Exercise Reduces Insulin Resistance in Type 2 Diabetes Mellitus via Mediating the lncRNA MALAT1/MicroRNA-382-3p/Resistin Axis

Sui-Xin Liu; Fan Zheng; Kang-Ling Xie; Mu-Rong Xie; Ling-Jun Jiang; Ying Cai

doi:10.1016/j.omtn.2019.08.002

Exercise Reduces Insulin Resistance in Type 2 Diabetes Mellitus via Mediating the lncRNA MALAT1/MicroRNA-382-3p/Resistin Axis

Mol Ther Nucleic Acids. 2019 Dec 6:18:34-44. doi: 10.1016/j.omtn.2019.08.002. Epub 2019 Aug 7.

Authors

Sui-Xin Liu¹, Fan Zheng¹, Kang-Ling Xie¹, Mu-Rong Xie¹, Ling-Jun Jiang¹, Ying Cai²

Affiliations

¹ Cardiac Rehabilitation Center, Department of Rehabilitation, Xiangya Hospital, Central South University, Changsha 410008, P.R. China.
² Cardiac Rehabilitation Center, Department of Rehabilitation, Xiangya Hospital, Central South University, Changsha 410008, P.R. China. Electronic address: 403991@csu.edu.cn.

Abstract

Insulin resistance (IR) is the primary pathological mechanism underlying type 2 diabetes mellitus (T2DM). Here, the study aimed to ascertain whether and how exercise mediates IR in T2DM. An in vivo mouse model of high-fat diet-induced IR and an in vitro high-glucose-induced IR model were constructed. High long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) expression was detected in T2MD and was positively correlated with HOMA-IR and resistin levels. Then, short hairpin RNA targeting MALAT1 (sh-MALAT1) or pcDNA-MALAT1 was delivered into human umbilical vein endothelial cells (HUVECs) to knock down or upregulate its expression, respectively. Silencing of MALAT1 resulted in reduced levels of resistin, Ang II, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), endothelin-1 (ET-1), and p-insulin receptor substrate-1 (p-IRS)/ISR-1, and decreased cell migration, as well as enhanced glucose uptake and levels of nitric oxide (NO) and p-Akt/Akt. In the IR mouse model, exercise was observed to downregulate MALAT1 to reduce resistin, whereby exercise reduced homeostatic model assessment-insulin resistance (HOMA-IR). Besides, exercise also elevated microRNA-382-3p (miR-382-3p) expression in the serum of IR mice. Dual-luciferase reporter and RNA binding protein immunoprecipitation (RIP) assays identified that MALAT1 could bind to miR-382-3p to upregulate resistin. Collectively, the key observations of the study provide evidence that inhibition of MALAT1 elevates miR-382-3p to repress resistin, which consequently underlies the mechanism of exercise protecting against IR, highlighting a direction for T2DM therapy development.

Keywords: exercise; insulin resistance; metastasis-associated lung adenocarcinoma transcript 1; microRNA-382-3p; resistin; type 2 diabetes mellitus; vascular endothelial cells.