Disruption of Hepatocyte Growth Factor/c-Met Signaling Enhances Pancreatic beta-Cell Death and Accelerates the Onset of Diabetes

作者：Mellado Gil Jose; Rosa Taylor C; Demirci Cem; Gonzalez Pertusa Jose A; Velazquez Garcia Silvia; Ernst Sara; Valle Shelley; Vasavada Rupangi C; Stewart Andrew F; Alonso Laura C; Garcia Ocana Adolfo^*

来源：Diabetes, 2011, 60(2): 525-536.

DOI：10.2337/db09-1305

OBJECTIVE-To determine the role of hepatocyte growth factor (HGF)/c-Met on beta-cell survival in diabetogenic conditions in vivo and in response to cytokines in vitro.
RESEARCH DESIGN AND METHODS-We generated pancreas-specific c-Met-null (PancMet KO) mice and characterized their response to diabetes induced by multiple low-dose streptozotocin (MLDS) administration. We also analyzed the effect of HGF/c-Met signaling in vitro on cytokine-induced beta-cell death in mouse and human islets, specifically examining the role of nuclear factor (NF)-kappa B.
RESULTS-Islets exposed in vitro to cytokines or from MLDS-treated mice displayed significantly increased HGF and c-Met levels, suggesting a potential role for HGF/c-Met in beta-cell survival against diabetogenic agents. Adult PancMet KO mice displayed normal glucose and beta-cell homeostasis, indicating that pancreatic c-Met loss is not detrimental for beta-cell growth and function under basal conditions. However, PancMet KO mice were more susceptible to MLDS-induced diabetes. They displayed higher blood glucose levels, marked hypoinsulinemia, and reduced beta-cell mass compared with wild-type littermates. PancMet KO mice showed enhanced intraislet infiltration, islet nitric oxide (NO) and chemokine production, and beta-cell apoptosis. c-Met-null beta-cells were more sensitive to cytokine-induced cell death in vitro, an effect mediated by NF-kappa B activation and NO production. Conversely, HGF treatment decreased p65/NF-kappa B activation and fully protected mouse and, more important, human beta-cells against cytokines.
CONCLUSIONS-These results show that HGF/c-Met is critical for beta-cell survival by attenuating NF-kappa B signaling and suggest that activation of the HGF/c-Met signaling pathway represents a novel strategy for enhancing beta-cell protection. Diabetes 60:525-536, 2011

• 出版日期2011-2