Abstract
Gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the central nervous system (CNS) and outside of the CNS, found in the highest concentrations in immune cells and pancreatic beta-cells. GABA is gaining increasing interest in diabetes research due to its immune-modulatory and beta-cell stimulatory effects and is a highly interesting drug candidate for the treatment of type 1 diabetes (T1D). GABA is synthesized from glutamate by glutamic acid decarboxylase (GAD), one of the targets for autoantibodies linked to T1D. Using mass spectrometry, we have quantified the endogenous circulating levels of GABA in patients with new-onset and long-standing T1D and found that the levels are unaltered when compared to healthy controls, i.e., T1D patients do not have a deficit of systemic GABA levels. In T1D, GABA levels were negatively correlated with IL-1 beta, IL-12, and IL-15 15 and positively correlated to levels of IL-36 beta and IL-37. Interestingly, GABA levels were also correlated to the levels of GAD-autoantibodies. The unaltered levels of GABA in T1D patients suggest that the GABA secretion from beta-cells only has a minor impact on the circulating systemic levels. However, the local levels of GABA could be altered within pancreatic islets in the presence of GAD-autoantibodies.
Highlights
Academic Editors: Björn Tyrberg and Department of Women’s and Children’s Health, Uppsala University, 75185 Uppsala, Sweden; Department of Medical Cell Biology, Uppsala University, 75123 Uppsala, Sweden; Department of Chemistry, Analytical, BMC, Uppsala University, 75237 Uppsala, Sweden; Science for Life Laboratory, Department of Medical Cell Biology, Uppsala University, 75123 Uppsala, Sweden
Endogenous Gamma-aminobutyric acid (GABA) levels were negatively correlated to age in both healthy controls (HC)
In light of recent experimental findings regarding GABAs effect on beta-cell proliferation, it is of interest to highlight that patients with type 1 diabetes (T1D) do not have a deficit in endogenous plasma GABA levels
Summary
Gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the central nervous system (CNS) and outside of the CNS, found in the highest concentrations in immune cells and pancreatic beta-cells. Endogenous GABA levels can be detected in blood in concentrations high enough to activate GABA-A receptors [5]; where it originates from and how the levels are regulated is not fully understood. It can be secreted from circulating immune cells [6,7] and pancreatic beta-cells [8]. In a sub-set, we detected circulating levels of GABA in plasma that correlated to several cytokines [10]
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