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Sex-biased islet β cell dysfunction is caused by the MODY MAFA S64F variant by inducing premature aging and senescence in males.

Citation
Walker, E. M., et al. “Sex-Biased Islet Β Cell Dysfunction Is Caused By The Mody Mafa S64F Variant By Inducing Premature Aging And Senescence In Males.”. Cell Reports, p. 109813.
Center University of Michigan Vanderbilt University
Multicenter
Multicenter
Author Emily M Walker, Jeeyeon Cha, Xin Tong, Min Guo, Jin-Hua Liu, Sophia Yu, Donato Iacovazzo, Franck Mauvais-Jarvis, Sarah E Flanagan, Márta Korbonits, John Stafford, David A Jacobson, Roland Stein
Keywords MafA, beta cell, cellular senescence, diabetes, islet biology, Sexual dimorphism
Abstract

A heterozygous missense mutation of the islet β cell-enriched MAFA transcription factor (p.Ser64Phe [S64F]) is found in patients with adult-onset β cell dysfunction (diabetes or insulinomatosis), with men more prone to diabetes than women. This mutation engenders increased stability to the unstable MAFA protein. Here, we develop a S64F MafA mouse model to determine how β cell function is affected and find sex-dependent phenotypes. Heterozygous mutant males (MafA) display impaired glucose tolerance, while females are slightly hypoglycemic with improved blood glucose clearance. Only MafA males show transiently higher MafA protein levels preceding glucose intolerance and sex-dependent changes to genes involved in Ca signaling, DNA damage, aging, and senescence. MAFA production in male human β cells also accelerate cellular senescence and increase senescence-associated secretory proteins compared to cells expressing MAFA. These results implicate a conserved mechanism of accelerated islet aging and senescence in promoting diabetes in MAFA carriers in a sex-biased manner.

Year of Publication
2021
Journal
Cell reports
Volume
37
Issue
2
Number of Pages
109813
Date Published
10/2021
ISSN Number
2211-1247
DOI
10.1016/j.celrep.2021.109813
Alternate Journal
Cell Rep
PMID
34644565
PMCID
PMC8845126
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