| First Author | Mellado-Gil J | Year | 2011 |
| Journal | Diabetes | Volume | 60 |
| Issue | 2 | Pages | 525-36 |
| PubMed ID | 20980460 | Mgi Jnum | J:170152 |
| Mgi Id | MGI:4944087 | Doi | 10.2337/db09-1305 |
| Citation | Mellado-Gil J, et al. (2011) Disruption of hepatocyte growth factor/c-Met signaling enhances pancreatic beta-cell death and accelerates the onset of diabetes. Diabetes 60(2):525-36 |
| abstractText | 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)-kappaB. 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-kappaB activation and NO production. Conversely, HGF treatment decreased p65/NF-kappaB 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-kappaB signaling and suggest that activation of the HGF/c-Met signaling pathway represents a novel strategy for enhancing beta-cell protection. |
