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

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Title: Paired box 6 programs essential exocytotic genes in the regulation of glucose-stimulated insulin secretion and glucose homeostasis
Authors: So, WY
Liu, WN
Teo, AKK
Rutter, GA
Han, W
Item 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.
Issue Date: 30-Jun-2021
Date of Acceptance: 1-Jun-2021
URI: http://hdl.handle.net/10044/1/91473
DOI: 10.1126/scitranslmed.abb1038
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/Funder: MRC Programme Grant
Wellcome Trust
Funder's Grant Number: MR/R022259/1
212625/Z/18/Z
Keywords: 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
Diabetes Mellitus, Type 2
Glucose
Homeostasis
Humans
Insulin
Insulin Secretion
Insulin-Secreting Cells
Islets of Langerhans
Islets of Langerhans
Humans
Diabetes Mellitus, Type 2
Insulin
Glucose
Homeostasis
Insulin-Secreting Cells
Insulin Secretion
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
06 Biological Sciences
11 Medical and Health Sciences
Publication Status: Published
Article Number: ARTN eabb1038
Online Publication Date: 2021-06-30
Appears in Collections:Department of Metabolism, Digestion and Reproduction
Faculty of Medicine