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Effects of diazoxide on gene expression in rat pancreatic islets are largely linked to elevated glucose and potentially serve to enhance beta cell sensitivity

¹Endocrine and Diabetes Unit, Department of Molecular Medicine and Surgery, Karolinska Hospital, Karolinska Institutet, S-171 76 Stockholm, Sweden
²Dept. of Biosciences, NOVUM, 14157 Huddinge, Sweden
³Endocrine Unit, Dept. of Abdominal Diseases, St. Olav's University Hospital, Norwegian University of Science and Technology, N-7006 Trondheim, Norway

Correspondence: anneli.bjorklund{at}ki.se

Diazoxide enhances glucose-induced insulin secretion from beta cells through mechanisms which are not fully elucidated. Here we used microarray analysis (Affymetrix) to investigate effects of diazoxide. Pancreatic islets were cultured overnight at 27 or 11 or 5.5 mmol/l glucose ± diazoxide. Inclusion of diazoxide up-regulated altogether 211 genes (signal log₂ ratio 0.5) and down-regulated 200 genes (signal log₂ ratio-0.5). 92 % of diazoxide's effects (up- and downregulation) were observed only after co-culture with 11 or 27 mmol/l glucose. At 11 mM diazoxide up-regulated 97 genes and down-regulated 21 genes. Increasing the glucose concentration to 27 mmol/l markedly shifted these proportions toward down-regulation (101 genes up- regulated, 160 genes down-regulated). At 27 mmol/l glucose most genes down-regulated by diazoxide were oppositely affected by glucose (80%). Diazoxide influenced expression of several genes central to beta cell metabolism. Diazoxide down-regulated genes of fatty acid oxidation, up-regulated genes of fatty acid synthesis and down-regulated uncoupling protein 2 and lactic acid dehydrogenase, Diazoxide up-regulated certain genes known to support ß-cell functionality, such as nkx6.1 and pdx 1. - Long term elevated glucose is permissive for most of diazoxide's effects on gene expression, the proportion of effects shifting to down-regulation with increasing glucose concentration. Effects of diazoxide on gene expression could serve to enhance ß-cell functionality during continuous hyperglycemia.

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