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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月1日

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  • 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

摘要

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.