Role of purinergic signalling and proinflammatory cytokines in diabetes

Abstract

Extracellular purines activate P1 adenosine receptors and P2 nucleotide receptors. These receptors are present on the pancreatic islet cells as well as on hepatocytes, adipocytes, pancreatic blood vessels and nerves. ATP is released together with insulin from b-cell granules in response to a rapid decrease in blood glucose levels. The ATP-dependent P2X receptor activation on pancreatic b-cells results in a positive autocrine signal and subsequent insulin secretion. Adenosine, through activation of P1 receptors present on adipocytes and pancreatic islet cells, inhibits the release of insulin. Adenosine activates A2B receptors thereby stimulating production of IL-6 and other cytokines, which increases insulin resistance. Interleukin-6 also plays an important role in diabetes. In type 2 diabetes and obesity, the long-Term increase of IL-6 concentration in blood above 5 pg/mL leads to the chronic and permanent increase in expression of SOCS3, contributing to the increase in insulin resistance in cells of the skeletal muscles, liver and adipose tissue. In diabetes there is an increased synthesis and release of pro-inflammatory cytokines, which cause the damage of the pancreatic islet cells, and in type 2 diabetes cause the development of insulin resistance. Ecto-enzymes metabolizing nucleotides are involved in the termination of the nucleotide signalling pathway and play the key role in regulation of extracellular ATP concentration. Ecto-NTPDases in cooperation with 5'-nucleotidase may significantly increase ecto-Adenosine concentration. NTPDase3 activity has only been demonstrated on Langerhans cells. NTPDase3 may influence the secretion of insulin by hydrolysing adenine nucleotides. In diabetes the pro-inflammatory cytokines such as interleukin 1b (IL-1b), tumour necrosis factor-A (TNF-A) and interferon-g (IFN-g), as well as pancreatic derived factor PANDER are involved in the apoptosis of pancreatic b-cells. This causes disturbance of the balance between pro-inflammatory and protective cytokines. We believe that neutralization of pro-inflammatory cytokines, especially interleukin 1b, with the IL-1 receptor antagonist (IL-1Ra) and/or IL-1b antibodies might cause the reduction of the inflammatory process in pancreas islets, normalize concentration of glucose in blood and decrease the insulin resistance. (Clin Diabetol 2017; 6, 3: 90-100).