Purinergic signaling in the pancreas and the therapeutic potential of ecto-nucleotidases in diabetes

SUMMARY Diabetes includes the metabolic disorders not only of the pancreas, but also other organs and tissues such as liver, skeletal muscles and adipose tissue. The key pathophysiological disorder is abnormal metabolism and glucose transport associated with inadequate secretion of insulin. This leads to an increase in blood glucose level, the formation of free fatty acids and the release of pro-inflammatory cytokines. In type 2 diabetes these processes lead to the phenomenon of insulin resistance, which is mainly responsible for the progression of the disease. Purinergic signaling plays a key role in the above processes. Purinergic receptors P1 and P2 are present on the pancreatic islet cells as well as on hepatocytes, adi-pocytes, in the circulatory system and pancreatic nerves. P2X3 receptor is of particular importance in human β-cells. The P2X3R activation results in a positive auto-crine signal and its subsequent amplification. Insulin se-cretion increases as a consequence of the process. ATP participates in this autocrine feedback loop associated with the secretion of insulin. ATP is released together with insulin from β-cell granules in response to the rapid increase in blood glucose concentration. ATP in the ex-tracellular environment, through the P2X3 receptor acti-vation initiates the increase in intracellular calcium ions concentration, and thus amplifies the release of insulin. At present, we do not know the other effects of activa-tion of P2X receptors, and the more P2Y receptors. It can be assumed that in the future the possibility of ac-tivation or blockade of P2 receptors, and/or the impact on nucleotides degradation may become an effective way to treat diabetes.Adenosine and P1 receptors (A1 and A2B), which are present on adipocytes and pancreatic islets cells, play an important role in the pathogenesis of diabetes. It has been demonstrated that adenosine inhibits the release of insulin, while it also stimulates the secretion of glucagon. It confirmes that the pancreatic α-cells are more sensitive to adenosine than β-cells. Through the activation of A1 receptor, adenosine inhibits lipolysis and the activity of adenylate cyclase, leading to the decrease in cAMP con-centration. Experimental studies in animals have shown that administration of A1 receptor agonists resulted in stabilization of normal glucose concentration in the blood, decrease in the concentration of free fatty acids and triglycerides and an increase in tissue sensitivity to insulin. Therefore, it can be assumed that adenosine or its analogues may become in the future drugs for dyslipi-demia and insulin resistance. Unfortunately, some of the adenosine analogues are endowed with notable side- ef-fects (i. e. hypotension and bradycardia) that result from the activation of A1 receptors present in the heart and the circulatory system.Adenosine A2B receptors activation contributes to increased insulin resistance by stimulation of IL-6 and other cytokines and regulatory molecules production. Long-term increase in IL-6 concentration, which leads to chronic and sustained increase in the expression of SOCS3 is especially harmful in type 2 diabetes and obe-sity. Thus, it is desirable to maintain the blood levels of IL-6 less than 5 pg/ml. Furthermore, A2B adenosine re-ceptors are involved in the activation of macrophages, resulting in inflammation and development of adipose tissue insulin resistance. Adenosine affects also glucose transport — this nucleoside lowers the number of glu-cose transporter GLUT4 molecules on the cell surface, thus reduces the effectiveness of insulin in glucose trans-port into skeletal muscle cells and adipocytes and con-tributes to the development of insulin resistance.It can be assumed, that enzymes involved in the con-version of adenosine (i.e. adenosine deaminase) and A2B receptor antagonists may prove to be effective drugs that increase tissue sensitivity to insulin. The pancreatic islet cells, as well as blood vessels have been shown to ex-press enzymes involved in the metabolism of ecto-nucle-otides. Among ecto-NTPDases (ectonucleoside triphos-phate diphosphohydrolases) the most important role is assigned to NTPDase3, that activity has only been dem-onstrated on Langerhans cells of the pancreas. On the contrary, 5’-nucleotidase activity has been demonstrated exclusively on capillaries of Langerhans islets, and not on pancreatic islet cells. NTPDase3 may influence the secre-tion of insulin by hydrolyzing adenine nucleotides, and thus affects the activation of P2 receptors. Experimental studies have demonstrated that an ecto-nucleotidase in-hibitor — ARL 67156 caused a considerable increase in insulin secretion despite a low concentration of glucose in the blood. It can be assumed that a similar effect can be achieved using monoclonal antibodies as a specific in-hibitor of human NTPDase3.The pancreas is a central organ in nutrient and energy homeostasis with endocrine, exocrine and immunoreac-tive cells, which participate in the complex processes. Even though we know for 50 years about the role of nucleotides in the secretion of insulin, an integrated un-derstanding of the involvement of purinergic signaling in physiology and pathology of pancreas is still required. The diversity of the purinergic system elements can be exploited in drug design for the treatment of diabetes mellitus.