Title | Disruption of hepatocyte growth factor/c-Met signaling enhances pancreatic beta-cell death and accelerates the onset of diabetes. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Mellado-Gil J, Rosa TC, Demirci C, Gonzalez-Pertusa JA, Velazquez-Garcia S, Ernst S, Valle S, Vasavada RC, Stewart AF, Alonso LC, Garcia-Ocaña A |
Journal | Diabetes |
Volume | 60 |
Issue | 2 |
Pagination | 525-36 |
Date Published | 2011 Feb |
ISSN | 1939-327X |
Keywords | Analysis of Variance, Animals, Blood Glucose, Blotting, Western, Cell Death, Cytokines, Diabetes Mellitus, Experimental, Enzyme-Linked Immunosorbent Assay, Hepatocyte Growth Factor, Humans, Immunohistochemistry, Insulin-Secreting Cells, Islets of Langerhans, Mice, Mice, Knockout, NF-kappa B, Proto-Oncogene Proteins c-met, Signal Transduction, Streptozocin |
Abstract | OBJECTIVE: To determine the role of hepatocyte growth factor (HGF)/c-Met on β-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 β-cell death in mouse and human islets, specifically examining the role of nuclear factor (NF)-κB. 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 β-cell survival against diabetogenic agents. Adult PancMet KO mice displayed normal glucose and β-cell homeostasis, indicating that pancreatic c-Met loss is not detrimental for β-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 β-cell mass compared with wild-type littermates. PancMet KO mice showed enhanced intraislet infiltration, islet nitric oxide (NO) and chemokine production, and β-cell apoptosis. c-Met-null β-cells were more sensitive to cytokine-induced cell death in vitro, an effect mediated by NF-κB activation and NO production. Conversely, HGF treatment decreased p65/NF-κB activation and fully protected mouse and, more important, human β-cells against cytokines. CONCLUSIONS: These results show that HGF/c-Met is critical for β-cell survival by attenuating NF-κB signaling and suggest that activation of the HGF/c-Met signaling pathway represents a novel strategy for enhancing β-cell protection. |
DOI | 10.2337/db09-1305 |
Alternate Journal | Diabetes |
PubMed ID | 20980460 |
PubMed Central ID | PMC3028352 |
Grant List | R01 DK067351 / DK / NIDDK NIH HHS / United States R01 DK077096 / DK / NIDDK NIH HHS / United States R01 DK078060 / DK / NIDDK NIH HHS / United States DK-067351 / DK / NIDDK NIH HHS / United States |