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

作者：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 Sampson, Mark A. Magnuson, David A. Jacobson, Ken S. Lau, Emily Hodges, Guoqiang Gu · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-60831-0 · 被引用次数：8 · 研究领域：Pancreatic function and diabetes、Diabetes and associated disorders、Diabetes Management and Research

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. Brown et al. show that mouse islet progenitors with different transcriptomes produce distinct β-cell subtypes and maternal diet alter the subtype proportions. Similar β-cell subsets exist in humans, with a subset enriched in genes related to β cell function reduced in diabetes.