β-cell 14-3-3-ζ and sex are key regulators of α-cell form and function

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ID: 326487
2026
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Abstract
α-cells exhibit heterogeneity in their hormone production, whereby distinct α-cell subpopulations can be induced to produce active glucagon-like peptide-1 (GLP-1). However, the mechanisms that govern α-cell GLP-1 production remain poorly defined and whether these differ between sex is unknown. We previously identified 14-3-3-ζ as an indirect negative regulator of α-cell GLP-1 production in vitro. Therefore, we tested the hypothesis that β-cell 14-3-3-ζ ablation exerts sex-dependent protection against metabolic disease through alteration of the α-cell endocrine profile. Male and female mice with targeted manipulation of GLP-1 production in α-cells and 14-3-3-ζ expression in β-cells were studied. Further, publicly available human pancreas data were analyzed to identify sex-dependent differences in islet cell populations. Loss of α-cell-derived GLP-1 impaired β-cell compensation in response to high fat diet-induced metabolic stress and β-cell 14-3-3-ζ ablation improved glucose tolerance during a mixed-meal tolerance test in male, but not female, mice. Conversely, overexpression of 14-3-3-ζ blunted the effect of a GLP-1 receptor agonist to promote insulin secretion in male, but not female, mice. Further, β-cell 14-3-3-ζ ablation increased α-cell abundance in male mice while enhancing α-cell GLP-1 production and secretion in both sexes. Finally, α-cell numbers were higher in females compared to males in both mouse and human islets, and α-cell GLP-1 production was higher in female compared to male mice. Together, these findings identify β-cell 14-3-3-ζ as an upstream constraint on α-cell GLP-1 production and reveal sex-dependent regulation of α-cell abundance, establishing β-cell 14-3-3-ζ and biological sex as key determinants of α-cell GLP-1 production.
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Authors Rahaf Shishani, Moreno RD, Madelynn E. Agabao‐Tucker, Sofie E. Dinglasan, Jessica Miranda Bustamante, Emily Eddy, A. V. Williams Jackson, Melanie A. Reuter, Mara K. Hon, Mark O. Huising, Gareth E. Lim, Bethany P. Cummings
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Journal american journal of physiology endocrinology and metabolism
Year 2026
DOI
10.1210/endocr/bqag098
URL
https://doi.org/10.1210/endocr/bqag098
Keywords Keywords not found

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