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

Abstract

OBJECTIVE-To determine the role of hepatocyte growth factor (HGF)/c-Met on b-cell survival in diabetogenic conditions in vivo and in response to cytokines in vitro.RESEARCH DESIGN AND METHODS-We generated pancreasspecific 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 b-cell death in mouse and human islets, specifically examining the role of nuclear factor (NF)-kB.RESULTS-Islets exposed in vitro to cytokines or from MLDStreated mice displayed significantly increased HGF and c-Met levels, suggesting a potential role for HGF/c-Met in b-cell survival against diabetogenic agents. Adult PancMet KO mice displayed normal glucose and b-cell homeostasis, indicating that pancreatic c-Met loss is not detrimental for b-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 b-cell mass compared with wild-type littermates. PancMet KO mice showed enhanced intraislet infiltration, islet nitric oxide (NO) and chemokine production, and b-cell apoptosis. c-Met-null b-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 important, human b-cells against cytokines.CONCLUSIONS-These results show that HGF/c-Met is critical for b-cell survival by attenuating NF-kB signaling and suggest that activation of the HGF/c-Met signaling pathway represents a novel strategy for enhancing b-cell protection. Diabetes 60: [525][526][527][528][529][530][531][532][533][534][535][536] 2011

Identification of particular groups of microRNAs that positively or negatively impact on beta cell function in obese models of type 2 diabetes

“…ntu.edu.tw/) and a literature search, we identified other miRNA targets potentially explaining the functional effects observed. In hepatocytes, miR-199a-3p regulates the expression of mTOR and of the transcription factor cMET [21], two proteins known to play important roles in the control of beta cell mass and survival [22,23]. We found that upregulation of miR-199a-3p results in decreased expression of mTOR and cMET also in MIN6B1 cells (ESM Fig.…”

“…Overexpression of miR-199a-3p resulted in a reduction of the levels of mTOR and cMET, two well-characterised targets of this miRNA [21,48]. Disruption of the signalling pathways involving these two proteins is detrimental for beta cells [23,49]. Moreover, mTOR is an important regulator of autophagy, a process thought to contribute to type 2 diabetes onset [50].…”

Short-term overexpression of VEGF-A in mouse beta cells indirectly stimulates their proliferation and protects against diabetes

“…3c). The expression of HGF, proposed as a beta cell survival factor [22] and as a downstream mediator of VEGF-A in pregnancy-associated compensatory beta cell growth [11], was similar in islets isolated from RIP rtTA TetO VEGF-A mice treated with DOX and those not treated (ESM Fig. 3d).…”

“…One potential endothelial cell-derived factor is HGF, which acts downstream of VEGF in hepatocyte proliferation and protection against a hepatotoxin [20] as well as during beta cell mass expansion during pregnancy [11]. In addition, HGF/c-Met signalling appears to be crucial for beta cell survival under diabetogenic conditions [22]. Nevertheless, we could not detect changes in Hgf gene expression in mice overexpressing VEGF-A, nor did HGF promote beta cell survival or protection in vitro, thereby precluding a major role for HGF in the current model.…”

Biological roles of hepatocyte growth factor‑Met signaling from genetically modified animals (Review)

“…However, the mice exhibited reduced glucose tolerance and reduced plasma insulin levels following glucose challenge; thus, the HGF-Met signaling pathway may be essential for normal glucose-dependent insulin secretion. In addition, cKO mice displayed markedly increased apoptosis and decreased proliferation following multiple low-dose streptozotocin treatments, and markedly reduced β-cell regeneration following pancreatectomy (54,55).…”