A molecule that can cure type 1 diabetes

A molecule that can cure type 1 diabetes
Gamma-aminobutyric acid (GABA) is familiar to neurophysiologists as an inhibitory neurotransmitter in the central nervous system. GABA suppresses the excitation of adult neurons. But in the developing embryonic brain, GABA supports neuronal development. GABA works similarly in a very different organ. GABA affects the cells of the islets of the pancreas, which produce hormones that regulate carbohydrate metabolism in the body.

The main transport form of carbohydrates is glucose. Through the blood, glucose is transferred from one organ to another. Human health depends on the stability of blood glucose levels. For example, if the sugar level drops sharply, the brain will no longer have enough energy and will fall into a coma. When glucose levels drop, the alpha cells of the islets of the pancreas release the hormone glucagon. In response to glucagon, the liver releases more glucose into the blood. In contrast, when there is too much glucose, the beta cells of the islets produce insulin, which activates the absorption of glucose from the blood. As a result, blood sugar levels drop. For example, this happens after a meal.
In people with type 1 diabetes (T1D), the immune system attacks and destroys the beta cells of the pancreas usually from adolescence. As a result, glucose levels are elevated more and longer. When glucose levels are dozens of times over normal, people begin to lose a lot of sugar through the urine, because the kidneys cannot cope with the load and break down. With glucose, people lose energy. And over time, people with T1D lose more energy through urine than they get from food. This depletes people with diabetes and they die.

People with diabetes need insulin. Until now, they receive the hormone through injections, automatic dispensers. It maintains the health of people with diabetes, but it does not cure their disease - it does not restore the beta cells of the pancreas. Therefore, the properties of GABA that are not related to the nervous system are very intriguing.

GABA helps the beta cells of the pancreas in a complex manner. First, GABA stimulates beta-cell division and function. The fact is that GABA, through receptors on the surface of beta cells, triggers the influx of calcium inside. As a result, the signaling pathway is activated, which affects the work and the increase in the population of beta cells, and the protein on which the sensitivity of beta cells to glucose levels and insulin production depends [1, 2]. That is, secondly, GABA stimulates the synthesis and release of insulin by beta cells. At the same time, GABA reduces the production of glucagon by alpha cells. This is beneficial because, in the absence of insulin, glucone can harm, further raising glucose levels. Third, GABA protects beta cells from the aggressive actions of the immune system. The fact is that many immune cells have receptors for GABA [3]. GABA reduces the activity of lymphocytes that kill beta cells, stops the production of antibodies against beta cells and cytokines that attract the attack of immune cells [4, 5]. Thus, GABA slows down inflammation in the islets of the pancreas. And beta cells can regenerate and start working normally.

The therapeutic effect of GABA on the immune system and pancreatic islets in T1D can be used for therapy. For example, it was tested in mice that Lesogaberan, a GABA agonist that acts like GABA, stops the destruction of beta cells by affecting immune cells [3]. In combination with other immunotherapy developments, the joint efficacy increased. Also, the combination of GABA with other therapeutic effects resulted in increased joint efficacy [6-9]. Consuming rice milk enriched with GABA with the help of bacteria stopped the work of proteins involved in increasing glucose levels [10].

GABA is not a random molecule in the islets of the pancreas. Healthy beta cells constantly produce GABA, thus affecting their work, the work of alpha cells, and cells of the immune system [11]. And this production of GABA is disrupted in diabetes mellitus. That is why exposure to therapeutic doses of GABA triggers the regeneration of beta cells and the restoration of their work.
So, GABA is an amazing molecule with powerful antidiabetic potential. And studies of the effect of GABA on beta cells are impossible without GABA receptor antagonists. Only when the use of antagonists in the framework of the experiment causes the opposite effect, we can confidently say that GABA protects cells. Therefore, it is convenient to use libraries of GABA receptor antagonists in such studies. Such a library can be ordered on the ChemDiv website.

References:

1. Purwana, Indri, et al. "GABA promotes human β-cell proliferation and modulates glucose homeostasis." Diabetes 63.12 (2014): 4197-4205.
2. Untereiner, Ashley, et al. "γ‐aminobutyric acid stimulates β‐cell proliferation through the mTORC1/p70S6K pathway, an effect amplified by Ly49, a novel γ‐aminobutyric acid type A receptor positive allosteric modulator." Diabetes, Obesity and Metabolism 22.11 (2020): 2021-2031.
3. Tian, Jide, et al. "GABAB-receptor agonist-based immunotherapy for type 1 diabetes in NOD mice." Biomedicines 9.1 (2021): 43.
4. Bhandage, Amol K., et al. "GABA regulates release of inflammatory cytokines from peripheral blood mononuclear cells and CD4+ T cells and is immunosuppressive in type 1 diabetes." EBioMedicine 30 (2018): 283-294.
5. Bhandage, Amol K., et al. "GABA regulates release of inflammatory cytokines from peripheral blood mononuclear cells and CD4+ T cells and is immunosuppressive in type 1 diabetes." EBioMedicine 30 (2018): 283-294.
6. Choat, Heather M., et al. "Effect of gamma aminobutyric acid (GABA) or GABA with glutamic acid decarboxylase (GAD) on the progression of type 1 diabetes mellitus in children: Trial design and methodology." Contemporary clinical trials 82 (2019): 93-100.
7. Zhu, Yunfeng, et al. "Evaluation of Gamma Amino Butyric Acid (GABA) and Glibenclamide Combination Therapy in Streptozotocin Induced Diabetes." Endocrine, Metabolic & Immune Disorders Drug Targets (2020).
8. Liu, Wenjuan, et al. "Combined use of GABA and sitagliptin promotes human β-cell proliferation and reduces apoptosis." Journal of Endocrinology 248.2 (2021): 133-143.
9. Rathwa, Nirali, et al. "Calorie Restriction in combination with GABA: improved glycaemic control in type 2 diabetes mouse model." bioRxiv (2021).
10. Kittibunchakul, Suwapat, et al. "Health beneficial properties of a novel plant-based probiotic drink produced by fermentation of brown rice milk with GABA-producing Lactobacillus pentosus isolated from Thai pickled weed." Journal of Functional Foods 86 (2021): 104710.
11. Menegaz, Danusa, et al. "Mechanism and effects of pulsatile GABA secretion from cytosolic pools in the human beta cell." Nature metabolism 1.11 (2019): 1110-1126.

Alexander Khazanov
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