Characterization of the concurrent metabolic changes in brain and plasma during insulin-induced moderate hypoglycemia using ¹H NMR spectroscopy in juvenile rats

Treatment of hypoglycemia in children is currently based on plasma glucose measurements. This approach may not ensure neuroprotection since plasma glucose does not reflect the dynamic state of cerebral energy metabolism. To determine whether cerebral metabolic changes during hypoglycemia could be better characterized using plasma metabolomic analysis, insulin-induced acute hypoglycemia was induced in 4-week-old rats. Brain tissue and concurrent plasma samples were collected from hypoglycemic (N = 7) and control (N = 7) rats after focused microwave fixation to prevent post-mortem metabolic changes. The concentration of 29 metabolites in brain and 34 metabolites in plasma were determined using ¹H NMR spectroscopy at 700 MHz and examined using partial least squares-discriminant analysis. The sensitivity of plasma glucose for detecting cerebral energy failure was assessed by determining its relationship to brain phosphocreatine. The brain and plasma metabolite profiles of the hypoglycemia group were distinct from the control group (brain: R² = 0.92, Q² = 0.31; plasma: R² = 0.95, Q² = 0.74). Concentration differences in glucose, ketone bodies and amino acids were responsible for the intergroup separation. There was 45% concordance between the brain and plasma metabolite profiles. Brain phosphocreatine correlated with brain glucose (control group: R² = 0.86; hypoglycemia group: R² = 0.59; p < 0.05), but not with plasma glucose. The results confirm that plasma glucose is an insensitive biomarker of cerebral energy changes during hypoglycemia and suggest that a plasma metabolite profile is superior for monitoring cerebral metabolism.