Disruption of HGF/ c-met Signaling Enhances Pancreatic Beta Cell Death and Accelerates the Onset of Diabetes.

Objective- To determine the role of 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 mice (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 NF-kB. 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 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-kB activation and NO production. Conversely, HGF treatment decreased p65/NF-kB activation and fully protected mouse and, more importantly, human beta cells against cytokines. Conclusions- These results show that HGF/ c-met is critical for beta cell survival by attenuating NFkB signaling and suggest that activation of the HGF/ c-met signaling pathway represents a novel strategy for enhancing beta cell protection.

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