Pancreatic islet β-cell subtypes are derived from biochemically-distinct and nutritionally-regulated islet progenitors

Monica E. Brown, Verda E. Miranda, Simone Nevills, Ruiying Hu, Prasanna K. Dadi, Alan J. Simmons, Yanwen Xu, Yilin Yang, Mahircan Yagan, Sadia Najam, Leesa L. Sampson, Mark A. Magnuson, David A. Jacobson, Ken S. Lau (), Emily Hodges () and Guoqiang Gu ()
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Monica E. Brown: Vanderbilt University School of Medicine
Verda E. Miranda: Vanderbilt University School of Medicine
Simone Nevills: Vanderbilt University School of Medicine
Ruiying Hu: Vanderbilt University School of Medicine
Prasanna K. Dadi: Vanderbilt University School of Medicine
Alan J. Simmons: Vanderbilt University School of Medicine
Yanwen Xu: Vanderbilt University School of Medicine
Yilin Yang: Vanderbilt University School of Medicine
Mahircan Yagan: Vanderbilt University School of Medicine
Sadia Najam: Vanderbilt University School of Medicine
Leesa L. Sampson: Vanderbilt University School of Medicine
Mark A. Magnuson: Vanderbilt University School of Medicine
David A. Jacobson: Vanderbilt University School of Medicine
Ken S. Lau: Vanderbilt University School of Medicine
Emily Hodges: Vanderbilt University School of Medicine
Guoqiang Gu: Vanderbilt University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Endocrine islet β cells comprise heterogenous subtypes with different gene expression and function levels. Here we study when/how this heterogeneity is induced and how long each subtype maintains its characteristic properties. We show that islet progenitors with distinct gene expression and DNA methylation patterns produce β-cell subtypes of different secretory function, proliferation rate, and viability in male and female mice. These subtypes have differential gene expression that regulates insulin vesicle production or stimulation-secretion coupling and differential DNA methylation in the putative enhancers of these genes. Maternal obesity, a major diabetes risk factor, reduces the proportion of the β-cell subtype with higher levels of glucose responsiveness. The gene signature that defines mouse β-cell subtypes can reliably divide human cells into two sub-populations, with the one having higher predicted glucose responsiveness reduced in diabetic donors. These results suggest that β-cell subtypes can be derived from islet progenitor subsets modulated by maternal nutrition.

Date: 2025
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DOI: 10.1038/s41467-025-60831-0

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