β-Cell-Specific Ablation of the Hepatocyte Growth Factor Receptor Results in Reduced Islet Size, Impaired Insulin Secretion, and Glucose Intolerance

Hepatocyte growth factor (HGF) and its c-met receptor consist of a paired signaling system that has been implicated in the regulation of pancreatic β-cell survival, proliferation, and function. To define the role of HGF/c-met signaling in β-cell biology in vivo, we have generated conditional knockout mice in which the c-met receptor gene was specifically inactivated in pancreatic β cells by the Cre-loxP system. Mice with β-cell-specific deletion of the c-met receptor (βmet−/−) displayed slight growth retardation, mild hyperglycemia, and decreased serum insulin levels at 6 months of age when compared with their control littermates. Deficiency of the c-met receptor in β cells resulted in a complete loss of acute-phase insulin secretion in response to glucose and an impaired glucose tolerance. Glucose transporter-2 expression was down-regulated in the β cells of βmet−/− mice. Compared to controls, βmet−/− mice exhibited reduced islet size and decreased insulin content in the pancreas, but displayed normal islet morphology. Therefore, HGF/c-met signaling plays an imperative role in controlling islet growth, in regulating β-cell function, and in maintaining glucose homeostasis.