Cell type-specific deletion in mice reveals roles for PAS kinase in insulin and glucagon production

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Title: Cell type-specific deletion in mice reveals roles for PAS kinase in insulin and glucagon production
Authors: Rutter, GA
Semplici, F
Mondragon, A
Macintyre, B
Madeyski-Bengston, K
Persson-Kry, A
Ramne, A
Marley, A
McGinty, J
French, P
Soedling, H
Yokosuka, R
Gaiten, J
Lang, J
Migrenne-Li, S
Philippe, E
Herrera, PL
Magnan, C
Da Silva Xavier, G
Item Type: Journal Article
Abstract: © 2016 The Author(s)Aims/hypothesis: Per-Arnt-Sim kinase (PASK) is a nutrient-regulated domain-containing protein kinase previously implicated in the control of insulin gene expression and glucagon secretion. Here, we explore the roles of PASK in the control of islet hormone release, by generating mice with selective deletion of the Pask gene in pancreatic beta or alpha cells. Methods: Floxed alleles of Pask were produced by homologous recombination and animals bred with mice bearing beta (Ins1Cre; PaskBKO) or alpha (PpgCre [also known as Gcg]; PaskAKO) cell-selective Cre recombinase alleles. Glucose homeostasis and hormone secretion in vivo and in vitro, gene expression and islet cell mass were measured using standard techniques. Results: Ins1Cre-based recombination led to efficient beta cell-targeted deletion of Pask. Beta cell mass was reduced by 36.5% (p < 0.05) compared with controls in PaskBKO mice, as well as in global Pask-null mice (38%, p < 0.05). PaskBKO mice displayed normal body weight and fasting glycaemia, but slightly impaired glucose tolerance, and beta cell proliferation, after maintenance on a high-fat diet. Whilst glucose tolerance was unaffected in PaskAKO mice, glucose infusion rates were increased, and glucagon secretion tended to be lower, during hypoglycaemic clamps. Although alpha cell mass was increased (21.9%, p < 0.05), glucagon release at low glucose was impaired (p < 0.05) in PaskAKO islets. Conclusions/interpretation: The findings demonstrate cell-autonomous roles for PASK in the control of pancreatic endocrine hormone secretion. Differences between the glycaemic phenotype of global vs cell type-specific null mice suggest important roles for tissue interactions in the control of glycaemia by PASK.
Issue Date: 24-Jun-2016
Date of Acceptance: 25-May-2016
URI: http://hdl.handle.net/10044/1/33595
DOI: https://dx.doi.org/10.1007/s00125-016-4025-1
ISSN: 1432-0428
Publisher: Springer Verlag
Start Page: 1938
End Page: 1947
Journal / Book Title: Diabetologia
Volume: 59
Issue: 9
Copyright Statement: © The Author(s) 2016. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Sponsor/Funder: Diabetes UK
Medical Research Council (MRC)
Diabetes UK
Wellcome Trust
Diabetes UK
European Foundation for the Study of Diabetes
European Foundation for the Study of Diabetes
Rosetrees Trust
Diabetes UK
Funder's Grant Number: BDA No:11/0004210- P/O 12705
BDA number 13/0004672
Keywords: Basic science
Beta cell signal transduction
PAS kinase
Endocrinology & Metabolism
1103 Clinical Sciences
1114 Paediatrics And Reproductive Medicine
1117 Public Health And Health Services
Publication Status: Published
Appears in Collections:Physics
Department of Medicine
Faculty of Medicine
Faculty of Natural Sciences

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