Human hippocampal energy metabolism is impaired during cognitive activity in a lipid infusion model of insulin resistance

• Published in: Brain and behavior Vol. 3; no. 2; pp. 134 - 144
• Main Authors: Emmanuel, Yaso, Cochlin, Lowri E., Tyler, Damian J., Jager, Celeste A., David Smith, A., Clarke, Kieran
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.03.2013; Blackwell Publishing Ltd
• Subjects: Brain; Brain glucose uptake; Cognitive ability; diabetes; Gene expression; Glucose; Hypotheses; Information storage; Insulin resistance; insulin signaling; Memory; Metabolism; neurometabolic coupling; Original Research; Spectrum analysis; Studies; Brain glucose uptake; insulin signaling; neurometabolic coupling; diabetes
• ISSN: 2162-3279; 2162-3279
• DOI: 10.1002/brb3.124

Neuronal glucose uptake was thought to be independent of insulin, being facilitated by glucose transporters GLUT1 and GLUT3, which do not require insulin signaling. However, it is now known that components of the insulin‐mediated glucose uptake pathway, including neuronal insulin synthesis and the insulin‐dependent glucose transporter GLUT4, are present in brain tissue, particularly in the hippocampus. There is considerable recent evidence that insulin signaling is crucial to optimal hippocampal function. The physiological basis, however, is not clear. We propose that while noninsulin‐dependent GLUT1 and GLUT3 transport is adequate for resting needs, the surge in energy use during sustained cognitive activity requires the additional induction of insulin‐signaled GLUT4 transport. We studied hippocampal high‐energy phosphate metabolism in eight healthy volunteers, using a lipid infusion protocol to inhibit insulin signaling. Contrary to conventional wisdom, it is now known that free fatty acids do cross the blood–brain barrier in significant amounts. Energy metabolism within the hippocampus was assessed during standardized cognitive activity. 31Phosphorus magnetic resonance spectroscopy was used to determine the phosphocreatine (PCr)‐to‐adenosine triphosphate (ATP) ratio. This ratio reflects cellular energy production in relation to concurrent cellular energy expenditure. With lipid infusion, the ratio was significantly reduced during cognitive activity (PCr/ATP 1.0 ± 0.4 compared with 1.4 ± 0.4 before infusion, P = 0.01). Without lipid infusion, there was no reduction in the ratio during cognitive activity (PCr/ATP 1.5 ± 0.3 compared with 1.4 ± 0.4, P = 0.57). This provides supporting evidence for a physiological role for insulin signaling in facilitating increased neuronal glucose uptake during sustained cognitive activity. Loss of this response, as may occur in type 2 diabetes, would lead to insufficient neuronal energy availability during cognitive activity. The physiological role of insulin in brain glucose uptake has not previously been well characterized. We propose that the kinetics of insulin mediated glucose uptake are such that in the brain, it may play a role in facilitating the required acute rapid increases in neuronal glucose uptake in response to cognitive activity. We present data from a new in vivo experimental in vivo approach which supports this proposed role.