  5. 5Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA. [email protected]
  6. 6The Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA. [email protected]
  7. 7The Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA. [email protected]
  8. 8Indiana University School of Medicine
  9. 9Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA
  10. 10Vanderbilt University School of Medicine
  11. 11Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
  12. 12Vanderbilt University Medical Center
  13. 13Department of Pediatrics, Stanford School of Medicine, Stanford, CA, USA
  14. 14Stanford School of Medicine
  15. 15Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
  16. 16Vanderbilt University
  17. 17Vanderbilt Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, USA
  18. 18VA Tennessee Valley Healthcare System, Nashville, TN, USA
  19. 19National Institutes of Health
  20. 20Division of Diabetes, Endocrinology, & Metabolic Diseases, National Institutes of Health, Bethesda, MD, USA
  21. 21Department of Genetics, Stanford School of Medicine, Stanford, CA, USA. [email protected]
  22. 22Department of Pediatrics, Stanford School of Medicine, Stanford, CA, USA. [email protected]
  23. 23Stanford Diabetes Center, Stanford School of Medicine, Stanford, CA, USA. [email protected]
  24. 24City of Hope
  25. 25Department of Diabetes and Cancer Discovery Science, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA. [email protected]
  26. 26Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. [email protected]
Open at sourceDOICite

Abstract

Phenotyping and genotyping initiatives within the Integrated Islet Distribution Program (IIDP), the largest source of human islets for research in the U.S., provide standardized assessment of islet preparations distributed to researchers and enable the integration of multiple data types. Data from islets of the first 299 organ donors without diabetes analyzed using this pipeline highlights substantial heterogeneity in islet cell composition associated with hormone secretory traits, sex, reported race and ethnicity, genetically predicted ancestry, and genetic risk for type 2 diabetes (T2D). While α and β cell composition influenced insulin and glucagon secretory traits, the abundance of δ cells showed the strongest association with insulin secretion and was also associated with the genetic risk score (GRS) for T2D. These findings have important implications for understanding mechanisms underlying diabetes heterogeneity and islet dysfunction and may provide insight into strategies for personalized medicine and β cell replacement therapy. Our investigation highlights substantial heterogeneity in islet cell composition associated with hormone secretory traits, sex, reported race and ethnicity, genetically predicted ancestry, and genetic risk for type 2 diabetes (T2D).

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Cite

BibTeXRIS
BibTeX
@article{evansmolina2026heterogeneous,
  title = {{Heterogeneous endocrine cell composition defines human islet functional phenotypes}},
  author = {Carmella Evans‐Molina and Yasminye D. Pettway and Diane C. Saunders and Seth A. Sharp and Thomas S. R. Bate and Han Sun and Heather H. Durai and Shaojun Mei and Anastasia Coldren and Corey Davis and Conrad Reihsmann and Alexander L. Hopkirk and Jay Taylor and Amber M. Bradley and Radhika Aramandla and Greg Poffenberger and Adel Eskaros and Regina Jenkins and Danni Shi and Ke Xu and Hakmook Kang and Varsha Rajesh and Swaraj Thaman and Fan Feng and Jean‐Philippe Cartailler and Alvin C. Powers and Kristin M. Abraham and Anna L. Gloyn and Joyce C. Niland and Marcela Briššová},
  journal = {Nature Communications},
  year = {2026},
  month = may,
  doi = {10.1038/s41467-026-70689-5},
  url = {https://doi.org/10.1038/s41467-026-70689-5},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Heterogeneous endocrine cell composition defines human islet functional phenotypes
AU  - Carmella Evans‐Molina
AU  - Yasminye D. Pettway
AU  - Diane C. Saunders
AU  - Seth A. Sharp
AU  - Thomas S. R. Bate
AU  - Han Sun
AU  - Heather H. Durai
AU  - Shaojun Mei
AU  - Anastasia Coldren
AU  - Corey Davis
AU  - Conrad Reihsmann
AU  - Alexander L. Hopkirk
AU  - Jay Taylor
AU  - Amber M. Bradley
AU  - Radhika Aramandla
AU  - Greg Poffenberger
AU  - Adel Eskaros
AU  - Regina Jenkins
AU  - Danni Shi
AU  - Ke Xu
AU  - Hakmook Kang
AU  - Varsha Rajesh
AU  - Swaraj Thaman
AU  - Fan Feng
AU  - Jean‐Philippe Cartailler
AU  - Alvin C. Powers
AU  - Kristin M. Abraham
AU  - Anna L. Gloyn
AU  - Joyce C. Niland
AU  - Marcela Briššová
PY  - 2026
DA  - 2026/05/12
JO  - Nature Communications
DO  - 10.1038/s41467-026-70689-5
UR  - https://doi.org/10.1038/s41467-026-70689-5
AB  - Phenotyping and genotyping initiatives within the Integrated Islet Distribution Program (IIDP), the largest source of human islets for research in the U.S., provide standardized assessment of islet preparations distributed to researchers and enable the integration of multiple data types. Data from islets of the first 299 organ donors without diabetes analyzed using this pipeline highlights substantial heterogeneity in islet cell composition associated with hormone secretory traits, sex, reported race and ethnicity, genetically predicted ancestry, and genetic risk for type 2 diabetes (T2D). While α and β cell composition influenced insulin and glucagon secretory traits, the abundance of δ cells showed the strongest association with insulin secretion and was also associated with the genetic risk score (GRS) for T2D. These findings have important implications for understanding mechanisms underlying diabetes heterogeneity and islet dysfunction and may provide insight into strategies for personalized medicine and β cell replacement therapy. Our investigation highlights substantial heterogeneity in islet cell composition associated with hormone secretory traits, sex, reported race and ethnicity, genetically predicted ancestry, and genetic risk for type 2 diabetes (T2D).
SN  - 2041-1723
ER  -