Involvement of P2Y signaling in the restoration of glucose-induced insulin exocytosis in pancreatic ß cells exposed to glucotoxicity.

Purinergic P2Y receptors, by binding adenosine triphosphate (ATP), are known for enhancing glucose-stimulated insulin secretion (GSIS) in pancreatic ß cells. However, the impact of these receptors in the actin dynamics and insulin granule exocytosis in these cells is not established, neither in normal nor in glucotoxic environment. In this study, we investigate the involvement of P2Y receptors on the behavior of insulin granules and the subcortical actin network dynamics in INS-1 832/13 ß cells exposed to normal or glucotoxic environment and their role in GSIS. Our results show that the activation of P2Y purinergic receptors by ATP or its agonist increase the insulin granules exocytosis and the reorganization of the subcortical actin network and participate in the potentiation of GSIS. In addition, their activation in INS-1832/13 ß-cells, with impaired insulin secretion following exposure to elevated glucose levels, restores GSIS competence through the distal steps of insulin exocytosis. These results are confirmed ex vivo by perifusion experiments on islets from type 2 diabetic (T2D) Goto-Kakizaki (GK) rats. Indeed, the P2Y receptor agonist restores the altered GSIS, which is normally lost in this T2D animal model. Moreover, we observed an improvement of the glucose tolerance, following the acute intraperitoneal injection of the P2Y agonist concomitantly with glucose, in diabetic GK rats. All these data provide new insights into the unprecedented therapeutic role of P2Y purinergic receptors in the pathophysiology of T2D.

P2-type purinergic signaling in the regulation of pancreatic ß-cell functional plasticity as a promising novel therapeutic approach for the treatment of type 2 diabetes?

Diabetes Mellitus is a metabolic disorder characterized by a chronic hyperglycemia due to an impaired insulin secretion and a decreased in peripheral insulin sensitivity. This disease is a major public health problem due to it sharp prevalence. Therefore, it is crucial to readapt therapeutic approaches for the treatment of this pathology. One of the strategies would be through P2-type purinergic receptors pathway via ATP binding. In addition to its well-known role as an intracellular energy intermediary in numerous biochemical and physiological processes, ATP is also an important extracellular signaling molecule. ATP mediates its effects by binding and activating two classes of P2 purinoreceptors: P2X receptors that are ligand-gated ion channel receptors, existing in seven isoforms (P2X 1 to 7) and P2Y receptors that are G-protein coupled receptors, existing in eight isoforms (P2Y 1/2/4/6/11/12/13/14). These receptors are ubiquitously distributed and involved in numerous physiological processes in several tissues. The concept of purinergic signaling, originally formulated by Geoffrey Burnstock (1929-2020), was also found to mediate various responses in the pancreas. Several studies have shown that P2 receptors are expressed in the endocrine pancreas, notably in ß cells, where ATP could modulate their function but also their plasticity and thus play a physiological role in stimulating insulin secretion to face some metabolic demands. In this review, we provide a historical perspective and summarize current knowledge on P2-type purinergic signaling in the regulation of pancreatic ß-cell functional plasticity, which would be a promising novel therapeutic approach for the treatment of type 2 diabetes.