Beta-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 beta-cell survival, proliferation, and function. To define the role of HGF/c-met signaling in beta-cell biology in vivo, we have generated conditional knockout mice in which the c-met receptor gene was specifically inactivated in pancreatic beta cells by the Cre-loxP system. Mice with beta-cell-specific deletion of the c-met receptor (betamet-/-) 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 beta 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 beta cells of betamet-/- mice. Compared to controls, betamet-/- 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 beta-cell function, and in maintaining glucose homeostasis.
Dai
Chunsun
C
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Huh
Chang-Goo
CG
Thorgeirsson
Snorri S
SS
Liu
Youhua
Y
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D005260:Female; D005838:Genotype; D018149:Glucose Intolerance; D051273:Glucose Transporter Type 2; D006943:Hyperglycemia / Q000209:etiology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D019426:Integrases; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001786:Blood Glucose; D051273:Glucose Transporter Type 2; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D019859:Proto-Oncogene Proteins c-met; C045073:Cre recombinase; D019426:Integrases