Long noncoding RNAs in type 2 diabetes mellitus: emerging regulators of insulin resistance, β-cell dysfunction and diabetic complications

Type 2 diabetes mellitus (T2DM) affects more than 537 million adults worldwide and is projected to exceed 780 million cases by 2045, driven by insulin resistance, β-cell dysfunction, and chronic inflammation. Over the past decade, long noncoding RNAs (lncRNAs)—regulatory transcripts > 200 nucleotides without protein-coding capacity—have emerged as key epigenetic and post-transcriptional regulators of metabolic homeostasis. Integrated evidence from human tissues, circulating biofluids (serum/plasma), primary cells, and validated experimental models shows that lncRNAs modulate insulin signaling, glucose and lipid metabolism, and β-cell transcriptional programs, thereby shaping insulin sensitivity and β-cell survival. Dysregulated lncRNAs are also implicated in diabetic nephropathy, retinopathy, and neuropathy, where they influence fibrotic, inflammatory, and caspase-dependent apoptotic pathways. Several circulating lncRNAs, including MALAT1, MIAT, and H19, show promise as diagnostic or prognostic biomarkers. Although lncRNA-targeted therapies remain at the preclinical stage, experimental silencing or restoration of specific transcripts improves insulin sensitivity, reduces inflammation, and protects metabolic tissues in diabetic models. This review synthesizes human-focused evidence on the molecular roles of lncRNAs in T2DM, highlighting their emerging value as circulating biomarkers and as candidate targets for precision therapies.