Research ArticleMetabolism

Paired box 6 programs essential exocytotic genes in the regulation of glucose-stimulated insulin secretion and glucose homeostasis

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Science Translational Medicine  30 Jun 2021:
Vol. 13, Issue 600, eabb1038
DOI: 10.1126/scitranslmed.abb1038

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Stimulating insulin secretion

Paired box 6 (PAX6) is a transcription factor involved in pancreatic development; now, So et al. report that PAX6 also indirectly regulates insulin secretion in mature pancreatic beta cells. The authors show that PAX6 promoted cAMP response element–binding protein (CREB)–mediated expression of Munc18-1/2 proteins known to be involved in core processes of exocytosis. Pancreatic beta cells and primary mouse islet models of type 2 diabetes showed reduced PAX6 expression, and adenoviral vector–mediated overexpression of PAX6 improved glucose homeostasis in db/db mice and glucose-stimulated insulin secretion in human islets, demonstrating the relevance of the PAX6/CREB/Munc18-1/2 axis to disease physiology and, potentially, its treatment.

Abstract

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 humans. However, the molecular mechanism of PAX6 in controlling insulin secretion in human beta cells and its pathophysiological role in type 2 diabetes (T2D) remain ambiguous. We investigated the molecular pathway of PAX6 in the regulation of insulin secretion and the potential therapeutic value of PAX6 in T2D by using human pancreatic beta cell line EndoC-βH1, the db/db mouse model, and primary human pancreatic islets. Through loss- and gain-of-function approaches, we uncovered a mechanism by which PAX6 modulates glucose-stimulated insulin secretion (GSIS) through a cAMP response element–binding protein (CREB)/Munc18-1/2 pathway. Moreover, under diabetic conditions, beta cells and pancreatic islets displayed dampened PAX6/CREB/Munc18-1/2 pathway activity and impaired GSIS, which were reversed by PAX6 replenishment. Adeno-associated virus–mediated PAX6 overexpression in db/db mouse pancreatic beta cells led to a sustained amelioration of glycemic perturbation in vivo but did not affect insulin resistance. Our study highlights the pathophysiological role of PAX6 in T2D-associated beta cell dysfunction in humans and suggests the potential of PAX6 gene transfer in preserving and restoring beta cell function.

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