Rapid opposite effects of glucose on XBP1 mRNA unconventional splicing and GADD153 expression in cultured rat islets

Excessive activation of the endoplasmic reticulum (ER) stress pathway by chronic hyperglycemia may contribute to [beta]-cell apoptosis in type 2 diabetes. To test whether glucose induces ER stress in [beta]-cells, XBP1 mRNA unconventional splicing and GADD153 mRNA and protein levels were measured in rat islets precultured for 1 week in 10 mmol/l glucose (G10) and further cultured for 18 h in G2, G5, G10, or G30. As expected, 1 [micro]mol/l thapsigargin, an inhibitor of ER [Ca.sup.2+]-ATPases that triggers ER stress in various cell types, increased islet XBP1 mRNA splicing and GADD153 expression (3- and 10-fold, respectively) in G10. In contrast, glucose exerted opposite effects on these two ER stress markers: a two- and threefold increase in XBP1 mRNA splicing after culture in G10 and G30 versus G2-G5 and an ~40 and ~90% reduction in GADD153 expression after culture in G5 and G10-G30 versus G2. After an overnight culture in G5 and further culture in G30, the increase in XBP1 mRNA splicing and decrease in GADD153 mRNA levels occurred within 2 h of stimulation. In conclusion, in contrast with thapsigargin, glucose activates only part of the ER stress pathway while reducing expression of the pro-apoptotic factor GADD153. These rapid glucose effects may play a physiological role in nutrient-induced maintenance of the [beta]-cell phenotype.
From the Unit of Endocrinology and Metabolism, Faculty of Medicine, Universite Catholique de Louvain, Brussels, Belgium. Address correspondence to Jean-Christophe Jonas. E-mail: jonas@ [...]