Targeted Inactivation of Hepatocyte Growth Factor Receptor c-met in β-Cells Leads to Defective Insulin Secretion and GLUT-2 Downregulation Without Alteration of β-Cell Mass

• Published in: Diabetes (New York, N.Y.) Vol. 54; no. 7; pp. 2090 - 2102
• Main Authors: Roccisana, Jennifer, Reddy, Vasumathi, Vasavada, Rupangi C, Gonzalez-Pertusa, Jose A, Magnuson, Mark A, Garcia-Ocaña, Adolfo
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.07.2005
• Subjects: Animals; Biological and medical sciences; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gene Expression Regulation; Glucose - pharmacology; Glucose Transporter Type 2; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - cytology; Islets of Langerhans - metabolism; Islets of Langerhans - physiology; Medical sciences; Mice; Mice, Knockout; Monosaccharide Transport Proteins - genetics; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Proto-Oncogene Proteins c-met - deficiency; Proto-Oncogene Proteins c-met - genetics; Endocrinopathy; Pancreatic hormone; Hepatocyte growth factor; Secretion; Diabetes mellitus; Langerhans islet; β Cell; Inactivation; Insulin; Endocrine pancreas; Biological receptor
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.54.7.2090

Targeted Inactivation of Hepatocyte Growth Factor Receptor c-met in β-Cells Leads to Defective Insulin Secretion and GLUT-2 Downregulation Without Alteration of β-Cell Mass Jennifer Roccisana 1 , Vasumathi Reddy 1 , Rupangi C. Vasavada 1 , Jose A. Gonzalez-Pertusa 1 , Mark A. Magnuson 2 and Adolfo Garcia-Ocaña 1 1 Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 2 Vanderbilt University Medical Center, Nashville, Tennessee Address correspondence and reprint requests to Adolfo Garcia-Ocaña, Division of Endocrinology, BST-E-1140, University of Pittsburgh, 200 Lothrop St., Pittsburgh, PA 15261. E-mail: ocana{at}msx.dept-med.pitt.edu Abstract Overexpression of hepatocyte growth factor (HGF) in the β-cell of transgenic mice enhances β-cell proliferation, survival, and function. In the current studies, we have used conditional ablation of the c-met gene to uncover the physiological role of HGF in β-cell growth and function. Mice in which c-met is inactivated in the β-cell (MetCKO mice) display normal body weight, blood glucose, and plasma insulin compared with control littermates. In contrast, MetCKO mice displayed significantly diminished glucose tolerance and reduced plasma insulin after a glucose challenge in vivo. This impaired glucose tolerance in MetCKO mice was not caused by insulin resistance because sensitivity to exogenous insulin was similar in both groups. Importantly, in vitro glucose-stimulated insulin secretion in MetCKO islets was decreased by ∼50% at high glucose concentrations compared with control islets. Furthermore, whereas insulin and glucokinase expression in MetCKO islets were normal, GLUT-2 expression was decreased by ∼50%. These changes in β-cell function in MetCKO mice were not accompanied by changes in total β-cell mass, islet morphology, islet cell composition, and β-cell proliferation. Interestingly, however, MetCKO mice display an increased number of small islets, mainly single and doublet β-cells. We conclude that HGF/c-met signaling in the β-cell is not essential for β-cell growth, but it is essential for normal glucose-dependent insulin secretion. BrdU, 5-bromo-2′-deoxyuridine GLP-1, glucagon-like peptide 1 GSIS, glucose-stimulated insulin secretion HGF, hepatocyte growth factor hGH, human growth hormone KRBB, Krebs-Ringer bicarbonate buffer RIA, radioimmunoassay TGF-α, transforming growth factor-α Footnotes J.R. and V.R. contributed equally to this work. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted April 4, 2005. Received January 18, 2005. DIABETES