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 [1-13C]glucose infusion to increase plasma 13C enrichment. In vivo brain 13C magnetic resonance spectroscopy was used to measure the time course of 13C label incorporation into different metabolites and to calculate the tricarboxylic acid cycle flux (VTCA) by a one-compartment metabolic model. We found that cerebral glucose metabolism, as reflected by the VTCA, was not significantly different comparing euglycemic and hypoglycemic conditions in patients with T1DM. However, the VTCA was inversely related to the HbA1C 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.

Figures

Figure 1. Plasma glucose concentration and 13C enrichment during clamp studies.

(A) Plasma glucose levels and (B) glucose 13C enrichment during euglycemic and hypoglycemic clamps. All data are expressed as mean ± SEM.

Figure 2. Counterregulatory hormone levels.

Levels of plasma glucagon, adrenalin, noradrenalin, growth hormone, and cortisol at baseline (BL) and at the end (End) of the euglycemic and hypoglycemic clamp. All data are expressed as mean ± SEM. *P < 0.05 compared with corresponding baseline value. †P < 0.05 compared with end value of euglycemic clamp.

Figure 3. 13C MR spectrum.

Representative MR spectrum acquired in 15 minutes after correction for baseline spectra to remove residual fat contamination (note that myo-inositol signal is also not visible because the concentration in the reference spectra is the same as in the dynamic spectra); this is an example of a spectrum fitted in jMRUI to derive concentrations of different labeled metabolites. ppm, parts per million.

Figure 4. Plasma lactate 13C enrichment during clamps.

Plasma lactate 13C enrichment during (A) euglycemic and (B) hypoglycemic clamps. Patients with T1DM are represented by black symbols; shaded areas represent values in healthy subjects, as reported in ref. . All data are expressed as mean ± SEM.

Figure 5. Brain glutamate 13C enrichment over time.

Brain Glu4 and Glu3 concentrations during (A) euglycemic and (B) hypoglycemic clamps, (C and D) together with the respective fits (solid lines) by the metabolic model. Patients with T1DM are represented by black symbols; shaded areas represent values in healthy subjects, as reported in ref. . All data were individually quantified and fitted and averaged afterward. All data are expressed as mean ± SEM.

Figure 6. VTCA.

VTCA during euglycemic and hypoglycemic clamps in patients with T1DM (this study) and healthy subjects (5). Individual symbols represent individual patients or healthy subjects; horizontal bars indicate the mean. *P = 0.014.

Figure 7. VTCA versus HbA1C.

Inverse correlation between the HbA1C and the VTCA (r = 0.56, P < 0.01). For paired measurements, the average VTCA was used. Individual symbols represent individual samples.