Unknown

Dataset Information

0

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


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.

SUBMITTER: Zhu K 

PROVIDER: S-EPMC6981167 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

2020-10-01 | GSE150291 | GEO
| S-EPMC2597714 | biostudies-literature
| S-EPMC4498276 | biostudies-literature
| S-EPMC2889771 | biostudies-literature
| S-EPMC4613979 | biostudies-literature
| S-EPMC5623973 | biostudies-literature
| S-EPMC3279542 | biostudies-literature
| S-EPMC3596243 | biostudies-literature
| S-EPMC1853279 | biostudies-literature
| S-EPMC7296971 | biostudies-literature