Acute Hyperglycemia Increases Brain Pregenual Anterior Cingulate Cortex Glutamate Concentrations in Type 1 Diabetes

Abstract

The brain mechanisms underlying the association of hyperglycemia with depressive symptoms are unknown. We hypothesized that disrupted glutamate metabolism in pregenual anterior cingulate cortex (ACC) in type 1 diabetes (T1D) without depression affects emotional processing. Using proton MRS, we measured glutamate concentrations in ACC and occipital lobe cortex (OCC) in 13 subjects with T1D without major depression (HbA1c 7.1 ± 0.7% [54 ± 7 mmol/mol]) and 11 healthy control subjects without diabetes (HbA1c 5.5 ± 0.2% [37 ± 3 mmol/mol]) during fasting euglycemia followed by a 60-min +5.5 mmol/L hyperglycemic clamp (HG). Intrinsic neuronal activity was assessed using resting-state blood oxygen level-dependent functional MRI to measure the fractional amplitude of low-frequency fluctuations in slow-4 band (fALFF4). Emotional processing and depressive symptoms were assessed using emotional tasks (emotional Stroop task, self-referent encoding task [SRET]) and clinical ratings (Hamilton Depression Rating Scale [HAM-D], Symptom Checklist-90 Revised [SCL-90-R]), respectively. During HG, ACC glutamate increased (1.2 mmol/kg, 10% P = 0.014) while ACC fALFF4 was unchanged (-0.007, -2%, P = 0.449) in the T1D group; in contrast, glutamate was unchanged (-0.2 mmol/kg, -2%, P = 0.578) while fALFF4 decreased (-0.05, -13%, P = 0.002) in the control group. OCC glutamate and fALFF4 were unchanged in both groups. T1D had longer SRET negative word response times (P = 0.017) and higher depression rating scores (HAM-D P = 0.020, SCL-90-R depression P = 0.008). Higher glutamate change tended to associate with longer emotional Stroop response times in T1D only. Brain glutamate must be tightly controlled during hyperglycemia because of the risk for neurotoxicity with excessive levels. Results suggest that ACC glutamate control mechanisms are disrupted in T1D, which affects glutamatergic neurotransmission related to emotional or cognitive processing. Increased prefrontal glutamate during acute hyperglycemic episodes could explain our previous findings of associations among chronic hyperglycemia, cortical thinning, and depressive symptoms in T1D.

© 2020 by the American Diabetes Association.

Figures

Figure 1

Experimental protocol. Plasma glucose levels vs. experiment time. Dotted lines represent subjects with T1D, and solid lines represent control subjects. During baseline, subjects with T1D received a low-dose insulin infusion to reduce their plasma glucose to euglycemia. An EU period was followed by an HG period. At the beginning of EU (time = 0) and during the entire experiment, subjects with T1D received a constant basal insulin infusion at 0.25 mU/kg/min. After EU scans, all subjects exited the scanner to initiate the HG period with a primed variable glucose infusion to attain a target increase in glycemic level of 5.5 mmol/L. Subjects were repositioned in the scanner when plasma glucose levels had stabilized at the EU +5.5 mmol/L level for the HG scanning period. Scans were performed during each of the two plasma glucose conditions, indicated by boxes beneath each plot. The mean ± SE values of plasma glucose are indicated for each visit and condition for the T1D and control groups.

Figure 2

MRS: localization of voxels and spectra analyzed using LCModel. A and B: Red-yellow scale boxes overlaid on a subject’s T1-weighted image in gray scale on sagittal (left) and axial (right) slices show the voxel regions where MRS data were acquired. The colors show the result of the brain tissue segmentation inside the voxel as follows: red, cerebrospinal fluid; orange, gray matter; and yellow, white matter. A: Pregenual ACC. B: OCC. C and D: In vivo point-resolved spectroscopy data are shown in black; the LCModel fit to data is shown in red. The top margin shows the residual to the fit, and the bottom line is the spectral baseline fit. C: Pregenual ACC. D: OCC. Glu, glutamate.

Figure 3

Effects of hyperglycemia on brain metabolites and ALFFs. Mean concentrations of brain metabolites (mmol/kg wet weight brain tissue) (A) and fALFF4 (0.027–0.073 Hz) (B) in ACC and OCC during EU and HG conditions. Open circles and dotted lines represent subjects with T1D; filled squares and solid lines represent control subjects. *Condition-by-group interaction effect; #condition effect; ‡group effect; all P values <0.039 (partial Bonferroni-corrected threshold for significance).

Figure 4

Clinical depression rating and emotional function scores (mean ± SE). A: HAM-D rating scores. B: SCL-90-R depression rating scores. C: SRET negative (Neg)-valence word response times (RT) (ms). D: Emotional Stroop (EmoStroop) color-naming response times (ms). *P < 0.05 by one-way ANOVA.

Figure 5

Emotional Stroop response time vs. ACC glutamate change during HG. Plot of response times vs. ACC ΔGlu concentration from euglycemia to hyperglycemia (mmol/kg wet weight brain tissue). Open circles represent T1D; filled squares represent controls. The dotted line represents the linear fit to the T1D data points (Pearson r = 0.553, P = 0.078). The solid line represents the linear fit to the control data points (Pearson r = 0.183, P = 0.590). Increased color-naming response times tended to associate with increased ACC ΔGlu for subjects with T1D only (group-by-ΔGlu interaction effect P = 0.091).