Long non-coding RNAs (lncRNAs) are single-stranded RNA biomolecules with a length of >200 nt, and they are currently considered to be master regulators of many pathological processes. Recent publications have shown that lncRNAs play important roles in the pathogenesis and progression of insulin resistance (IR) and glucose homeostasis by regulating inflammatory and lipogenic processes. lncRNAs regulate gene expression by binding to other non-coding RNAs, mRNAs, proteins, and DNA. In recent years, several mechanisms have been reported to explain the key roles of lncRNAs in the development of IR, including metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), imprinted maternal-ly expressed transcript (H19), maternally expressed gene 3 (MEG3), myocardial infarction-associated transcript (MIAT), and steroid receptor RNA activator (SRA), HOX transcript antisense RNA (HOTAIR), and downregulated Expression-Related Hexose/Glucose Transport Enhancer (DREH). LncRNAs participate in the regulation of lipid and carbohydrate metabolism, the inflammatory process, and oxidative stress through different pathways, such as cyclic adenosine monophosphate/protein kinase A (cAMP/PKA), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), polypyrimidine tract-binding protein 1/element-binding transcription factor 1c (PTBP1/SREBP-1c), AKT/nitric oxide synthase (eNOS), AKT/forkhead box O1 (FoxO1), and tumor necrosis factor-alpha (TNF-α)/c-Jun-N-terminal kinases (JNK). On the other hand, the mechanisms linked to the molecular, cellular, and biochemical actions of lncRNAs vary according to the tissue, biological species, and the severity of IR. Therefore, it is essential to elucidate the role of lncRNAs in the insulin signaling pathway and glucose and lipid metabolism. This review analyzes the function and molecular mechanisms of lncRNAs involved in the development of IR.

A western diet and increased intestinal permeability may contribute to systemic inflammation and the development of cardio-metabolic alterations. The aim of this study was to assess the relationship between diet, biomarkers of intestinal permeability, and chronic low-grade inflammation on the cardiometabolic profile. A cross-sectional study was carried out in 238 young subjects aged 18–29 years, divided into two groups: with <3 cardiometabolic risk factors (CRF) and ≥3 risk factors. Anthropometric parameters, biochemical profile, and serum levels of zonulin, lipopolysaccharide (LPS), and high-sensitivity C-reactive protein (hs-CRP) were measured, and the macronutrient intake was evaluated. Interaction models showed elevated glucose levels in the presence of high biomarker levels: zonulin ≥51.6 ng/mL plus LPS ≥ 1.35 EU/mL (β = 1.1, p = 0.006), and LPS ≥1.35 EU/mL plus hs-CRP ≥ 4.3 mg/L (β = 1.2, p = 0.007). In addition, triglyceride levels increased in the presence of LPS ≥ 1.35 EU/mL and hs-CRP ≥ 4.3 mg/L (β = 3.9, p = 0.01). Despite having increased biomarker levels, a higher consumption of water (≥2100 mL), polyunsaturated fatty acids (≥6.0 g), or fiber (≥30 g) decreased triglyceride (β = −9.6, p = 0.03), total cholesterol (β = −5.1, p = 0.01), and LDL-C levels (β = −7.7, p = 0.01). These findings suggest that the increased consumption of water, PUFA and fiber may improve lipid profile in subjects with intestinal permeability dysfunction or low-grade systemic inflammation.

Insulin resistance (IR) is a key contributor to the development of metabolic diseases, and metformin has been shown to help mitigate IR. Long non-coding RNAs (lncRNAs) are emerging as important regulators in metabolic disorders. This study aimed to investigate the differential expression of lncRNAs in IR and assess the impact of metformin on these lncRNAs. Using the Huh7 cell line to model IR (Huh7-IR), we treated the cells with metformin (Huh7-IR+Metf). Microarray analysis, followed by bioinformatic analysis in RStudio, identified 127 downregulated and 109 upregulated lncRNAs, among which 60 showed reduced expression following metformin treatment in Huh7-IR cells. Notably, the upregulated lncRNAs HOX transcript antisense RNA (HOTAIR), long intergenic non-protein coding RNA, muscle differentiation 1 (LINCMD1) and Prader-Willi region non-protein coding RNA 2 (PWRN2) were found to be associated with genes involved in the insulin signaling pathway. These three lncRNAs were further validated using real-time RT-PCR. This study highlights the differential expression of lncRNAs in IR and their modulation by metformin. Specifically, metformin restores the expression of lncRNAs that were deregulated in IR, including HOTAIR, LINCMD1, and PWRN2, likely through the regulation of critical biological processes and signaling pathways associated with IR. In conclusion, our findings demonstrate that metformin modulates the expression of key lncRNAs, including HOTAIR, LINCMD1, and PWRN2, which are deregulated in insulin resistance. This regulation likely occurs through the modulation of critical signaling pathways, such as NFκB and AMPK, suggesting that targeting lncRNAs could offer new therapeutic avenues for managing IR and related metabolic disorders.