The mechanisms of nucleotide actions in insulin resistance

Insulin resistance contributes to metabolic disorders in obesity and type 2 diabetes. In mechanisms of insulin resistance, the roles of glucose, fatty acids, and amino acids have been extensively documented in literature. However, the activities of nucleotides remain to be reviewed comprehensively in the regulation of insulin sensitivity. Nucleotides are well known for their activities in biosynthesis of DNA and RNA as well as their signaling activities in the form of cAMP and cGAMP. Their activities in insulin resistance are dependent on the derivatives and corresponding receptors. ATP and NADH, derivatives of adenosine, inhibit insulin signaling inside cells by downregulation of activities of AMPK and SIRT1, respectively. ATP, ADP and AMP, the well-known energy carriers, regulate cellular responses to insulin outside cells through the purinergic receptors in cell surface. Current evidence suggests that ATP, NADH, cGAMP, and uridine are potential biomarkers of insulin resistance. However, GTP and cGMP are likely the markers of insulin sensitization. Here, studies crossing the biomedical fields are reviewed to characterize nucleotide activities in the regulation of insulin sensitivity. The knowledge brings new insights into the mechanisms of insulin resistance. Copyright (C) 2022, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press. All rights reserved.

Automated summary

Insulin resistance is a major factor in metabolic disorders associated with obesity and type 2 diabetes. While the roles of glucose, fatty acids, and amino acids in insulin resistance have been extensively studied, the activities of nucleotides in regulating insulin sensitivity remain to be fully reviewed. This article examines the activities of nucleotides, such as ATP, NADH, and cGAMP, in insulin signaling and resistance and discusses their potential as biomarkers. It also highlights the importance of interdisciplinary research in uncovering the mechanisms of insulin resistance.