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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 ß-Cell Sensitivity

¹ Endocrine and Diabetes Unit, Department of Molecular Medicine and Surgery, Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden
² Department of Biosciences, Novum, Huddinge, Sweden
³ Endocrine Unit, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
⁴ Department of Endocrinology, St. Olav's University Hospital, Trondheim, Norway

Address correspondence and reprint requests to Anneli Björklund, MD, PhD, Endocrine Lab L6B: 01, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail: anneli.bjorklund{at}ki.se

Abbreviations: CREM, cAMP response element modulator; UCP, uncoupling protein-2

Diazoxide enhances glucose-induced insulin secretion from ß-cells through mechanisms that are not fully elucidated. Here, we used microarray analysis (Affymetrix) to investigate effects of diazoxide. Pancreatic islets were cultured overnight at 27, 11, or 5.5 mmol/l glucose with or without diazoxide. Inclusion of diazoxide upregulated altogether 211 genes (signal log₂ ratio 0.5) and downregulated 200 genes (signal log₂ ratio –0.5 or lower), and 92% of diazoxide's effects (up- and downregulation) were observed only after coculture with 11 or 27 mmol/l glucose. We found that 11 mmol/l diazoxide upregulated 97 genes and downregulated 21 genes. Increasing the glucose concentration to 27 mmol/l markedly shifted these proportions toward downregulation (101 genes upregulated and 160 genes downregulated). At 27 mmol/l glucose, most genes downregulated by diazoxide were oppositely affected by glucose (80%). Diazoxide influenced expression of several genes central to ß-cell metabolism. Diazoxide downregulated genes of fatty acid oxidation, upregulated genes of fatty acid synthesis, and downregulated uncoupling protein 2 and lactic acid dehydrogenase. Diazoxide upregulated certain genes known to support ß-cell functionality, such as NKX6.1 and PDX1. Long-term elevated glucose is permissive for most of diazoxide's effects on gene expression, the proportion of effects shifting to downregulation with increasing glucose concentration. Effects of diazoxide on gene expression could serve to enhance ß-cell functionality during continuous hyperglycemia.

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