Patients with type 1 diabetes exhibit altered cerebral metabolism during hypoglycemia

Abstract

Patients with type 1 diabetes mellitus (T1DM) experience, on average, 2 to 3 hypoglycemic episodes per week. This study investigated the effect of hypoglycemia on cerebral glucose metabolism in patients with uncomplicated T1DM. For this purpose, hyperinsulinemic euglycemic and hypoglycemic glucose clamps were performed on separate days, using [1-13 C]glucose infusion to increase plasma 13 C enrichment. In vivo brain 13 C magnetic resonance spectroscopy was used to measure the time course of 13 C label incorporation into different metabolites and to calculate the tricarboxylic acid cycle flux (V TCA ) by a one-compartment metabolic model. We found that cerebral glucose metabolism, as reflected by the V TCA , was not significantly different comparing euglycemic and hypoglycemic conditions in patients with T1DM. However, the V TCA was inversely related to the HbA 1C and was, under hypoglycemic conditions, approximately 45% higher than that in a previously investigated group of healthy subjects. These data suggest that the brains of patients with T1DM are better able to endure moderate hypoglycemia than those of subjects without diabetes. IntroductionPatients with type 1 diabetes mellitus (T1DM) experience on average 2 hypoglycemic episodes per week and 1 severe episode of hypoglycemia each year (1). Because the brain depends almost exclusively on glucose, recurrent hypoglycemia may be a threat for cognitive dysfunction and cerebral damage. Patients with T1DM are at increased risk for accelerated cognitive decline and possibly for dementia (2, 3). Interestingly, however, patients with T1DM enduring recurrent episodes of severe hypoglycemia do not appear at greater risk of developing cognitive function impairment than patients without such a history (4). This suggests that recurrent hypoglycemia can induce protective adaptations with respect to cerebral glucose metabolism or that hyperglycemia is at least as detrimental for the brain as hypoglycemia.Recently, we showed that brain glucose metabolism in healthy subjects at glucose levels of approximately 3 mmol/l did not differ from that at normal glucose levels, as reflected by similar tricarboxylic acid (TCA) cycle rates (V TCA ) (5). This remarkable maintenance of normal V TCA during symptomatic hypoglycemia indicates that the glucose threshold for effects on cerebral metabolism lies below 3 mmol/l, either because the brain can endure low glucose levels or because entrance of nonglucose energy substrates such as lactate compensates for the fall in glucose (6-9). Whether these findings can be extrapolated to patients with T1DM remains to be determined.This study was therefore undertaken to investigate the effect of hypoglycemia on brain glucose metabolism in a representative group of patients with longstanding, uncomplicated, reasonably well-controlled T1DM. To do so, we used 13 C magnetic resonance spectroscopy (MRS) of the human brain during euglycemic and hypoglycemic glucose clamps with infusion of [1-13 C]glucose, as described previously (5, 10). With this appro...

Mechanisms of Hypoglycemia-Associated Autonomic Failure in Diabetes

“…There was no significant difference in brain glucose concentrations between the nondiabetic persons and the patients with type 1 diabetes in the study by van de Ven and colleagues, 45 suggesting no difference in blood-to-brain glucose transport. Assuming the patients with type 1 diabetes did not have HAAF (epinephrine responses in these patients were similar to those in nondiabetic persons, and symptoms of hypoglycemia were not reported), commentators suggested that blood-to-brain glucose uptake might have been increased in patients with HAAF, if they had been included in the study.…”

“…The rate of blood-to-brain glucose transport exceeds the rate of cerebral glucose metabolism even at plasma glucose concentrations of 65 mg per deciliter (3.6 mmol per liter) in humans. 30,42 Extrapolation of the linear relationship between plasma and brain glucose concentrations, the latter measured with 13 C magnetic resonance spectroscopy, in nondiabetic persons and patients with type 1 diabetes during euglycemia and hypoglycemia, as reported by van de Ven and colleagues, 45 suggests that the plasma glucose concentration at which the brain glucose concentration would become zero -at which point brain glucose metabolism would have to decrease -is less than 36 mg per deciliter (2.0 mmol per liter). An increase in blood-to-brain glucose transport would not increase brain glucose metabolism unless it shifted from below to above that unknown, but seemingly low, glycemic threshold.…”

“…46 That inference was made on the basis of two observations: a 15% higher occipital-cortical brain glucose concentration in patients with type 1 diabetes than in nondiabetic persons, as measured with 1 Notably, the same investigative group found no effect of recurrent episodes of hypoglycemia, which produced a model of HAAF (attenuated epinephrine and neurogenic symptom responses to hypoglycemia), on brain glucose concentrations measured with 1 H magnetic resonance spectroscopy under similar nonphysiologic conditions with hyperglycemia. 49 Because the brain glucose concentration is a direct function of the plasma glucose concentration, 45 the unaltered brain glucose concentration does not support the conclusion that increased blood-to-brain glucose transport might be the mechanism of HAAF. 46 If the normally small astrocytic brain glycogen pool 1 increases substantially (reflecting glycogen supercompensation) after hypoglycemia, that expanded source of glucose within the brain could result in an attenuated sympathoadrenal response during subsequent hypoglycemia.…”

Adaptation of the brain to hypoglycemia: Does the brain stand by for the next hypoglycemia event?

“…van de Ven et al 3 reported that type 1 diabetes mellitus patients showed altered cerebral glucose metabolism during hypoglycemia compared with healthy controls. In their previous study, they used 13 C magnetic resonance spectroscopy to explore cerebral glucose metabolism during hypoglycemic glucose clamp in healthy subjects and evaluated the tricarboxylic acid cycle flux (V TCA ).…”

“…Although most type 1 diabetes mellitus patients experience hypoglycemia, the frequency of hypoglycemia is not related to a higher risk of cognitive impairment. On the basis of this result, van de Ven et al 3 hypothesized that the brain physiologically adapts to protect itself from hypoglycemia. To test this hypothesis, they carried out euglycemic and hypoglycemic glucose clamp on type 1 diabetes mellitus patients and compared their cerebral glucose metabolism with that of healthy subjects.…”