Disruption of hepatocyte growth factor/c-Met signaling enhances pancreatic beta-cell death and accelerates the onset of diabetes.
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.


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.
Mellado-Gil
Jose
J
Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Rosa
Taylor C
TC
Demirci
Cem
C
Gonzalez-Pertusa
Jose A
JA
Velazquez-Garcia
Silvia
S
Ernst
Sara
S
Valle
Shelley
S
Vasavada
Rupangi C
RC
Stewart
Andrew F
AF
Alonso
Laura C
LC
Garcia-Ocaña
Adolfo
A
D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D016923:Cell Death; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013311:Streptozocin / Q000494:pharmacology
D001786:Blood Glucose; D016207:Cytokines; D016328:NF-kappa B; D013311:Streptozocin; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met