Current Insights into Long Non-Coding RNAs Role for Insulin Resistance Emerging in Type 2 Diabetes Mellitus and its Complications

Insulin resistance (IR) is a key factor in the development and progression of diabetes and other metabolic disorders. It occurs when insulin target tissues do not respond to normal insulin levels. Further research is needed to identify the specific mechanisms underlying IR. Long non-coding RNAs (lncRNAs) refers to non-protein coding RNA molecules longer than 200 nucleotides. LncRNAs play important roles in cell development, proliferation, apoptosis, and metabolism. Recent investigations suggested that lncRNAs have a significant role in the pathophysiology of metabolic disorders, including IR. Although lncRNAs have gained a lot of interest as promising and reliable biomarkers in the development and progression of a number of disease states, little is known about their clinical significance and regulatory mechanisms in relation to metabolic disorders. It has been demonstrated that various lncRNAs regulate glucose/lipid metabolism and insulin signaling such as LncRNAs H19, MEG3, GAS5, and MALAT1. The current review summarized and discussed the most recent developments on the roles and mechanisms of lncRNAs in IR after providing a brief introduction to the general characteristics of lncRNAs. LncRNAs and transcription factors associated with the development of insulin resistance (IR). (a) Increased lipogenic activity correlates with heightened levels of H19, MALAT1, MEG3, and MIAT, along with their interactions with nuclear proteins such as SREBP-1c, FoxO1 and PPARγ. Consequently, this interaction promotes the expression of lipogenic genes, including, FAS, ACC1and SCO1, as well as other proteins like LOXL2 through MIAT, resulting in lipid accumulation. (b) The upregulation of MEG3 activates the CRTC2, which subsequently activates the CREB by binding to ATF4 and FoxO1. Furthermore, hepatocyte nuclear factor 4 alpha HNF4A and FoxO1 are activated due to H19 overexpression, leading to the induction of gluconeogenesis. Conversely, the downregulation of H19 enhances the transcription of FoxO1 and gluconeogenic genes. (c) The overexpression of MALAT1 triggers the expression of EZH2/PRC2, MCP-1, and SAA3, which subsequently elevate both IL1β and IL6, as well as TNF-α. Additionally, H19 expression leads to the dephosphorylation of AKT and eNOS, while levels of NADPH and TNF-α increase due to the expression of c-JNK as a result of MIAT. (d) The downregulation of MEG3 enhances the expression of miR-140-5p, which is associated with cellular senescence. The overexpression of MALAT1 activates PTBPI, which plays a role in pancreatic β-cell dysfunction. The downregulation of MIAT impacts the PI3K/AKT signaling pathway, leading to reduced insulin sensitivity and cell viability 1. 1 V. Tello-Flores, F. Beltrán-Anaya, M. Ramirez-Vargas, B. Esteban-Casales, N. Navarro Tito, L. Alarcón-Romero, C. Luciano Villa, M. Ramírez, O. Moral-Hernández, E. Flores-Alfaro, Role of Long Non-Coding RNAs and the Molecular Mechanisms Involved in Insulin Resistance, International Journal of Molecular Sciences, 22 (2021) 7256. • Long non coding RNA has a significant role in insulin resistance • This review explains LncRNA classification and its role in β pancreatic cell. • Clarifying the role of LncRNAs in controlling insulin sensitivity and secretion • Role of LncRNA in DM complications • This review discusses the Metabolic origin of insulin resistance