Effect of acute hypoglycemia on human cerebral glucose metabolism measured by ¹³C magnetic resonance spectroscopy

Abstract

Objective: To investigate the effect of acute insulin-induced hypoglycemia on cerebral glucose metabolism in healthy humans, measured by (13)C magnetic resonance spectroscopy (MRS).

Research design and methods: Hyperinsulinemic glucose clamps were performed at plasma glucose levels of 5 mmol/L (euglycemia) or 3 mmol/L (hypoglycemia) in random order in eight healthy subjects (four women) on two occasions, separated by at least 3 weeks. Enriched [1-(13)C]glucose 20% w/w was used for the clamps to maintain stable plasma glucose labeling. The levels of the (13)C-labeled glucose metabolites glutamate C4 and C3 were measured over time in the occipital cortex during the clamp by continuous (13)C MRS in a 3T magnetic resonance scanner. Time courses of glutamate C4 and C3 labeling were fitted using a one-compartment model to calculate metabolic rates in the brain.

Results: Plasma glucose (13)C isotopic enrichment was stable at 35.1 ± 1.8% during euglycemia and at 30.2 ± 5.5% during hypoglycemia. Hypoglycemia stimulated release of counterregulatory hormones (all P < 0.05) and tended to increase plasma lactate levels (P = 0.07). After correction for the ambient (13)C enrichment values, label incorporation into glucose metabolites was virtually identical under both glycemic conditions. Calculated tricarboxylic acid cycle rates (V(TCA)) were 0.48 ± 0.03 μmol/g/min during euglycemia and 0.43 ± 0.08 μmol/g/min during hypoglycemia (P = 0.42).

Conclusions: These results indicate that acute moderate hypoglycemia does not affect fluxes through the main pathways of glucose metabolism in the brain of healthy nondiabetic subjects.

Figures

FIG. 1.

One-compartment model for uptake of [1-13C]glucose and its conversion into labeled metabolites. Brain glucose uptake from the blood was modeled by reversible Michaelis-Menten kinetics (40). Vgly represents the glycolysis rate and has a value of 0.5 × VTCA. The cycling of glutamate and glutamine between neurons and astroglia is approached by the parameter Vgln and assumed equal to VTCA. VTCA, Vdil, and Vefflux are the free parameters of the model, representing TCA cycle flux, exchange of plasma, and brain lactate and efflux of labeled glutamine, respectively. VLDH represents lactate dehydrogenase and was assumed to be 3 μmol/g/min; VX represents the exchange between α-ketoglutarate and glutamate over the mitochondrial membrane and was assumed to be 5 μmol/g/min. Furthermore, the following assumptions were made for total pool concentrations: [Glu]: 10 mmol/L; [Gln]: 2.5 mmol/L; [OAA]; 0.3 mmol/L; [αKG]: 0.25 mmol/L; [Asp]: 1.5 mmol/L; and [Pyr]: 0.15 mmol/L.

FIG. 2.

Plasma glucose concentration (A), plasma glucose 13C enrichment (B), plasma lactate concentration (C), and plasma lactate 13C enrichment (D) as a function of time during the euglycemic and hypoglycemic clamps. Data are shown as means ± SEM.

FIG. 3.

Representative 13C magnetic resonance spectra of the human brain measured at the end of a euglycemic experiment and a hypoglycemic experiment. PPM, parts per million.

FIG. 4.

A: Time courses of glutamate C4 and C3 labeling in brain tissue during euglycemic and hypoglycemic clamps. B: Time courses of glutamate C4 and C3 labeling in brain tissue corrected by plasma glucose 13C enrichment. C: Averaged time courses of glutamate C4 and C3 labeling in brain tissue with natural abundance signal added for modeling purposes together with averaged best fits of individual datasets.