Effect of Acute Hypoglycemia on Human Cerebral Glucose Metabolism Measured by 13C Magnetic Resonance Spectroscopy

Abstract

OBJECTIVETo investigate the effect of acute insulin-induced hypoglycemia on cerebral glucose metabolism in healthy humans, measured by 13C magnetic resonance spectroscopy (MRS).RESEARCH DESIGN AND METHODSHyperinsulinemic 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 [1-13C]glucose 20% w/w was used for the clamps to maintain stable plasma glucose labeling. The levels of the 13C-labeled glucose metabolites glutamate C4 and C3 were measured over time in the occipital cortex during the clamp by continuous 13C 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.RESULTSPlasma glucose 13C 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 13C enrichment values, label incorporation into glucose metabolites was virtually identical under both glycemic conditions. Calculated tricarboxylic acid cycle rates (VTCA) were 0.48 ± 0.03 μmol/g/min during euglycemia and 0.43 ± 0.08 μmol/g/min during hypoglycemia (P = 0.42).CONCLUSIONSThese results indicate that acute moderate hypoglycemia does not affect fluxes through the main pathways of glucose metabolism in the brain of healthy nondiabetic subjects.

Lactate preserves neuronal metabolism and function following antecedent recurrent hypoglycemia

“…Indeed, measurement of glucose concentrations and calculation of glucose uptake rates revealed that control animals were limited by transport in their ability to take up sufficient amounts of glucose at a plasma glucose level of 2.5 mM to support normal TCA cycle function, which was not the case after exposure to antecedent recurrent hypoglycemia. This is in contrast to prior reports of healthy and type 1 diabetic humans that underwent a 13 C-glucose infusion during hypoglycemia, which did not exhibit a significant drop in TCA cycle activity under clamped hypoglycemia (36). However, based on differences in brain glucose concentration among these studies conducted in humans and our study one may have predicted this discrepancy in results: the brain glucose levels during hypoglycemia achieved in human controls and type 1 diabetic subjects of 0.5 and 0.6 μmol/g (37) are several times higher than the K m of hexokinase I (the major brain isozyme) for glucose (0.045-0.07 mM; refs.…”

Metabolic Flux and Compartmentation Analysis in the Brain In vivo

“…Although devoid of major effects in modeling 13 C data from short experiments where isotopic steady-state is not reached, the inclusion of V Gln and dilution from glutamine are crucial for reliable determination of V TCA and V X in one-compartment modeling. This model was employed in recent studies to estimate fluxes from 13 C curves of glutamate C4 and C3 (25–28). …”

Changes in Human Brain Glutamate Concentration during Hypoglycemia: Insights into Cerebral Adaptations in Hypoglycemia-Associated Autonomic Failure in Type 1 Diabetes

“…3 The cerebral response to hypoglycemia in the healthy brain involves changes in regional blood flow 4,5 and sequential adjustments in cerebral metabolism in order to provide sufficient fuel for brain activity. As the levels of glucose, the principal cerebral energy substrate, drop from 5 to B3 mmol/L in plasma, cerebral metabolic rate of glucose (CMRglc) and cerebral metabolic rate of oxygen (CMRO 2 ) are preserved [6][7][8] despite lower brain glucose uptake. 9 The brain starts using alternative fuels such as glycogen in this glycemic range.…”