Hyperglycemia and hyperinsulinemia effects on anterior cingulate cortex myoinositol-relation to brain network functional connectivity in healthy adults

Brain mechanisms underlying the association of diabetes metabolic disorders-hyperglycemia and insulin resistance-with cognitive impairment are unknown. Myoinositol is a brain metabolite involved in cell osmotic balance, membrane phospholipid turnover, and second messenger neurotransmission, which affect brain function. Increased brain myoinositol and altered functional connectivity have been found in diabetes, mild cognitive impairment, and Alzheimer's disease, but the independent effects of plasma glucose and insulin on brain myoinositol and function are not characterized. We measured myoinositol concentrations in the pregenual anterior cingulate cortex (ACC), a region involved in self-reflective awareness and decision making, using proton magnetic resonance spectroscopy, and whole brain resting-state functional connectivity using fMRI, during acute hyperglycemia (with attendant hyperinsulinemia) and euglycemic-hyperinsulinemia compared with basal fasting-euglycemia (EU) in 11 healthy nondiabetic participants (5 women/ 6 men, means +/- SD, age: 27 +/- 7 yr, fasting-glucose: 5.2 +/- 0.4 mmol/L, fasting-insulin: 4.9 +/- 4.4 mu U/mL). Brain MR data were acquired during two separate visits: 1) EU followed by a 60-min hyperglycemic-clamp (glucose: 10.7 +/- 02 mmol/L, insulin: 33 +/- 6 mu U/mL); 2) EU followed by a hyperinsulinemic-euglycemic-clamp (glucose: 5.3 +/- 0.1 mmol/L, insulin: 27 +/- 5 mu U/mL) designed to match individual insulin levels achieved during the visit 1 hyperglycemic-clamp. Myoinositol decreased by 14% during the hyperglycemic-clamp (from 7.7 +/- 1.5 mmol/kg to 6.6 +/- 0.8 mmol/kg, P = 0.031), and by 9% during the hyperinsulinemic-euglycemic-clamp (from 7.1 +/- 0.7 mmoVkg to 6.5 +/- 0.7 mmol/kg, P = 0.014), with no significant difference between the two clamps. Lower myoinositol was associated with higher functional connectivity of the thalamus and precentral cortex with insula-ACC-related networks, suggesting myoinositol is involved in insulin modulation of cognitive/emotional network function in healthy adults. Regional brain myoinositol levels may be useful biomarkers for monitoring cognitive and mood-enhancing treatment responses. NEW & NOTEWORTHY Hyperinsulinemia-related decreases of brain anterior cingulate cortex (ACC) myoinositol independent of plasma glucose levels and the association of low ACC myoinositol with increased functional connectivity between sensorimotor regions and ACC/insula-related networks suggest involvement of myoinositol in insulin-modulated brain network function in healthy adults. In diabetes, elevated brain myoinositol may be due to reduced brain insulin levels or action, rather than hyperglycemia, and may be involved in brain network dysfunctions leading to cognitive or mood disorders.