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

• Published in: Diabetes (New York, N.Y.) Vol. 60; no. 2; pp. 525 - 536
• Main Authors: MELLADO-GIL, Jose, ROSA, Taylor C, GARCIA-OCANA, Adolfo, DEMIRCI, Cem, GONZALEZ-PERTUSA, Jose A, VELAZQUEZ-GARCIA, Silvia, ERNST, Sara, VALLE, Shelley, VASAVADA, Rupangi C, STEWART, Andrew F, ALONSO, Laura C
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.02.2011
• Subjects: Analysis; Analysis of Variance; Animals; Biological and medical sciences; Blood Glucose - metabolism; Blotting, Western; Cell Death; Cellular signal transduction; Cytokines - metabolism; Cytokines - pharmacology; Development and progression; Diabetes; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme-Linked Immunosorbent Assay; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Genetic aspects; Growth factors; Hepatocyte Growth Factor - genetics; Hepatocyte Growth Factor - metabolism; Humans; Hyperglycemia; Immunohistochemistry; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Islet Studies; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Islets of Langerhans - pathology; Medical sciences; Mice; Mice, Knockout; NF-kappa B - metabolism; Pancreatic beta cells; Physiological aspects; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; Risk factors; Signal Transduction - physiology; Streptozocin - pharmacology; United States; Endocrinopathy; Signal transduction; Hepatocyte growth factor; Cell death; Diabetes mellitus; Langerhans islet; β Cell; Endocrine pancreas
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db09-1305

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. 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. 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. 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.