Deletion of Ascl1 in pancreatic β-cells improves insulin secretion, promotes parasympathetic innervation, and attenuates dedifferentiation during metabolic stress.

Objective: ASCL1, a pioneer transcription factor, is essential for neural cell differentiation and function. Previous studies have shown that Ascl1 expression is increased in pancreatic β-cells lacking functional K channels or after feeding of a high fat diet (HFD) suggesting that it may contribute to the metabolic stress response of β-cells.

Methods: We generated β-cell-specific Ascl1 knockout mice (Ascl1) and assessed their glucose homeostasis, islet morphology and gene expression after feeding either a normal diet or HFD for 12 weeks, or in combination with a genetic disruption of Abcc8, an essential K channel component.