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

Date:	July 1, 2025
PMID:	PMC12217943
Category:	N/A
Authors:	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, Guoqiang Gu
Abstract:	40593675

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.

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Acknowledgements:

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, or the National Institute of Health.

The Translational and Basic Science Research in Early Lesions (TBEL) Research Consortia is supported and funded by grants from the National Cancer Institute and the National Institutes of Health under the following award numbers:

Project Number:	Awardee Organization
U54CA274374	Fred Hutchinson Cancer Center
U54CA274375	Houston Methodist Research Institute
U54CA274370	Johns Hopkins University
U54CA274371	UT MD Anderson Cancer Center
U54CA274367	Vanderbilt University Medical Center