INS and diabetes mellitus: What is established (diabetes/islet biology and PDAC-relevant models). In diabetes, chronic gluco-lipotoxic stress activates the UPR, reduces β-cell transcription factor expression (pancreatic and duodenal homeobox 1 (PDX1), MAF bZIP transcription factor A (MAFA), and NK6 homeobox 1 (NKX6.1)), and impairs granule priming and metabolic coupling, yielding muted first-phase insulin and damped/irregular insulin release pulsatility [64,65,66].