Bolo_T1D_glutamate_SUPPLEMENTAL_MATERIAL_Revision2-clean.docx (157.27 kB)
Acute Hyperglycemia Increases Brain Pregenual Anterior Cingulate Cortex Glutamate Concentrations in Type 1 Diabetes Mellitus
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posted on 2020-04-15, 14:21 authored by Ada AdminAda Admin, Nicolas R. Bolo, Alan M. Jacobson, Gail Musen, Matcheri S. Keshavan, Donald C. SimonsonThe
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 magnetic resonance
spectroscopy (MRS), we measured glutamate concentrations in ACC and occipital
cortex (OCC) in 13 T1D without major depression (HbA1c=7.1±0.7% [54±7mmol/mol])
and 11 healthy non-diabetic controls (HbA1c=5.5±0.2% [37±3mmol/mol]) during
fasting euglycemia (EU) followed by a 60-minute +5.5mmol/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-band 4 (fALFF4). Emotional processing and depressive symptoms
were assessed using emotional tasks (Emotional-Stroop,
Self-Referent-Encoding-Task SRET) and clinical ratings (HAM-D, SCL-90-R),
respectively. During HG, ACC glutamate
increased (1.2mmol/kg, +10%, p=0.014) while ACC fALFF4
was unchanged (-0.007, -2%, p=0.449) in T1D; in
contrast, glutamate was unchanged (-0.2mmol/kg,
-2%, p=0.578) while fALFF4 decreased (-0.05, -13%, p=0.002) in controls. 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 due to 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 between chronic hyperglycemia, cortical thinning and
depressive symptoms in T1D.