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

Abstract

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.

Maternal high-fat feeding leads to alterations of brain glucose metabolism in the offspring: positron emission tomography study in a porcine model

“…Furthermore, insulin-sensitive glucose transporters like GLUT4, and partially insulinElectronic supplementary material The online version of this article (doi:10.1007/s00125-015-3848-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users. sensitive GLUT1, are expressed in different brain regions [7][8][9].…”

Cerebral cortex: a target and source of insulin?

“…One can speculate that insulin release could be synchronised to elevated overall activity in networks around neurogliaform neurons. This way transient local energy demand could be met by insulin release-driven additional glucose transport through insulindependent GLUT4, as suggested for epochs of intense hippocampal or cortical activity during cognitive processing [58]. At the same time, the overall excitation-suppressing activity of insulin released from neurogliaform cells is likely to be coupled with the synchronous release and inhibitory action of GABA from neurogliaform cells, which might curtail energy demand.…”

“…Insulin receptors and the insulinsensitive glucose transporter GLUT4 have been shown to colocalise on neurons [53], and cellular mechanisms supporting neuronal metabolic functions of insulin involve translocation of GLUT4 to the cell surface [54], so providing an alternative to insulin-independent glucose uptake through GLUT3. The insulin dependence of brain metabolism at the neural network level has also been revisited by a number of human in vivo studies [55][56][57], which suggest that insulin can effectively stimulate glucose uptake in the medial temporal lobe, especially during periods of intensive neuronal activity [58]. Moreover, a rapid increase in local glycolysis following insulin administration was found in the hippocampus and was suppressed in type 2 diabetes [59].…”

“…First, neuronal ensembles in the hippocampus and the neocortex are engaged in increased high-frequency epochs of firing during memory formation or cognitive tasks and the extra metabolic demand created by intensive action potential generation might be met by alternative routes of supply. An unorthodox pathway of glucose supply during cognitive surges in energy demand was suggested by Emmanuel et al [58], who proposed that non-insulin-dependent GLUT1 and GLUT3 transport is sufficient for resting brain activity, while sustained cognitive activity induces the addition of insulinsignalled GLUT4 transport. Second, unlike in other organs, glucose is central for the energy metabolism of the brain and temporary or sustained changes in glucose supply could be crucial in differentiating the normal and pathological functions of neural circuits.…”

“…Second, unlike in other organs, glucose is central for the energy metabolism of the brain and temporary or sustained changes in glucose supply could be crucial in differentiating the normal and pathological functions of neural circuits. Cognitive deficits are associated with insulin resistance and diabetes [60,61] and impaired insulindependent mechanisms for glucose uptake during tasks requiring extra supply might lead to deficient energy metabolism [58]. Along the same vein, 'type 3 diabetes' was suggested as an alternative term for Alzheimer's disease [35], based on observations showing reduced insulin expression and signalling mechanisms in the sporadic form of the disease [62].…”