Gabaergic System in the Regulation of the Functioning of Pancreas Beta-Cells in Normal Physiological Conditions and in Diabetes

Abstract

Abstract—The incidence of diabetes mellitus (DM) is steadily increasing all over the world, and at the same time there is an increase in its complications, which are the main causes of early disability and premature death. The pathogenesis of DM is based on a steady decrease in pancreatic β-cells. A decrease in β-cell mass leads to a decrease in insulin production and the development of hyperglycemia and associated severe complications. Therefore, the need to prevent the death of β-cells and stimulate their regeneration is obvious. In recent literature, much attention has been paid to the role of GABA in the regulation of the function of α- and β-cells of the pancreas and carbohydrate metabolism, which is the subject of this review. Gamma-aminobutyric acid (GABA) in β-cells and pancreatic islets is determined in quantities comparable to those in the brain. It also contains a high amount of glutamadecarboxylase, an enzyme that synthesizes GABA. In DM, the level of GABA in pancreatic β-cells decreases and this correlates with the severity of DM. GABA plays an important role in the paracrine regulation of α- and β-cell functions and carbohydrate homeostasis. The potential possibility of using GABA to achieve a decrease in apoptosis and, at the same time, an increase in the regeneration of β-cells, an increase in the β-cell mass of the pancreas has been proven. It has been proven that the positive effect of GABA on the structure and functions of pancreatic β-cells in DM can be significantly higher when combined with antidiabetic agents: GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitors, and others. The antidiabetic properties of GABA are explained by its interaction with various signaling proteins (Kloto protein, SIRT, PI3K/Akt, CREB-IRS2, NF-kB, Nrf2 and many others), through which these effects are realized. Data on the pancreatic protective effect of GABA and its derivatives can form the basis for the development of a new pharmacotherapeutic strategy for the treatment of DM and associated complications.