Ana M. Fernandez, 1,2 Edwin Hernandez-Garzón, 1,2 Paloma Perez-Domper, 1,2 Alberto Perez-Alvarez, 1,3 Sara Mederos, 1 Takashi Matsui, 4 Andrea Santi, 1,2 Angel Trueba-Saiz, 1,2 Lucía García-Guerra, 2,5 Julia Pose-Utrilla, 2,5 Jens Fielitz, 6,7 Eric N. Olson, 8 Ruben Fernandez de la Rosa, 9 Luis Garcia Garcia, 9 Miguel Angel Pozo, 9 Teresa Iglesias, 2,5 Alfonso Araque, 1 Hideaki Soya, 4 Gertrudis Perea, 1 Eduardo D. Martin, 10 and Ignacio Torres Aleman 1,2 Insulin Regulates Astrocytic Glucose Handling Through Cooperation With IGF-I Diabetes 2017;66:64–74 | DOI: 10.2337/db16-0861 Brain activity requires a flux of glucose to active regions to sustain increased metabolic demands. Insulin, the main regulator of glucose handling in the body, has been traditionally considered not to intervene in this process. However, we now report that insulin modulates brain glucose metabolism by acting on astrocytes in concert with IGF-I. The cooperation of insulin and IGF-I is needed to recover neuronal activity after hypoglycemia. Anal- ysis of underlying mechanisms show that the combined action of IGF-I and insulin synergistically stimulates a mitogen-activated protein kinase/protein kinase D pathway resulting in translocation of GLUT1 to the cell membrane through multiple protein-protein interac- tions involving the scaffolding protein GAIP-interacting protein C terminus and the GTPase RAC1. Our obser- vations identify insulin-like peptides as physiological modulators of brain glucose handling, providing further support to consider the brain as a target organ in diabetes. Contrary to its glucoregulatory actions in peripheral tissues, physiological variations of circulating insulin levels do not modulate glucose handling by brain cells (1). Only under pathological circumstances, such as diabetes, do brain glucoregulatory actions of insulin manifest (2). Therefore, mechanisms of neurovascular coupling, whereby active brain regions locally increase glucose and oxygen uptake, are not considered to involve insulin under phys- iological circumstances. Moreover, both endothelial cells and astrocytes, the main cellular constituents of the blood- brain barrier (BBB) express GLUT1 as their main facilitative transporter (3), and GLUT1 is considered to be largely in- sulin insensitive (4). At the same time, there is evidence that the structurally related peptide IGF-I affects glucose metabolism in the brain (5). Importantly, in animal models of diabetes, not only is there brain insulin resistance (6), but also brain IGF-I levels are reduced (7). We now describe a cooperative mechanism whereby insulin stimulates glu- cose uptake by forebrain astrocytes acting in concert with IGF-I. Cooperation of insulin and IGF-I (I+I) may explain brain glucose uptake on demand without changes in circu- lating insulin levels. RESEARCH DESIGN AND METHODS Animals Adult (3–5 months old) and newborn C57BL6/J mice were used. To obtain mice with glial fibrillary acidic protein (GFAP)–specific deletion of PKD1, PKD1 loxP/loxP mice (8) 1 Cajal Institute, Consejo Superior de Investigaciones Científicas, Madrid, Spain 2 CIBERNED, Madrid, Spain 3 Center for Molecular Neurobiology Hamburg, Hamburg, Germany 4 Laboratory of Exercise Biochemistry and Neuroendocrinology, University of Tsu- kuba, Tsukuba, Japan 5 Instituto de Investigaciones Biomédicas “Alberto Sols,” Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain 6 Experimental and Clinical Research Center, Charité-Universitätsmedizin, Max Delbrück Center for Molecular Medicine, Berlin, Germany 7 Brandenburg Heart Center and Medical University of Brandenburg, Brandenburg, Germany 8 University of Texas Southwestern Medical Center, Dallas, TX 9 Pluridisciplinary Institute, Complutense University of Madrid, Madrid, Spain 10 Science and Technology Park, Institute for Research in Neurological Disabilities, University of Castilla-La Mancha, Albacete, Spain Corresponding author: Ignacio Torres Aleman, torres@cajal.csic.es. Received 19 July 2016 and accepted 28 September 2016. This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/doi:10.2337/db16-0861/-/DC1. A.M.F. and E.H.-G. contributed equally to this work. © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license. 64 Diabetes Volume 66, January 2017 SIGNAL TRANSDUCTION Downloaded from http://diabetesjournals.org/diabetes/article-pdf/66/1/64/418515/db160861.pdf by guest on 01 April 2023