Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease in which impaired insulin sensitivity in peripheral tissues leads to lower glucose tolerance, resulting mainly in high blood glucose levels (hyperglycemia) [1]. Thus, hyperglycemia can cause macro- and microvascular changes that associate T2DM with vascular and nervous system complications [2]. Currently, the increase in blood glucose levels in those affected by this disease is associated with modern lifestyle habits, such as high consumption of fast food, lack of physical activity, and genetic factors. This makes T2DM the most common form of diabetes, it comprises about 90% of the cases and is associated with long-term complications, which can lead to death [3,4].

Vitamin D3 (cholecalciferol, VIT D3), a fat-soluble steroid, is produced in the skin from 7-dehydrocholesterol by ingestion of various foods or after exposure to solar ultraviolet B (UVB) radiation. Hydroxylation reactions in the liver and kidney then transform cholecalciferol into calcidiol or 25-hydroxyvitamin D3 (25(OH)D3) and calcitriol or 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), respectively [5,6,7,8,9]. It is known that VIT D3 in its active form, 1,25(OH)2D3, exerts its biological functions in several cell types, having a potential involvement in the pathogenesis of the inflammatory process and the prevention and control of diabetes. In addition, it promotes insulin secretion, as it regulates the metabolism of β cells and stimulates the genes involved in their structural organization [5,7,10]. Therefore, VIT D3 may decrease insulin resistance in T2DM [5].

In this context, the purinergic signaling pathway through the action of its nucleotides ATP, ADP, AMP, and its adenosine nucleoside (Ado), plays an important role in the regulation of glucose metabolism [2]. Thus, the concentration of these molecules is regulated by the enzymatic chain activity of ectonucleotidases. Such activity begins with the action of ectonucleoside triphosphate diphosphohydrolase (E-NTPDase), which catalyzes the hydrolysis of ATP and/or ADP to AMP, the enzyme E-5’-nucleotidase, which hydrolyzes AMP and forms Ado, which is degraded by adenosine deaminase (ADA), generating inosine [11].

On the other hand, in the diabetic state, ATP at high concentrations can exert proinflammatory effects by activating the P2 × 7R receptor, which is a trimeric ion channel present on the surface of many cell types [12]. In the pancreas, P2 × 7R activation is related to the release of proinflammatory cytokines and the apoptotic process of β cells in T2DM [13,14,15,16]. In addition to ATP, nucleoside adenosine (Ado) plays an important role in modulating platelet activity. Thus, Ado is considered a vasodilator molecule and an endogenous inhibitor of platelet aggregation [17]. Also, Ado has immunosuppressive and anti-inflammatory effects, inhibiting proinflammatory cytokines [18]. In general, the signaling outcome of these molecules is mediated by purinergic receptors and is partially determined by receptor density.

In this sense, VIT D3 was related to the improvement of the diabetic state since it modulates insulin levels and glucose metabolism, regulating blood glucose. This suggests a potential therapeutic role of VIT D3 to decrease the risks and complications associated with T2DM. In addition, VIT D3 deficiency has been associated with microvascular changes in T2DM [9]. Thus, several are the proposed mechanisms involved in this protective role of VIT D3 against endothelial dysfunction, chronic hyperglycemia, and insulin resistance, conditions related to T2DM [4,9,19,20].

Previously, our research group has demonstrated the role of the purinergic system and VIT D3 in complications associated with DM [17,20]. However, the mechanisms by which VIT D3 exerts its beneficial effects mediated by the purinergic system are still unclear. Thus, this study aimed to evaluate the potential effect of VIT D3 on the purinergic system as a possible therapeutic target to mitigate the changes observed in T2DM, focusing mainly on inflammatory processes associated with vascular complications.