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OBJECTIVE To 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 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 [1-13C]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. RESULTS Plasma 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). 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.

β-Cells are the core effector of glycemic control, and when largely lost in the course of type 1 diabetes, glycemic control is no longer guaranteed. Although glycemic control can be established by insulin injections, diabetic patients still suffer from microvascular (nephropathy, retinopathy, neuropathy) and macrovascular (ischemic heart disease, cerebrovascular disease, peripheral vascular disease) complications, resulting in a lower life expectancy (1). Therefore, islet transplantation has been implemented as one therapeutic means to achieve a more physiologic form of glycemic control. Although high rates of insulin independence can be achieved shortly after transplantation, the rate of insulin independence after longer time intervals remains suboptimal, especially in view of the potential complications of immunosuppressive treatment (2). One of the reasons for the limited clinical success of islet transplantation is the exposure of the islets to stress prior to and in the first weeks after transplantation. The liver may actually not be an optimal transplantation site (although it connects the islets to the blood flow from the portal vein). Also, it has been shown that islet grafts will only be fully vascularized after 1–2 weeks, reaching the final state of vascularization even later (3). As a consequence of the lack of nutrients and hypoxia, together with other factors such as hyperglycemia and immunosuppressant toxicity, to name only two of them, a considerable proportion of the transplanted β-cells will undergo apoptosis, further limiting the success of islet transplantation. In order …