Background and Aims. Per-Arnt-Sim domain containing kinase (PASK) is a nutrient regulated protein kinase previously implicated in the control of insulin gene expression and glucagon secretion. Here, we explore the roles of the kinase in the control of islet hormone release by generating mice deleted selectively for 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 (PPG-
Cre; 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 to controls in PaskBKO mice, as well as in global null Pask mice (38%, p<0.05). PaskBKO mice displayed normal body weight and fasting glycemia, 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 lowe
r, during hypoglycemic clamps. Though alpha cell mass was increased (21.9%, p<0.05), glucagon release at low glucose was impaired (p<0.05) in
PaskAKO islets.

Conclusions. The present findings demonstrate cell autonomous roles for PASK in the control of pancreatic endocrine hormone secretion. Differences
between the glycemic phenotype of global versus cell type specific null mice suggest important roles for tissue interactions in the control of glycemia by the kinase.