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Glucose-Stimulated Insulin Production in Mice Deficient for the PAS Kinase PASKIN

¹ Institute of Physiology and ZIHP (Zürich Center for Integrative Human Physiology), University of Zürich, Zürich, Switzerland
² Clinic for Endocrinology and Diabetes, University Hospital Zürich, University of Zürich, Zürich, Switzerland

Address correspondence and reprint requests to Roland H. Wenger, Institute of Physiology, University of Zürich-Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. E-mail: roland.wenger{at}access.unizh.ch

Abbreviations: HBSS, Hank’s balanced salt solution; PAS, Per-ARNT-Sim; PDX-1, pancreatic duodenum homeobox 1; X-gal, 5-bromo-4-chloro-3-indolyl-ß-D-galactopyranoside

The Per-ARNT-Sim (PAS) domain serine/threonine kinase PASKIN, or PAS kinase, links energy flux and protein synthesis in yeast and regulates glycogen synthase in mammals. A recent report suggested that PASKIN mRNA, protein, and kinase activity are increased in pancreatic islet ß-cells under hyperglycemic conditions and that PASKIN is necessary for insulin gene expression. We previously generated Paskin knockout mice by targeted replacement of the kinase domain with the ß-geo fusion gene encoding ß-galactosidase reporter activity. Here we show that no 5-bromo-4-chloro-3-indolyl-ß-D-galactopyranoside (X-gal) staining was observed in islet ß-cells derived from Paskin knockout mice, irrespective of the ambient glucose concentration, whereas adenoviral expression of the lacZ gene in ß-cells showed strong X-gal staining. No induction of PASKIN mRNA could be detected in insulinoma cell lines or in islet ß-cells. Increasing glucose concentrations resulted in PASKIN-independent induction of insulin mRNA levels and insulin release. PASKIN mRNA levels were high in testes but undetectable in pancreas and in islet ß-cells. Finally, blood glucose levels and glucose tolerance after intraperitoneal glucose injection were indistinguishable between Paskin wild-type and knockout mice. These results suggest that Paskin gene expression is not induced by glucose in pancreatic ß-cells and that glucose-stimulated insulin production is independent of PASKIN.

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