Elevated brain glutamate levels in type 1 diabetes: correlations with glycaemic control and age of disease onset but not with hypoglycaemia awareness status

Evita C Wiegers, Hanne M Rooijackers, Jack J A van Asten, Cees J Tack, Arend Heerschap, Bastiaan E de Galan, Marinette van der Graaf, Evita C Wiegers, Hanne M Rooijackers, Jack J A van Asten, Cees J Tack, Arend Heerschap, Bastiaan E de Galan, Marinette van der Graaf

Abstract

Aims/hypothesis: Chronic hyperglycaemia in type 1 diabetes affects the structure and functioning of the brain, but the impact of recurrent hypoglycaemia is unclear. Changes in the neurochemical profile have been linked to loss of neuronal function. We therefore aimed to investigate the impact of type 1 diabetes and burden of hypoglycaemia on brain metabolite levels, in which we assumed the burden to be high in individuals with impaired awareness of hypoglycaemia (IAH) and low in those with normal awareness of hypoglycaemia (NAH).

Methods: We investigated 13 non-diabetic control participants, 18 individuals with type 1 diabetes and NAH and 13 individuals with type 1 diabetes and IAH. Brain metabolite levels were determined by analysing previously obtained 1H magnetic resonance spectroscopy data, measured under hyperinsulinaemic-euglycaemic conditions.

Results: Brain glutamate levels were higher in participants with diabetes, both with NAH (+15%, p = 0.013) and with IAH (+19%, p = 0.003), compared with control participants. Cerebral glutamate levels correlated with HbA1c levels (r = 0.40; p = 0.03) and correlated inversely (r = -0.36; p = 0.04) with the age at diagnosis of diabetes. Other metabolite levels did not differ between groups, apart from an increase in aspartate in IAH.

Conclusions/interpretation: In conclusion, brain glutamate levels are elevated in people with type 1 diabetes and correlate with glycaemic control and age of disease diagnosis, but not with burden of hypoglycaemia as reflected by IAH. This suggests a potential role for glutamate as an early marker of hyperglycaemia-induced cerebral complications of type 1 diabetes. ClinicalTrials.gov NCT03286816; NCT02146404; NCT02308293.

Keywords: 1H MRS; Brain; Euglycaemia; Glutamate; Type 1 diabetes.

Conflict of interest statement

The authors declare that there is no duality of interest associated with this manuscript.

Figures

Fig. 1
Fig. 1
Example of LCModel analysis of one 1H MR spectrum (top row). The peaks identified include macromolecules (MM), aspartate (Asp), creatine (Cre), glutamine (Gln), glutamate (Glu), glycerophosphocholine (GPC), glutathione (GSH), myo-inositol (mI), N-acetylaspartate (NAA), N-acetylaspartylglutamate (NAAG), phosphocholine (PCh), phosphocreatine (PCr), scyllo-inositol (Scyllo) and taurine (Tau). The insert shows the localisation of the MRS voxel
Fig. 2
Fig. 2
Mean metabolite levels in participants with type 1 diabetes and IAH (T1DM IAH), participants with type 1 diabetes and NAH (T1DM NAH) and non-diabetic control participants. Between group differences were assessed with ANOVA with Bonferroni post hoc tests to accommodate the three groups design; *p < 0.05. Data are mean + SD, with individual data points shown as dots. GSH, glutathione; mI, myo-inositol; MM, macromolecules; Scyllo, scyllo-inositol; Tau, taurine; tCho, total choline; tCre, total creatine; tNAA, total NAA; ww, wet weight
Fig. 3
Fig. 3
Correlation between cerebral glutamate levels and HbA1c levels (a) and between cerebral glutamate levels and the age at diagnosis of type 1 diabetes (b). Data from participants with type 1 diabetes and IAH (T1DM IAH; white triangles) and participants with type 1 diabetes and NAH (T1DM NAH; black circles), together with the linear fits of the data and the 95% CI, obtained from linear regression analysis. (a) p = 0.03; r = 0.40; (b) p = 0.04; r = −0.36; ww, wet weight
Fig. 4
Fig. 4
Cerebral glutamate levels. Group means are depicted in black circles. Participants with type 1 diabetes are further subdivided into those with optimal glycaemic control (HbA1c <53 mmol/mol [7.0%]) and those with suboptimal glycaemic control (HbA1c ≥53 mmol/mol). ANOVAs were conducted to detect differences among non-diabetic individuals, and diabetic individuals with NAH and optimal glycaemic control, NAH and suboptimal glycaemic control, IAH and optimal glycaemic control, and IAH and suboptimal glycaemic control; *p < 0.05, **p < 0.01 vs non-diabetic control participants. ND, non-diabetic control; T1DM, type 1 diabetes; ww, wet weight

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Source: PubMed

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