Kindlin-2 modulates MafA and β-catenin expression to regulate β-cell function and mass in mice

Ke Zhu, Yumei Lai, Huiling Cao, Xiaochun Bai, Chuanju Liu, Qinnan Yan, Liting Ma, Di Chen, Giedrius Kanaporis, Junqi Wang, Luyuan Li, Tao Cheng, Yong Wang, Chuanyue Wu, Guozhi Xiao

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

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.

Original languageEnglish (US)
Article number484
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020
Externally publishedYes

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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