| First Author | Zhu K | Year | 2020 |
| Journal | Nat Commun | Volume | 11 |
| Issue | 1 | Pages | 484 |
| PubMed ID | 31980627 | Mgi Jnum | J:283948 |
| Mgi Id | MGI:6387987 | Doi | 10.1038/s41467-019-14186-y |
| Citation | Zhu K, et al. (2020) Kindlin-2 modulates MafA and beta-catenin expression to regulate beta-cell function and mass in mice. Nat Commun 11(1):484 |
| abstractText | beta-Cell dysfunction and reduction in beta-cell mass are hallmark events of diabetes mellitus. Here we show that beta-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, Ca(2+) release in beta-cells. Kindlin-2 loss activates GSK-3beta and downregulates beta-catenin, leading to reduced beta-cell proliferation and mass. Kindlin-2 loss reduces the percentage of beta-cells and concomitantly increases that of alpha-cells during early pancreatic development. Genetic activation of beta-catenin in beta-cells restores the diabetes-like phenotypes induced by Kindlin-2 loss. Finally, the inducible deletion of beta-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. |
