Pancreatic β-cells and adipocytes have a major role in the regulation of whole-body glucose and lipid homeostasis. Impaired functionalities of these two cell types promote the onset and progression of metabolic disturbances such as obesity and diabetes. Type 2 diabetes is increasing worldwide and represents one of today’s biggest global health challenges. There are indications that extracellular ATP and purinergic signaling are involved in the control of glucose homeostasis and their deregulation could contribute to the onset and progression of these pathological conditions. However, the pathophysiological role of extracellular ATP and purinergic signaling in β-cells and adipocytes are not yet well characterized. Therefore, in this PhD project we aimed to reveal novel mechanisms underlying the purinergic signaling regulation of physiological and pathological functions in both pancreatic β-cells and adipocytes with the perspective of providing new knowledge and innovative therapeutic targets and strategies for obesity and diabetes treatment.
Pancreatic β-cells and adipocytes have been selected as a results of an initial ATP release screening of several cell types relevant in diabetes. We showed that β-cells and adipocytes release significant amount of ATP, which regulates several physiological and pathological functions in both cell types. Particularly, study 1 revealed that β-cells release ATP after acute glucose stimulation via both vesicular and non-vesicular mechanisms, involving pannexin-1 and P2X7 receptor. We showed also that extracellular ATP, via P2X7 receptor, stimulates Ca2+ influx and oscillations, insulin secretion and modulates cell proliferation. In another independent study, study 2, we showed that both white and brown adipocytes release ATP after adrenergic stimulation mainly via pannexin-1. We identified the adrenergically-activated pathway promoting the release of ATP and we found that this process is regulated by glucose and strictly inhibited by insulin. Furthermore, we provided evidence that ATP released in white adipocytes activates P2 receptors, including P2X7, and regulates intracellular Ca2+ signaling, lipolysis and macrophages migration. In conclusion, the research presented in this thesis provides novel insights into the role of extracellular ATP and purinergic signaling as autocrine and paracrine regulators of β-cells and adipose tissue functions. Importantly, these new findings could contribute to the understanding of diabetes pathogenesis and may provide potential therapeutic targets for obesity and diabetes.