Paired box 6 programs essential exocytotic genes in the regulation of glucose-stimulated insulin secretion and glucose homeostasis
File(s)
Accepted version
Author(s)
So, Wing Yan
Liu, Wai Nam
Teo, Adrian Kee Keong
Rutter, Guy A
Han, Weiping
Type
Journal Article
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.
Date Issued
2021-06-30
Date Acceptance
2021-06-01
Citation
Science Translational Medicine, 2021, 13 (600), pp.1-14
ISSN
1946-6234
Publisher
American Association for the Advancement of Science
Start Page
1
End Page
14
Journal / Book Title
Science Translational Medicine
Volume
13
Issue
600
Copyright Statement
© 2021 American Association for the Advancement of Science. All rights reserved. AAAS is a partner of HINARI, AGORA, OARE, CHORUS, CLOCKSS, CrossRef and COUNTER. Science Translational Medicine ISSN 1946-6234.
Sponsor
MRC Programme Grant
Wellcome Trust
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000678119000002&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
MR/R022259/1
212625/Z/18/Z
Subjects
Science & Technology
Life Sciences & Biomedicine
Cell Biology
Medicine, Research & Experimental
Research & Experimental Medicine
DIABETES-MELLITUS
CYCLIC-AMP
BETA-CELLS
TRANSCRIPTIONAL REGULATION
PANCREATIC-ISLETS
PAX6 MUTATION
EARLY-ONSET
EXPRESSION
CREB
INDUCTION
Publication Status
Published
Article Number
ARTN eabb1038
Date Publish Online
2021-06-30