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.

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). V_gly represents the glycolysis rate and has a value of 0.5 × V_TCA. The cycling of glutamate and glutamine between neurons and astroglia is approached by the parameter V_gln and assumed equal to V_TCA. V_TCA, V_dil, and V_efflux are the free parameters of the model, representing TCA cycle flux, exchange of plasma, and brain lactate and efflux of labeled glutamine, respectively. V_LDH represents lactate dehydrogenase and was assumed to be 3 μmol/g/min; V_X 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.