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 HbA1c 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 HbA1c 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.
Highlights
Normal brain function relies on the stringent control of the levels of the main inhibitory (GABA) and excitatory (Glutamate) neurotransmitters
A significant statistical difference was found for GABA+corr concentration (t40 = -2.15; p = 0.038; GABA+error to water: T2DM = 4±0.9%, Ctrl2 = 3±0.9%; Cohen’s d = 0.68) with lower levels in T2DM group, yet no significant difference was found for Glxcorr levels between groups (N = 42, Z = -0.91, p = 0.365; Glxerror to water: T2DM = 5±1.7%, Ctrl2 = 5±1.3%; Cohen’s d = 0.28)
Since Glx reflects a mixed signal of Glutamate and Glutamine, we compared Glutamate levels estimated from Point RESolved Spectroscopy (PRESS) data
Summary
Normal brain function relies on the stringent control of the levels of the main inhibitory (GABA) and excitatory (Glutamate) neurotransmitters. GABA and Glutamate pools are commonly compartmentalized into neurotransmitter and metabolic parcels [3,4] having dual roles These key metabolites are dependent on brain Glucose [5] and synaptic signaling strongly relies on the interactions between astrocytes and neurons through the GABA-Glutamate-Glutamine shuttle [6,7,8]. This cycling is pivotal to the production, reuse and metabolism of both GABA and Glutamate as well as in the context of energy production [6,7]. Since the neural tissue relies mainly on glucose content to fulfill the high energetic demands, the brain becomes a vulnerable target of damage in conditions characterized by impaired metabolic activity [10]
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