<p>Type 2 diabetes mellitus (T2D) is no longer viewed solely as a metabolic disorder but rather as a chronic, low-grade inflammatory disease shaped by the interplay of immune signaling and metabolic stress across key organs. This study explored inflammatory molecular signatures in pancreatic islets, adipose tissue (AT), and liver associated with T2D. Publicly available human genomic and transcriptomic datasets were identified through a PubMed search. Differentially expressed genes and all identified non-coding RNAs (ncRNAs) from the three tissues were subjected to bioinformatic and enrichment analyses to identify tissue-specific and common inflammatory mediators. Through integrative multi-omics and functional analyses, we delineated both shared and tissue-specific inflammatory circuits in pancreatic islets, liver, and AT, highlighting the convergence of cytokine networks, particularly TNF-α, IL-6 and IL-17, as potential mediators of inter-organ dysfunction. These cytokines can contribute to a pathological feedback loop whereby inflammatory cues originating in AT propagate to pancreatic and hepatic compartments, compounding insulin resistance and β-cell failure. AKT1, MAPK3, and CCL2 may represent key cross-tissue effectors linking inflammatory signaling and metabolic control, whose activity is also sensitive to age-related molecular drift and stress response imbalances. Additionally, ncRNAs such as miR-3064 and miR-21 emerged as potential key post-transcriptional regulators of NF-κB, IL-6 and IL-17 signaling pathways, supporting the notion that epigenetic and transcriptomic reprogramming is involved in metabolic inflammation. Overall, our findings suggest a multi-layered inflammatory architecture underlying T2D, highlighting inflammatory mediators and regulatory RNAs as potential targets for precision therapeutic strategies.</p> Graphical Abstract <p></p>