EC Pharmacology And Toxicology

Recently, experimental studies related to the role of GABA in the development of diabetes and related angio- and neuropathies have attracted great interest. Gamma-aminobutyric acid (GABA) has long been known as an inhibitory neurotransmitter in the central nervous system. At the same time, GABA has been found in many peripheral organs and, which is especially important in the context of our study, in the pancreas. Moreover, its concentration in the pancreas is the highest among other organs and is comparable to that in the central nervous system.

Healthy beta cells have been shown to continually produce and release GABA throughout their life cycle. Once released, GABA influences the activity of many types of islet cells through its ionotropic and metabotropic receptors. GABA has the ability to stimulate pancreatic beta cell function and prevent the development of diabetes. GABA stimulates beta cell division and function. GABA is able to activate Ca²⁺- P13K/Akt dependent cell growth and survival, thereby preventing apoptosis in streptozotocin-treated islet cell lines. GABA stimulates the synthesis and release of insulin by beta cells and reduces the production of glucagon by alpha cells. In vitro experiments have shown that blockade of GABA receptors in isolated human islets of Langerhans leads to a decrease in the synthesis and release of insulin.

Moreover, GABA is able to protect beta cells from the aggressive action of the immune system by interacting with GABA receptors of immune cells. This leads to a decrease in the activity of lymphocytes, stopping the production of antibodies to beta cells and cytokines that initiate and enhance the immune attack. In addition, GABA regulates the release of proinflammatory cytokines in T and B cells and mononuclear cells in the peripheral blood.

In conclusion: In the endocrine part of the pancreas, GABA takes an active part in paracrine regulation, i.e. it plays the role of a tissue hormone that acts on beta cells that produce insulin and alpha cells that produce glucagon. In the first case, GABA activates cells, and in the second, it inhibits their function. Animal experiments have shown that GABA is capable of delaying the onset of diabetes and even restoring normal blood glucose levels when the disease has already begun to develop.

 Keywords: Gamma-Aminobutyric Acid (GABA); Central Nervous System; Diabetes Treatment

1. Almutairi S., et al. “The effect of oral GABA on the nervous system: Potential for therapeutic intervention”. Nutraceuticals 2 (2024): 241-259.
2. Bourgeois S., et al. “Harnessing beta cell regeneration biology for diabetes therapy”. Trends in Endocrinology and Metabolism11 (2024): 951-966.
3. Cao R., et al. “Signaling pathways and intervention for therapy of type 2 diabetes mellitus”. MedComm (2020)3 (2023): e283.
4. Chau GC., et al. “mTOR controls ChREBP transcriptional activity and pancreatic β cell survival under diabetic stress”. Journal of Cell Biology 7 (2017): 2091-2105.
5. Dastgerdi HA., et al. “GABA administration improves liver function and insulin resistance in offspring of type 2 diabetic rats”. Scientific Reports 1 (2021): 23155.
6. Deanfield J., et al. “Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial”. Lancet10454 (2024): 773-786.
7. Dong H., et al. “Gamma-aminobutyric acid up- and downregulates insulin secretion from beta cells in concert with changes in glucose concentration”. Diabetologia 4 (2006): 697-705.
8. Espes D., et al. “GABA induces a hormonal counter-regulatory response in subjects with long-standing type 1 diabetes”. BMJ Open Diabetes Research and Care 1 (2021): e002442.
9. Franklin IK and Wollheim CB. “GABA in the Endocrine Pancreas”. Journal of General Physiology 3 (2004): 185-190.
10. Freemerman AJ., et al. “Metabolic reprogramming of macrophages: glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype”. Journal of Biological Chemistry 11 (2014): 7884-7896.
11. Fu J., et al. “GABA regulates IL-1β production in macrophages”. Cell Reports10 (2022): 111770.
12. Gladkevich A., et al. “The peripheral GABAergic system as a target in endocrine disorders”. Autonomic Neuroscience 1-2 (2006): 1-8.
13. Gu L., et al. “Gamma-aminobutyric acid modulates alpha-cell hyperplasia but not beta-cell regeneration induced by glucagon receptor antagonism in type 1 diabetic mice”. Acta Diabetologica 1 (2022): 19-28.
14. Hagan DW., et al. “The role of GABA in islet function”. Frontiers in Endocrinology 13 (2022): 972115.
15. Jafari-Vayghan H., et al. “A comprehensive insight into the effect of glutamine supplementation on metabolic variables in diabetes mellitus: a systematic review”. Nutrition and Metabolism (London) 17 (2020): 80.
16. Jin Z and Korol SV. “GABA signalling in human pancreatic islets”. Frontiers in Endocrinology | Diabetes: Molecular Mechanisms 14 (2023): 1059110.
17. Katz LS., et al. “Maladaptive positive feedback production of ChREBPβ underlies glucotoxic β-cell failure”. Nature Communications1 (2022): 4423.
18. Li J., et al. “Study of GABA in healthy volunteers: Pharmacokinetics and pharmacodynamics”. Frontiers in Pharmacology 6 (2015): 260.
19. Martin A., et al. “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 1Diabetes”. Nature Communications1 (2022): 7928.
20. Matsubara А., et al. “Effects of GABA supplementation on blood pressure and safety in adults with mild hypertension”. Japanese Pharmacology and Therapeutics11 (2002): 963-972.
21. Prud’homme Gérald J., et al. “GABA protects pancreatic beta cells against apoptosis by increasing SIRT1 expression and activity”. Biochemical and Biophysical Research Communications3 (2014): 649-654.
22. Reetz A., et al. “GABA and pancreatic beta-cells: colocalization of glutamic acid decarboxylase (GAD) and GABA with synaptic-like microvesicles suggests their role in GABA storage and secretion”. The EMBO Journal 5 (1991): 1275-1284.
23. Rezazadeh H., et al. “Gamma-aminobutyric acid attenuates insulin resistance in type 2 diabetic patients and reduces the risk of insulin resistance in their offspring”. Biomedicine and Pharmacotherapy 138 (2021): 111440.
24. Sarrazy V., et al. “Maintenance of macrophage redox status by ChREBP limits inflammation and apoptosis and protects against advanced atherosclerotic lesion formation”. Cell Reports1 (2015): 132-144.
25. Tang Y., et al. “Adipose tissue mTORC2 regulates ChREBP-driven de novo lipogenesis and hepatic glucose metabolism”. Nature Communications 7 (2016): 11365.
26. Tian J., et al. “G-aminobutyric acid regulates both the survival and replication of human Β-cells”. Diabetes11 (2013): 3760-3765.
27. Tong X., et al. “The glucose-responsive transcription factor ChREBP contributes to glucose-dependent anabolic synthesis and cell proliferation”. Proceedings of the National Academy of Sciences of the United States of America 51 (2009): 21660-21665.
28. Tyurenkov IN., et al. “Synergistic effects of GABA and hypoglycemic drugs”. Problemy Endokrinologii 4 (2023): 61-69.
29. Wan Y., et al. “GABAergic system in the endocrine pancreas: a new target for diabetes treatment”. Diabetes, Metabolic Syndrome and Obesity 8 (2015): 79-87.
30. Wang L., et al. “Oral L-glutamine increases GABA levels in striatal tissue and extracellular fluid”. The FASEB Journal 4 (2007): 1227-1232.
31. Yi Z., et al. “Gimmicks of gamma-aminobutyric acid (Gaba) in pancreatic beta-cell regeneration through transdifferentiation of pancreatic alpha- to beta-cells”. Cell Biology International4 (2020): 926-936.