Islets of Langerhans are anatomically dispersed within the pancreas and exhibit regulatory coordination between islets in response to nutritional and inflammatory stimuli. However, within individual islets, there is also multi-faceted coordination of function between individual beta-cells, and between beta-cells and other endocrine and vascular cell types. This is mediated partly through circulatory feedback of the major secreted hormones, insulin and glucagon, but also by autocrine and paracrine actions within the islet by a range of other secreted products, including somatostatin, urocortin 3, serotonin, glucagon-like peptide-1, acetylcholine, and ghrelin. Their availability can be modulated within the islet by pericyte-mediated regulation of microvascular blood flow. Within the islet, both endocrine progenitor cells and the ability of endocrine cells to trans-differentiate between phenotypes can alter endocrine cell mass to adapt to changed metabolic circumstances, regulated by the within-islet trophic environment. Optimal islet function is precariously balanced due to the high metabolic rate required by beta-cells to synthesize and secrete insulin, and they are susceptible to oxidative and endoplasmic reticular stress in the face of high metabolic demand. Resulting changes in paracrine dynamics within the islets can contribute to the emergence of Types 1, 2 and gestational diabetes.

Pancreatic ductal adenocarcinoma (PDAC) is frequently associated with new-onset diabetes (NOD) in adults aged ≥ 50 years. Accordingly, NOD may serve as an early clinical marker for PDAC, although the causal links remain incompletely defined. This review synthesises clinical and experimental evidence into an islet-centric view in which tumour-derived signals and microenvironmental changes impair β-cell insulin secretion and disrupt α- and δ-cell regulation. We distinguish findings established in PDAC from mechanisms inferred from islet physiology and systemic metabolism. Key uncertainties include the timing of systemic versus local drivers, the clinical relevance of tumour-derived signals in driving dysglycaemia, the status of endocrine cell signalling and endocrine–exocrine crosstalk, and the effects of microvascular and matrix changes on endocrine–vascular exchange. This synthesis highlights mechanisms that remain incompletely defined and prioritises areas for further research.