The role of GABA in type 1 diabetes

Abstract

Gamma aminobutyric acid (GABA) is synthesized from glutamate by glutamic decarboxylase (GAD). The entero-pancreatic biology of GABA, which is produced by pancreatic islets, GAD-expressing microbiota, enteric immune cells, or ingested through diet, supports an essential physiologic role of GABA in the health and disease. Outside the central nervous system (CNS), GABA is uniquely concentrated in pancreatic β-cells. They express GAD65, which is a type 1 diabetes (T1D) autoantigen. Glutamate constitutes 10% of the amino acids in dietary protein and is preeminently concentrated in human milk. GABA is enriched in many foods, such as tomato and fermented cheese, and is an over-the-counter supplement. Selected microbiota in the midgut have the enzymatic capacity to produce GABA. Intestinal microbiota interact with gut-associated lymphoid tissue to maintain host defenses and immune tolerance, which are implicated in autoimmune disease. Although GABA is a widely known inhibitory neurotransmitter, oral GABA does not cross the blood brain barrier. Three diabetes-related therapeutic actions are ascribed to GABA, namely, increasing pancreatic β-cell content, attenuating excess glucagon and tamping down T-cell immune destruction. These salutary actions have been observed in numerous rodent diabetes models that usually employed high or near-continuous GABA doses. Clinical studies, to date, have identified positive effects of oral GABA on peripheral blood mononuclear cell cytokine release and plasma glucagon. Going forward, it is reassuring that oral GABA therapy has been well-tolerated and devoid of serious adverse effects.

Keywords: GABA treatment/diabetes; GABA-producing microbes; Type 1 diabetes; diabetes/new therapies; gamma aminobutyric acid (GABA); microbiome/GABA/glutamate; α-cells/glucagon; β-cells/pancreatic islets.

Figure 1

GABA in health and diabetes. This figure summarizes the role of GABA in the entero-pancreatic system, its anti-diabetic actions and potential as a therapeutic agent in type 1 diabetes (T1D). (A) GABA is synthesized from glutamate by glutamate decarboxylase (GAD65) which is also a T1D autoantigen. GABA is uniquely concentrated in β-cells but is also consumed in foods and produced by select GAD-containing microbiota in the upper and lower intestinal tract. From birth, gut associated lymph tissue (GALT) within the lamina propria are intricately involved in bodily defenses against autoimmunity and inflammation. (B) The key anti-diabetic actions of GABA are presented as validated in numerous preclinical rodent and human islet studies. In children with new onset T1D, oral GABA, with or without recombinant GAD, reduced serum glucagon as well as inflammatory cytokines. (C) The potential therapeutic role of GABA in T1D is shown from birth through stage 3 diabetes. The perinatal acquired microbiome is pivotal to lifetime immune defense. Whether GABA producing microbiota or glutamate have salutary immune actions is unexamined. In stage 1 diabetes (asymptomatic autoimmunity), GABA supplementation or precision probiotics might restrain the autoimmune process, particularly if GABA/GABA-producing microbiota are deficient. Combination therapy with a low risk oral therapy such as an islet antigen or anti-apoptosis agent might further preserve or expand β−cell mass. In stage 2 diabetes (autoimmunity with dysglycemia), GABA supplementation, with or without more potent combination therapies, might hamper autoimmune destruction. Possible co-therapies, noted to be effective in diabetic rodent studies, include oral T1D antigens, GLP-1 agonists, and positive allosteric modifiers that augment GABA action. Longer acting GABA formulations could also improve efficacy. In stage 3 diabetes (insulin dependent), higher dose GABA along with combination agents that preserve β-cell mass or induce β-cell proliferation are a consideration (anti-apoptotic agent, low dose immune therapies, GLP1 agonists, GABA receptor agonists). Finally, in humanized rodent diabetic models, GABA preserves implanted human islets while promoting β-cell proliferation - whether this has application for human islet transplant survival is intriguing.

Figure 2

Comparison of experimental GABA doses used in rodent versus human studies. To compare the experimental GABA doses (mg/kg/day) used in rodent versus human studies, we estimated daily water intake and tabulated average adult rodent weights. When GABA was added to drinking water or given by injection, the daily intake approximated 1500 mg/kg/day based on estimated daily water consumption (148). This calculation does not take into account that diabetic animals have polydipsia, thus the actual GABA dose is vastly underestimated. Mouse body weights - unless noted by investigators in the methods section- were based on species and the average, non-diabetic weight in healthy animals. Figure 2 references (Y-axis): Wang, et al. (68), Gu, et al. (80), Ackermann et al. (69), Ben-Othman et al. (44), Feng et al. (75), Soltani et al. (20). Tian et al. (23), Martin et al. (82), Tian et al. (43), Hwang et al. (45), Sohrabipour et al. (48), Untereiner et al. (51), Liu et al. (22), Prud’homme et al. (47), Purwana et al. (24). Figure adapted from "A randomized trial of oral gamma aminobutyric acid (GABA) or the combination of GABA with glutamic acid decarboxylase (GAD) on pancreatic islet endocrine function in children with newly diagnosed type 1 diabetes," by Martin A, Mick GJ, Choat HM, Lunsford AA, Tse HM, McGwin GG Jr, and McCormick KL. Nat Commun. 2022 Dec 24;13(1):7928, Supplementary Data, Figure 6 (https://doi.org/10.1371/journal.pone.0197160).