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- Title
Kindlin-2 modulates MafA and β-catenin expression to regulate β-cell function and mass in mice.
- Authors
Zhu, Ke; Lai, Yumei; Cao, Huiling; Bai, Xiaochun; Liu, Chuanju; Yan, Qinnan; Ma, Liting; Chen, Di; Kanaporis, Giedrius; Wang, Junqi; Li, Luyuan; Cheng, Tao; Wang, Yong; Wu, Chuanyue; Xiao, Guozhi
- Abstract
β-Cell dysfunction and reduction in β-cell mass are hallmark events of diabetes mellitus. Here we show that β-cells express abundant Kindlin-2 and deleting its expression causes severe diabetes-like phenotypes without markedly causing peripheral insulin resistance. Kindlin-2, through its C-terminal region, binds to and stabilizes MafA, which activates insulin expression. Kindlin-2 loss impairs insulin secretion in primary human and mouse islets in vitro and in mice by reducing, at least in part, Ca2+ release in β-cells. Kindlin-2 loss activates GSK-3β and downregulates β-catenin, leading to reduced β-cell proliferation and mass. Kindlin-2 loss reduces the percentage of β-cells and concomitantly increases that of α-cells during early pancreatic development. Genetic activation of β-catenin in β-cells restores the diabetes-like phenotypes induced by Kindlin-2 loss. Finally, the inducible deletion of β-cell Kindlin-2 causes diabetic phenotypes in adult mice. Collectively, our results establish an important function of Kindlin-2 and provide a potential therapeutic target for diabetes. Beta cell dysfunction and reduction in beta cell mass are hallmark events in the pathogenesis of diabetes mellitus. We identify focal adhesion protein Kindlin-2 as a key factor that controls insulin synthesis and secretion and beta cell mass by modulating MafA and beta-catenin proteins in pancreatic beta cells.
- Subjects
PANCREATIC beta cells; INSULIN synthesis; FOCAL adhesions; MICE; PATHOLOGY
- Publication
Nature Communications, 2020, Vol 11, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-14186-y