Long non-coding RNA GAS5 binds to miR-137 and regulates Nrf2 to ameliorate insulin resistance in adipose tissue in gestational diabetes mellitus.
Guo Yuanyuan, Jiao Jingru, Zheng Xian
Abstract
OBJECTIVE: This study aimed to explore whether GAS5 improves gestational diabetes mellitus (GDM)-associated insulin resistance (IR) via the miR-137/Nrf2 axis, thereby elucidating a potential novel mechanism underlying GDM pathogenesis. METHODS: GAS5 and Nrf2 expression was compared between GDM patients and normal glucose tolerance pregnant women, and their correlations with IR and lipid metabolism indexes were analysed. A dexamethasone-induced adipocyte IR model was constructed. Cellular functional changes in glucose uptake, fatty acid metabolism and lipid deposition were detected following GAS5 overexpression and miR-137/Nrf2 intervention to validate the regulatory mechanism. RESULTS: GAS5 and Nrf2 were markedly decreased in GDM peripheral blood and closely correlated with IR and lipid metabolic phenotypes. GAS5 overexpression increased adipocyte glucose uptake and alleviated IR and lipid disorders. Mechanistically, GAS5 directly binds and inhibits miR-137 to upregulate Nrf2. Rescue assays showed that miR-137 elevation or Nrf2 suppression partially reversed the protective effects of GAS5, reducing glucose uptake and fatty acid oxidation while increasing free fatty acid release and lipid accumulation. CONCLUSION: GAS5 and Nrf2 are lowly expressed in GDM patients. This study demonstrates that GAS5 ameliorates adipocyte IR and lipid metabolic dysfunction by sponging miR-137 to elevate Nrf2 expression, providing a novel mechanistic insight for GDM.
Key Findings
- GAS5 and Nrf2 expression are decreased in gestational diabetes mellitus (GDM) patients and correlate with insulin resistance and lipid metabolism abnormalities.
- GAS5 overexpression in adipocytes improves glucose uptake, reduces insulin resistance, and ameliorates lipid metabolic dysfunction.
- GAS5 acts by binding and inhibiting miR-137, which leads to upregulation of Nrf2; modulation of this pathway affects glucose and lipid metabolism in adipocytes.
Clinical Significance
This study identifies the GAS5/miR-137/Nrf2 axis as a novel mechanism underlying insulin resistance and lipid metabolic dysfunction in GDM, suggesting potential therapeutic targets for improving metabolic outcomes in affected pregnant women.
Citation
Guo Yuanyuan, Jiao Jingru, Zheng Xian. Long non-coding RNA GAS5 binds to miR-137 and regulates Nrf2 to ameliorate insulin resistance in adipose tissue in gestational diabetes mellitus. Diabetic medicine : a journal of the British Diabetic Association. 2026-Sep-04.