Insulin-Like Growth Factor 1 Regulates Developing Brain Glucose Metabolism

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 97; no. 18; pp. 10236 - 10241
• Main Authors: Cheng, C M, Reinhardt, R R, Lee, W H, Joncas, G, Patel, S C, Bondy, C A
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 29.08.2000; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Animals; Biological Sciences; Brain; Brain - drug effects; Brain - growth & development; Brain - physiology; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Deoxyglucose - pharmacokinetics; Gene Expression Regulation; Glucose; Glucose - metabolism; Glucose Transporter Type 4; Glycogen; Glycogen - biosynthesis; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Insulin; Insulin-Like Growth Factor I - deficiency; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - pharmacology; Insulin-Like Growth Factor I - physiology; Male; Mental retardation; Metabolism; Mice; Mice, Knockout; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Monosaccharide Transport Proteins - genetics; Monosaccharide Transport Proteins - metabolism; Muscle Proteins; Neurology; Neurons; Neurons - physiology; Phosphorylation; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Purkinje cells; Rats; Rats, Sprague-Dawley; Receptors; Signal Transduction; Synaptosomes; Transcription, Genetic
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.170008497

The brain has enormous anabolic needs during early postnatal development. This study presents multiple lines of evidence showing that endogenous brain insulin-like growth factor 1 (Igf1) serves an essential, insulin-like role in promoting neuronal glucose utilization and growth during this period. Brain 2-deoxy-D-[1-14C]glucose uptake parallels Igf1 expression in wild-type mice and is profoundly reduced in Igf1-/- mice, particularly in those structures where Igf1 is normally most highly expressed. 2-Deoxy-D-[1-14C]glucose is significantly reduced in synaptosomes prepared from Igf1-/- brains, and the deficit is corrected by inclusion of Igf1 in the incubation medium. The serine/threonine kinase Akt/PKB is a major target of insulin-signaling in the regulation of glucose transport via the facilitative glucose transporter (GLUT4) and glycogen synthesis in peripheral tissues. Phosphorylation of Akt and GLUT4 expression are reduced in Igf1-/- neurons. Phosphorylation of glycogen synthase kinase 3β and glycogen accumulation also are reduced in Igf1-/- neurons. These data support the hypothesis that endogenous brain Igf1 serves an anabolic, insulin-like role in developing brain metabolism.