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Gene Networks Modified by Sulphonylureas in Beta Cells: A Pathway‐based Analysis of Insulin Secretion and Cell Death
Author(s) -
Magnusson Nils E.,
Dyrskjøt Lars,
Grimm Daniela,
Wehland Markus,
Pietsch Jessica,
Rungby Jørgen
Publication year - 2012
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2012.00902.x
Subject(s) - glimepiride , glibenclamide , insulin , gliclazide , beta cell , programmed cell death , medicine , endocrinology , biology , secretion , diabetes mellitus , sulfonylurea receptor , islet , apoptosis , biochemistry , metformin
Sulphonylureas ( SU s) used in the treatment for type 2 diabetes have been shown to result in different clinical outcome. This study hypothesized that three widely used SU s, glibenclamide, glimepiride and gliclazide, may affect function and survival of insulin‐producing cells differently. To evaluate differences between SU s, insulin secretion and cell death were measured, and genome‐wide gene expression patterns were compared using a bioinformatics approach focusing on functional relationships between molecules. Insulin‐producing INS ‐1 E cells exposed to SU s for 6 and 24 hr were assayed using G ene C hip. Cluster and pathway analyses were used to identify differentially expressed genes and patterns of potential biological functions associated with SU treatment. Cell death was measured using acridine orange/ H oechst 33342 staining. Short‐term treatment (6 hr) yielded up‐regulation of insulin secretion and genes associated with insulin secretion for all three SUs applied. While long‐term treatment (24–72 hr) with gliclazide did not change gene expression or cell survival, treatment with glibenclamide or glimepiride up‐regulated genes associated with oxidative stress and hypoxia, but did not induce cell death. Short‐term treatment with SU s initiates gene regulation that can be attributed to insulin secretion with few differences between individual SU s. This regulation was temporal and returned to baseline after 24 hr. Individual differences observed after 24–72 hr indicate that glibenclamide and glimepiride induce potentially harmful cell signalling insufficient for triggering beta cell death.