ATP Secretion and Metabolism in Regulating Pancreatic Beta Cell Functions and Hepatic Glycolipid Metabolism

Abstract

Diabetes (DM), especially type 2 diabetes (T2DM) has become one of the major diseases severely threatening public health worldwide. Islet beta cell dysfunctions and peripheral insulin resistance including liver and muscle metabolic disorder play decisive roles in the pathogenesis of T2DM. Particularly, increased hepatic gluconeogenesis due to insulin deficiency or resistance is the central event in the development of fasting hyperglycemia. To maintain or restore the functions of islet beta cells and suppress hepatic gluconeogenesis is crucial for delaying or even stopping the progression of T2DM and diabetic complications. As the key energy outcome of mitochondrial oxidative phosphorylation, adenosine triphosphate (ATP) plays vital roles in the process of almost all the biological activities including metabolic regulation. Cellular adenosine triphosphate participates intracellular energy transfer in all forms of life. Recently, it had also been revealed that ATP can be released by islet beta cells and hepatocytes, and the released ATP and its degraded products including ADP, AMP and adenosine act as important signaling molecules to regulate islet beta cell functions and hepatic glycolipid metabolism via the activation of P2 receptors (ATP receptors). In this review, the latest findings regarding the roles and mechanisms of intracellular and extracellular ATP in regulating islet functions and hepatic glycolipid metabolism would be briefly summarized and discussed.

Keywords: ATP; glucolipid metabolism; insulin secretion; mitochondrial dysfunction; purinergic P2 receptor.

FIGURE 1

Metabolism of extracellular ATP and its biological functions. ATP is synthesized and then secreted from the cells through CX or PANX channels. Extracellular ATP can be degraded into ADP and AMP by the catalysis of E-NTPDases, APs and E-NPPs. AMP can be further hydrolysed into adenosine by APs or E-5′NT. P1 receptors can be activated by adenosine and promote its influx into the cell. Nucleotides existing in the extracellular also activate P2 receptors, including P2X and P2Y receptors, with the induction of Ca²⁺-CaM signal pathways or G-protein-PLC mediated activation of PI3K, or other biological regulations. Aden, adenosine. APs, alkaline phosphatases. CaM, calmodulin. CaN, Calcineurin. CX, connexin channels. E-5′NT, ecto-5′-nucleotidase. E-NTPDases, ecto-nucleoside triphosphate diphosphohydrolases. E-NPPs, ectonucleotide pyrophosphatase and phosphodiesterases. P1, P1 receptors. P2X, P2X receptors. P2Y, P2Y receptors. PANX, pannexin channels. PI3K, phosphatidylinositol 3-kinase. PLC, phospholipase C.

FIGURE 2

FAM3A is a novel target for treating diabetes and NAFLD. FAM3A is a new mitochondrial protein that enhances ATP production and release in pancreatic β cells and hepatocytes. In physiological condition, FAM3A-ATP-P2R signaling pathway plays important roles in controlling PDX-1 and insulin expressions in pancreatic β cells, and suppressing gluconeogenesis and lipogenesis independent of insulin in liver. Under diabetic condition, inhibition of FAM3A-ATP-P2R signaling pathway causes pancreatic β dysfunctions, and increases hepatic gluconeogenesis and lipogenesis. Clearly, activating FAM3A-ATP-P2R signaling pathway represents a novel strategy for treating T2DM and NAFLD. Akt, protein kinase B; ATP, adenosine triphosphate; FFAs, free fatty acids; NAFLD, non-alcoholic fatty liver disease. P2R, purinergic P2 receptors (ATP, ADP and UTP as ligands); PDX-1, pancreatic and duodenal homeobox 1.