Abstract:

Synthetic glucocorticoids such as dexamethasone are widely used to treat a variety of inflammatory and autoimmune conditions, but they may induce adverse events including hyperglycemia. To shed light on the effect and action mechanism
of dexamethasone, we examined the alterations of gene expression levels caused by dexamethasone.Microarray analysis was performed on whole blood collected from 24 physically healthy subjects at baseline and after dexamethasone administration. The expression levels of resistin mRNA were found to be significantly increased after the dexamethasone administration. In a separate sample of 12 subjects, we examined plasma resistin protein levels and found that they were increased after dexamethasone administration. Furthermore, the plasma mRNA and protein levels of resistin were significantly higher in individuals who carried the A allele of RETN single nucleotide polymorphism rs3219175 than in those who did not carry the allele. There was no significant interaction between the genotype and dexamethasone administration. No significant correlation was found between plasma levels of cortisol and resistin. Consistent with previous studies, the genotype of RETN rs3219175 was a strong determinant of resistin levels. The present study showed that oral administration of dexamethasone increases the protein and mRNA levels of resistin irrespective of the rs3219175 genotype.

日本語要旨:

身体的に健康な対象者24名において、ベースライン及びデキサメサゾン(合成グルココルチコイド)経口投与後の全血中mRNA発現量をマイクロアレイで解析したところ、耐糖能異常において重要な役割を果たすレジスチンの発現量がデキサメサゾン投与後に有意に増加していた。別の対象者12名においてベースライン及びデキサメサゾン経口投与後の血漿レジスチン濃度を測定したところ、デキサメサゾン投与後に有意な増加を認めた。RETN rs3219175のＡアレルを保有する対象者は非保有者と比較して、全血中のレジスチンmRNA発現量及び血漿中レジスチン蛋白濃度が有意に高かったが、デキサメサゾン投与はいずれのrs3219175遺伝子型においても血中レジスチン濃度を増加させることが示された。本研究結果から、耐糖能異常の分子基盤としてストレスホルモンと遺伝子多型との相互作用が関与する可能性が示唆された。