Inflammatory mechanisms of pancreatic β-cell dysfunction and therapeutic strategies in type 2 diabetes mellitus: a narrative review.

Purpose: Inflammatory signalling within and around pancreatic islets is increasingly recognised as an important component of β-cell dysfunction in type 2 diabetes mellitus (T2DM). Current evidence, however, supports a bidirectional relationship in which metabolic stress initiates inflammatory responses and inflammation subsequently amplifies β-cell dysfunction, rather than inflammation acting as a single primary cause of T2DM. This review critically examines the evidence linking metabolic stress to β-cell inflammatory injury and evaluates therapeutic strategies aimed at preserving β-cell function. Methods: PubMed and Web of Science were searched without a lower publication-date restriction through 1 June 2026, with Google Scholar used as a supplementary source. Search strategies combined terms related to T2DM, pancreatic β-cells/islets, inflammatory and metabolic stress pathways, and therapeutic interventions using the Boolean operators AND and OR. A representative search strategy was: ("type 2 diabetes mellitus" OR T2DM) AND ("pancreatic β-cell" OR "pancreatic islet") AND (inflammation OR glucotoxicity OR lipotoxicity OR "oxidative stress" OR "endoplasmic reticulum stress" OR inflammasome OR cytokine) AND (therapy OR treatment OR protection OR regeneration). Reference lists of relevant reviews and primary studies were also screened to identify additional publications. Results: Evidence from human and experimental studies supports interactions among glucotoxicity, lipotoxicity, oxidative and endoplasmic reticulum stress, mitochondrial dysfunction, islet macrophage activation, cytokine signalling, and β-cell dysfunction. In contrast, evidence for the causal importance of individual inflammasome, regulated cell-death, extracellular-vesicle, and gene-regulatory pathways remains predominantly preclinical. Randomised trials have reported improvements in glycaemic control or β-cell functional indices with anakinra, salsalate, liraglutide, dapagliflozin, thiazolidinediones, and short-term intensive insulin therapy. However, these trials generally assessed metabolic or β-cell functional outcomes rather than pancreatic islet inflammation directly. Canakinumab did not reduce new-onset diabetes or provide sustained glycaemic improvement, whereas regenerative and gene-editing approaches remain experimental. Conclusion: Inflammatory signalling and metabolic stress interact bidirectionally and contribute to progressive β-cell dysfunction in T2DM. Selected anti-inflammatory and glucose-lowering interventions improve glycaemic or β-cell functional outcomes, but direct suppression of pancreatic islet inflammation and durable modification of T2DM progression have not been established. IL-1 pathway modulation warrants further investigation, whereas regenerative and gene-based approaches remain experimental. Patient stratification based on β-cell functional status and inflammatory profiles requires prospective validation before clinical implementation.