Gene networks modified by sulphonylureas in beta cells: a pathway-based analysis of insulin secretion and cell death.
Sulphonylureas (SUs) used in the treatment for type 2 diabetes have been shown to result in different clinical outcome. This study hypothesized that three widely used SUs, glibenclamide, glimepiride and gliclazide, may affect function and survival of insulin-producing cells differently. To evaluate differences between SUs, 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-1E cells exposed to SUs for 6 and 24 hr were assayed using GeneChip. 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/Hoechst 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 SUs initiates gene regulation that can be attributed to insulin secretion with few differences between individual SUs. 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.
Institute of Biomedicine, Pharmacology, University of Aarhus, Aarhus, Denmark. nm@farm.au.dk
Nils E
NE
Magnusson
Lars
L
Dyrskjøt
Daniela
D
Grimm
Markus
M
Wehland
Jessica
J
Pietsch
Jørgen
J
Rungby
D000818:Animals; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D016000:Cluster Analysis; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D053263:Gene Regulatory Networks; D005907:Gliclazide / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D046228:Microarray Analysis; D051381:Rats; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D015854:Up-Regulation
D007004:Hypoglycemic Agents; D007328:Insulin; D013453:Sulfonylurea Compounds; C057619:glimepiride; D005907:Gliclazide; D005905:Glyburide