Purinergic signalling and diabetes

Abstract

The pancreas is an organ with a central role in nutrient breakdown, nutrient sensing and release of hormones regulating whole body nutrient homeostasis. In diabetes mellitus, the balance is broken—cells can be starving in the midst of plenty. There are indications that the incidence of diabetes type 1 and 2, and possibly pancreatogenic diabetes, is rising globally. Events leading to insulin secretion and action are complex, but there is emerging evidence that intracellular nucleotides and nucleotides are not only important as intracellular energy molecules but also as extracellular signalling molecules in purinergic signalling cascades. This signalling takes place at the level of the pancreas, where the close apposition of various cells—endocrine, exocrine, stromal and immune cells—contributes to the integrated function. Following an introduction to diabetes, the pancreas and purinergic signalling, we will focus on the role of purinergic signalling and its changes associated with diabetes in the pancreas and selected tissues/organ systems affected by hyperglycaemia and other stress molecules of diabetes. Since this is the first review of this kind, a comprehensive historical angle is taken, and common and divergent roles of receptors for nucleotides and nucleosides in different organ systems will be given. This integrated picture will aid our understanding of the challenges of the potential and currently used drugs targeted to specific organ/cells or disorders associated with diabetes.

Hyperglycemia alters E-NTPDases, ecto-5′-nucleotidase, and ectosolic and cytosolic adenosine deaminase activities and expression from encephala of adult zebrafish (Danio rerio)

“…The blood glucose levels from glucose-treated and washout animals demonstrated the same profile already developed in previous works [8,42]. Nucleotides are important extracellular messengers in both physiological and pathological conditions [11]. After its release in the synaptic cleft, ATP can be catabolized to ADP, AMP, and adenosine.…”

“…One possible strategy to correct the changes in synaptic efficiencies caused by DM can be through of analysis of the presynaptic neuromodulation systems, as purinergic system [11,12]. Adenine nucleotides represent an important class of extracellular molecules involved in modulation of signaling pathways that are essential to the normal functioning of the central nervous system (CNS) [13].…”

Loss of P2X7 nucleotide receptor function leads to abnormal fat distribution in mice

“…Moreover, P2X7 signaling can cause the formation of large nonselective membrane pores and induce dynamic membrane blebbing [12,13]. This receptor plays important roles in chronic pain [14,15], apoptosis [16][17][18], bone remodeling [19][20][21], immune responses [22][23][24][25] and the function of exocrine and endocrine organs [26,27].…”

Purinergic P2Y1 receptors take centre stage in autocrine stimulation of human beta cells

“…The small size of ATP and related nucleotides allows them to escape through the granule fusion pore before insulin is released, and sometimes even without concomitant protein secretion [6]. The purine nucleotides exert auto-and paracrine actions on beta cells, and although there is extensive literature on the subject (reviewed in [7,8]), the precise receptors and molecular mechanisms involved have not been clarified.Two classes of purinergic P2 receptors mediate the effects of ATP and ADP: ionotropic P2X receptors and G-proteincoupled P2Y receptors. The P2X receptors constitute a group of seven isoforms that act as ATP-gated cation channels, several of which are expressed in beta cells [7,8].…”

“…The purine nucleotides exert auto-and paracrine actions on beta cells, and although there is extensive literature on the subject (reviewed in [7,8]), the precise receptors and molecular mechanisms involved have not been clarified.…”