Distinct Classes of Central GLUT2-Dependent Sensors Control Counterregulation and Feeding

Distinct Classes of Central GLUT2-Dependent Sensors Control Counterregulation and Feeding Nell Marty , Isabelle Bady and Bernard Thorens From the Department of Physiology and Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland Address correspondence and reprint requests to Bernard Thorens, Center for Integrative Genomics, Genopode Building, University of Lausanne, CH-1015 Lausanne, Switzerland. E-mail: bernard.thorens{at}unil.ch Abstract The pancreatic β-cell paradigm for glucose sensing has been proposed to apply to brain glucose sensors controlling counterregulation to hypoglycemia and feeding behavior. Over recent years, we tested this model in mice by first showing that inactivation of the GLUT2 gene suppressed glucose sensing and correctly regulated insulin secretion by pancreatic β-cells. Then, we restored the function of the β-cell in GLUT2-null mice by transgenic expression of a glucose transporter under the control of the rat insulin promoter. Using these rescued mice, we showed that GLUT2-dependent sensors are present in several anatomical sites, including the hepatoportal vein and the central nervous system. When these extrapancreatic glucose sensors are inactivated, the mice display loss of first-phase insulin secretion and hyperglucagonemia in the fed state, and they eat more than control mice—defects characteristic of developing obesity/diabetes. By gene complementation experiments, we further showed that glucose sensors controlling glucagon secretion require GLUT2 expression in glial cells. However, transgenic expression of GLUT2 in astrocytes or neurons failed to restore the normal control of feeding, indicating that different classes of glucose sensors control the response to hypoglycemia and food intake. 2-DG, 2-deoxy-d-glucose GLP-1, glucagon-like peptide 1 Footnotes This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted May 5, 2006. Received March 28, 2006. DIABETES