Insulin Regulates Astrocytic Glucose Handling Through Cooperation With IGF-I

Abstract

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. Analysis 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 interactions involving the scaffolding protein GAIP-interacting protein C terminus and the GTPase RAC1. Our observations identify insulin-like peptides as physiological modulators of brain glucose handling, providing further support to consider the brain as a target organ in diabetes.

Unravelling the regulation of insulin transport across the brain endothelial cell

“…While we [25] and others [3, 4, 6, 47] found a delay of insulin entry into or action in the brains of HFD-fed animals, this is the first study to our knowledge to report impaired insulin transport at the level of the BEC. Our co-culture findings, as well as recent work regarding insulin signalling in astrocytes [48, 49], may suggest a role for astrocytes in the effect of an HFD on BBB insulin transport. Given the clinical importance of brain insulin resistance, the latter possibly warrants further investigation.…”

Glycogen metabolism is impaired in the brain of male type 2 diabetic Goto‐Kakizaki rats

“…Previous 13 C‐MRS studies in rats under light α‐chloralose anesthesia, have estimated similar (Choi, Tkác, Ugurbil, & Gruetter, ) or slightly faster (0.7 µmol/g/h, van Heeswijk, Morgenthaler, Xin, & Gruetter, ) glycogen turnover rates. The discrepancy on the measured turnover rates in our study and these previous publications could be caused by either the deepness of anesthesia that modulates brain activity and metabolism (Sonnay, Gruetter, & Duarte, ), or the brain levels of insulin that might stimulate glycogen synthesis (Fernandez et al, ; Muhič et al, ). Accordingly, administration of insulin to anaesthetized rats was previously reported to increase brain glycogen levels (Morgenthaler et al, ).…”

“…levels of insulin that might stimulate glycogen synthesis (Fernandez et al, 2017;Muhič et al, 2015). Accordingly, administration of insulin to anaesthetized rats was previously reported to increase brain glycogen levels (Morgenthaler et al, 2006).…”

The regulation of glycogenolysis in the brain

“…Because Rac1 is expressed widely and to a great extent in brain (52) and because bGP essentially conserves the entire Rac1-binding site found in mGP (70), it is possible that (73)(74)(75)(76) brain glycogenolysis may also be mediated by Rac1 similar to its effect in muscle. In a recent report, Fernandez et al (72) demonstrated that glucose uptake in forebrain through GLUT1 translocation is synergistically stimulated by insulin and insulin-like growth factor-1 (IGF1) through mitogen-activated protein kinase/protein kinase D activation of Rac1 in astrocytes, which have been reported to express insulin, IGF1, and insulin receptors (73,74). In response to sensory stimulation, blockade of IGF1 receptors in the somato-sensory cortex was shown to diminish neuronal activity and glucose uptake by astrocytes (72).…”