The Paired box 6 (PAX6) transcription factor is crucial for normal pancreatic islet development and function. Heterozygous mutations of PAX6 are associated with impaired insulin secretion and early-onset diabetes mellitus in human. Previous studies demonstrated that PAX6 plays critical roles in insulin biosynthesis, glucose-sensing and glucose-induced ATP synthesis (the proximal signaling of insulin secretion). Yet the molecular mechanism of PAX6 in controlling beta-cell insulin secretion, especially the involvement of distal signaling, remains ambiguous. This study investigated the regulatory role of PAX6 in exocytotic proteins, the core components of distal signaling of insulin secretion, by using human pancreatic beta-cell line EndoC-bH1. The correlation between PAX6 and type 2 diabetes mellitus (T2DM)-associated beta-cell dysfunction was also assessed. Loss-of-function and gain-of-function studies showed that PAX6 positively regulated the expression of exocytotic proteins Munc18-1 and Munc18-2 in beta-cells by modulating the activity of cAMP response element-binding protein (CREB). The PAX6/CREB/Munc18-1/2 axis in turn controlled glucose-stimulated insulin secretion. On the other hand, EndoC-bH1 cells under diabetic condition displayed diminished PAX6 expression, blunted CREB phosphorylation and Munc18-1/2 down-regulation which were rescued by PAX6 overexpression. We conclude that PAX6 regulates distal signaling of insulin secretion through CREB/Munc18-1/2 axis; while maintenance of normal PAX6 expression or activity in human beta-cells may serve as a promising strategy in preserving beta-cell function and delaying the onset of T2DM.
W. So: None. W. Han: None.
National Medical Research Council of Australia