Abstract
Adenosine triphosphate (ATP) is the key energy intermediate of cellular metabolic processes and a ubiquitous extracellular messenger. As an extracellular messenger, ATP acts at plasma membrane P2 receptors (P2Rs). The levels of extracellular ATP (eATP) are set by both passive and active release mechanisms and degradation processes. Under physiological conditions, eATP concentration is in the low nanomolar range but can rise to tens or even hundreds of micromoles/L at inflammatory sites. A dysregulated eATP homeostasis is a pathogenic factor in several chronic inflammatory diseases, including type 2 diabetes mellitus (T2DM). T2DM is characterized by peripheral insulin resistance and impairment of insulin production from pancreatic β-cells in a landscape of systemic inflammation. Although various hypoglycemic drugs are currently available, an effective treatment for T2DM and its complications is not available. However, counteracting systemic inflammation is anticipated to be beneficial. The postulated eATP increase in T2DM is understood to be a driver of inflammation via P2X7 receptor (P2X7R) activation and the release of inflammatory cytokines. Furthermore, P2X7R stimulation is thought to trigger apoptosis of pancreatic β-cells, thus further aggravating hyperglycemia. Targeting eATP and the P2X7R might be an appealing novel approach to T2DM therapy.
Highlights
Diabetes mellitus (DM) is a widespread metabolic disorder featuring decreased peripheral insulin sensitivity, impaired insulin secretion from pancreatic β-cells, and overall dysregulation of glucose metabolism [1,2]
Diabetes is conventionally divided into: (i) type 1 diabetes mellitus (T1DM; autoimmune form) which is characterized by increased blood levels of autoantibodies directed against insulin-producing β-cells, and (ii) type 2 diabetes mellitus (T2DM; non-autoimmune form) which is characterized by increased peripheral resistance to insulin and decreased insulin secretion by pancreatic β-cells [3,5,6]
While the main trigger of P2X7 receptor (P2X7R)-dependent NLRP3 inflammasome stimulation is a drop in intracellular K+, the parallel increase in the cytoplasmic Ca2+ and Na+ concentrations on one hand activates a number of additional pathways such as nuclear factor kappa B (NF-kB), nuclear factor of activated T-cells (NFAT), phosphoinositide 3-kinases/serine/threonine-protein kinase (PI3K/Akt), and on the other causes down modulation of glycogen synthase kinase 3 beta (GSK3β) [26,32]
Summary
Diabetes mellitus (DM) is a widespread metabolic disorder featuring decreased peripheral insulin sensitivity, impaired insulin secretion from pancreatic β-cells, and overall dysregulation of glucose metabolism [1,2]. Diabetes is conventionally divided into: (i) type 1 diabetes mellitus (T1DM; autoimmune form) which is characterized by increased blood levels of autoantibodies directed against insulin-producing β-cells, and (ii) type 2 diabetes mellitus (T2DM; non-autoimmune form) which is characterized by increased peripheral resistance to insulin and decreased insulin secretion by pancreatic β-cells [3,5,6]. Ecently, a correlation has been suggested between proinflammatory cytokines secreted by adipose tissue and T1DM [7]. Macrophages and other immune cells residing in the immune tissue secrete large quantities of proinflammatory cytokines exacerbating inflammation and insulin resistance [9]. Some experimental models for studying DM are available; they all have limitations Both large (non-human primates, pigs, dogs, and cats) and small (rabbits, rats, and mice) mammals are used. The purinergic system, extracellular ATP (eATP) and P2 receptors (P2Rs), might be an appealing target
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