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 () and Guozhi Xiao ()
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Ke Zhu: Rush University Medical Center
Yumei Lai: Rush University Medical Center
Huiling Cao: Southern University of Science and Technology
Xiaochun Bai: Southern Medical University
Chuanju Liu: New York University School of Medicine
Qinnan Yan: Southern University of Science and Technology
Liting Ma: Southern University of Science and Technology
Di Chen: Rush University Medical Center
Giedrius Kanaporis: Rush University Medical Center
Junqi Wang: Southern University of Science and Technology
Luyuan Li: State Key Laboratory of Medicinal Chemical Biology and Nankai University College of Pharmacy
Tao Cheng: Institute of Hematology and Blood Disease Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College
Yong Wang: the University of Virginia
Chuanyue Wu: University of Pittsburgh
Guozhi Xiao: Southern University of Science and Technology

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14186-y

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