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.

Fig. 1

Integrated function of pancreas in nutrient breakdown, nutrient sensing and release of pancreatic hormones. Purinergic signalling plays significant roles in physiological responses as well as in diabetes. Distribution of key receptors in pancreatic cells is shown and also locally produced and blood-born factors that could affect insulin release and/or β-cell viability. Pancreatic acini secrete digestive enzymes and ATP. Pancreatic ducts express receptors that are involved in regulation of bicarbonate-rich fluid secretion. Both exocrine cells can contribute to the interstitial milieu in the form of nucleotides/nucleosides or secreted cytokines. β Cells secrete insulin and ATP and purinergic receptors stimulate or inhibit insulin secretion, while others regulate cell viability. In addition, α cells express receptors that regulate glucagon secretion. Figure also shows GLP-1 and GIP that regulate both insulin secretion and β-cell mass. For details, see the text

Fig. 2

Perfusion of isolated rat pancreas with ADPβS and glucose. a Pancreata isolated from Zucker lean controls (ZLC) were perfused for 30 min with perfusate containing 5 mM glucose (first 15 min not shown). ADPβS (15 μM) was applied into perfusate as shown by horizontal bar. ADPβS produced a biphasic insulin release. Raising glucose to 10 mM produced a biphasic insulin secretion. b Pancreata isolated from Zucker diabetic fatty (ZDF) rats were perfused using the same protocol as in a. ADPβS (15 μM) caused a much larger biphasic insulin secretion while glucose induced a small and transient insulin release. c Perfusion of isolated rat pancreas from Wistar rats with ADPβS and glucose. (Reproduced from [66], with permission)

Fig. 3

Purinergic receptors have effects on β-cell mass. Receptors marked in green increase β-cell mass (proliferation/replication), while those marked in red mediate β-cell death (apoptosis). Some purinergic receptors exert cytoprotective actions when cells are exposed to other factors, e.g. cytokines. The effects of P1 and P2 receptor stimulation on cell viability and/or insulin release may be dependent on concentrations of nucleotides/sides. For details, see the text