The neurometabolic profiles of GABA and Glutamate as revealed by proton magnetic resonance spectroscopy in type 1 and type 2 diabetes

Abstract

Glucose metabolism is pivotal for energy and neurotransmitter synthesis and homeostasis, particularly in Glutamate and GABA systems. In turn, the stringent control of inhibitory/excitatory tonus is known to be relevant in neuropsychiatric conditions. Glutamatergic neurotransmission dominates excitatory synaptic functions and is involved in plasticity and excitotoxicity. GABAergic neurochemistry underlies inhibition and predicts impaired psychophysical function in diabetes. It has also been associated with cognitive decline in people with diabetes. Still, the relation between metabolic homeostasis and neurotransmission remains elusive. Two 3T proton MR spectroscopy studies were independently conducted in the occipital cortex to provide insight into inhibitory/excitatory homeostasis (GABA/Glutamate) and to evaluate the impact of chronic metabolic control on the levels and regulation (as assessed by regression slopes) of the two main neurotransmitters of the CNS in type 2 diabetes (T2DM) and type 1 diabetes (T1DM). Compared to controls, participants with T2DM showed significantly lower Glutamate, and also GABA. Nevertheless, higher levels of GABA/Glx (Glutamate+Glutamine), and lower levels of Glutamate were associated with poor metabolic control in participants with T2DM. Importantly, the relationship between GABA/Glx and HbA 1c found in T2DM supports a relationship between inhibitory/excitatory balance and metabolic control. Interestingly, this neurometabolic profile was undetected in T1DM. In this condition we found strong evidence for alterations in MRS surrogate measures of neuroinflammation (myo-Inositol), positively related to chronic metabolic control. Our results suggest a role for Glutamate as a global marker of T2DM and a sensitive marker of glycemic status. GABA/Glx may provide a signature of cortical metabolic state in poorly controlled patients as assessed by HbA 1c levels, which indicate long-term blood Glucose control. These findings are consistent with an interplay between abnormal neurotransmission and metabolic control in particular in type 2 diabetes thereby revealing dissimilar contributions to the pathophysiology of neural dysfunction in both types of diabetes.

Differential impact of glycemic control and comorbid conditions on the neurophysiology underlying task switching in older adults with type 2 diabetes

“…Gamma dynamics are thought to regulated by local GABA-ergic inhibitory circuitry [37,38]. Indeed, in previous studies in people with type 2 diabetes, GABA levels in occipital and prefrontal cortices were shown to be significantly altered, with some effects directly associated with cognitive task performance [39][40][41][42]. These alterations in GABA could be a critical mechanism underlying many of our findings in the current study, as many effects in our task switching paradigm were in the gamma range.…”

Evaluation of altered brain activity in type 2 diabetes using various indices of brain function: A resting-state functional magnetic resonance imaging study

“…White matter lesions, cerebral atrophy, and lacunar infarcts are commonly reported and are assumed to correlate with cognitive dysfunction (van Agtmaal et al, 2018 ; Zhuo et al, 2019 ; Xiong et al, 2022 ). Disordered concentrations of brain metabolites were detected using magnetic resonance spectroscopy in patients with T2DM and were also reported to be related to cognitive impairment (d'Almeida et al, 2020 ; Yang et al, 2020 ). However, neural activity cannot be monitored using these methods, which would make it a sensitive biomarker ahead of a brain lesion (Jones, 2012 ; Yao et al, 2021 ).…”

Effects of Tang Luo Ning on diabetic peripheral neuropathy in rats revealed by LC–MS metabolomics approach

“…Glutamic acid plays an important role in the protein metabolism of organisms, and it participates in many important chemical reactions in animals, plants, and microorganisms. l ‐Glutamic acid can be used as a drug to participate in the metabolism of protein and sugar in the brain and promote the oxidation process (d'Almeida et al, 2020).…”