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.

High Sucrose Diet-Induced Subunit I Tyrosine 304 Phosphorylation of Cytochrome c Oxidase Leads to Liver Mitochondrial Respiratory Dysfunction in the Cohen Diabetic Rat Model

“…Also noteworthy is the fact that there is mounting evidence that ATP deficiency is involved in the development of liver insulin resistance, glucose and lipid metabolism disorders, and even diabetes in cell and animal models as well as human diabetic patients [30][31][32]. Consequently, augmenting hepatic ATP synthesis has been proposed as a therapeutic strategy for the treatment of metabolic disorders including diabetes [33] and our finding of Y304 phosphorylation may provide a new mechanistic target for such an approach. Taken together, our data imply that excessive sucrose consumption leads to mitochondrial respiratory dysfunction and that factors beyond dietary intake, such as genetic predisposition, significantly contribute to the heightened susceptibility of (pre-)diabetic metabolic disorders observed in the liver.…”

Exploring the Multi-Faceted Role of Sirtuins in Glioblastoma Pathogenesis and Targeting Options

“…SIRT4 functions as an ADP-ribosyltransferase, and lipoamidase, but also exhibits weak deacetylase activity [ 70 , 71 ]. These catalytic activities implicate SIRT4 in the regulation of insulin secretion, ATP homeostasis, lipid catabolism, neurological disorders, and tumorigenesis [ 72 , 73 , 74 ]. As an ADP-ribosyltransferase, SIRT4 is responsible for the transfer of the ADP-ribosyl group from NAD + to the C172 histone residue of glutamate dehydrogenase (GDH), inhibiting the metabolism of glutamine and reducing ATP production [ 75 ].…”