Islet extracellular matrix remodelling in type 2 diabetes: implications for β-cell failure and therapeutic opportunities

Abstract

Type 2 diabetes mellitus (T2DM) is characterised by progressive insulin resistance and pancreatic β-cell dysfunction, ultimately resulting in impaired glucose homeostasis. While metabolic and genetic factors are central to disease development, increasing evidence indicates that disruption of the pancreatic islet extracellular matrix (ECM) may be an important contributor to β-cell failure. The islet ECM is not merely a structural scaffold but a dynamic signalling network that regulates β-cell adhesion, survival, proliferation and insulin secretion through integrin-mediated signalling and mechanotransduction pathways. In healthy islets, a tightly organised ECM composed of collagens, laminins, fibronectin and glycosaminoglycans maintains basement membrane integrity, vascular support and coordinated cell-matrix communication. In T2DM, chronic hyperglycaemia, inflammation and oxidative stress are associated with pathological ECM remodelling and are thought to contribute to alterations in islet ECM composition characterised by fibrosis, altered matrix composition, dysregulated proteolysis and excessive ECM protein deposition. These changes are potentially associated with impaired integrin signalling, altered mechanotransduction and compromised β-cell function and viability in experimental models. ECM remodelling may also promote islet stiffening, vascular dysfunction, amyloid deposition and inflammatory signalling, further amplifying β-cell decline. This review synthesises current understanding of islet ECM composition, cell-matrix interactions and the molecular mechanisms linking metabolic stress to ECM remodelling. It also highlights emerging preclinical evidence that incretin-based therapies, including semaglutide and tirzepatide, are associated with changes in ECM-related pathways, while emphasising that these effects may be secondary to improved metabolic control and that direct ECM-targeting effects have yet to be established. Finally, we discuss emerging therapeutic strategies targeting fibrosis, mechanotransduction and matrix signalling pathways, and identify key knowledge gaps regarding the causal contribution of ECM remodelling to β-cell dysfunction and loss in T2DM.

Keywords

type 2 diabetes mellitus / pancreatic islets / extracellular matrix / incretin therapy / β-cell dysfunction / β-cell failure / integrin signalling

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