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(American Journal of Pathology. 2005;167:429-436.)
© 2005 American Society for Investigative Pathology

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

Chunsun Dai*, Chang-Goo Huh{dagger}, Snorri S. Thorgeirsson{dagger} and Youhua Liu*

From the Department of Pathology,* University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Laboratory of Experimental Carcinogenesis,{dagger} Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Hepatocyte growth factor (HGF) and its c-met receptor consist of a paired signaling system that has been implicated in the regulation of pancreatic ß-cell survival, proliferation, and function. To define the role of HGF/c-met signaling in ß-cell biology in vivo, we have generated conditional knockout mice in which the c-met receptor gene was specifically inactivated in pancreatic ß cells by the Cre-loxP system. Mice with ß-cell-specific deletion of the c-met receptor (ßmet–/–) 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 ß 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 ß cells of ßmet–/– mice. Compared to controls, ßmet–/– 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 ß-cell function, and in maintaining glucose homeostasis.




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