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

Research output: Contribution to journalArticlepeer-review

Authors

  • Francesca Semplici
  • Angeles Mondragon
  • Benedict Macintyre
  • Katja Madeyski-Bengston
  • Anette Persson-Kry
  • Sara Barr
  • Anna Ramne
  • Anna Marley
  • James A Mcginty
  • Paul M French
  • Helen Soedling
  • Ryohsuke Yokosuka
  • Julien Gaitan
  • Jochen Lang
  • Stéphanie Migrenne Li
  • Erwann Philippe
  • Pedro L Herrera
  • Christophe Magnan
  • Guy A Rutter

Colleges, School and Institutes

Abstract

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 (Ins1 Cre; PaskBKO) or alpha (Ppg Cre [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: Ins1 Cre-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.

Details

Original languageEnglish
Pages (from-to)1938-1947
Number of pages10
JournalDiabetologia
Volume59
Issue number9
Early online date24 Jun 2016
Publication statusPublished - Sep 2016

Keywords

  • Basic science, Beta cell signal transduction, Islets, Mouse, PAS kinase