School of Clinical and Experimental MedicineInstitute of Biomedical Research, Centre for Endocrinology, Diabetes and Metabolism, Queen Elizabeth Hospital, University of Birmingham, Birmingham B15 2TT, UKNIHR/Wellcome Trust Clinical Research FacilityQueen Elizabeth Hospital, Birmingham, UK.
School of Clinical and Experimental MedicineInstitute of Biomedical Research, Centre for Endocrinology, Diabetes and Metabolism, Queen Elizabeth Hospital, University of Birmingham, Birmingham B15 2TT, UKNIHR/Wellcome Trust Clinical Research FacilityQueen Elizabeth Hospital, Birmingham, UK
Eur J Endocrinol. 2014 Oct;171(4):433-42. doi: 10.1530/EJE-14-0256. Epub 2014 Jul 1.
Dysregulation of enzymes that control local tissue steroid metabolism has been implicated in the pathogenesis of obesity and insulin resistance; however, longitudinal changes in glucocorticoid metabolism have not been investigated. This study was performed to evaluate the role of glucocorticoid metabolism in the development of insulin resistance and obesity and to identify biomarkers for future development of metabolic disease.
This was a prospective longitudinal observation study conducted over 5 years.
A 24-h collection was used to serially analyze urinary glucocorticoid and mineralocorticoid metabolites in 57 obese and overweight patients with no prior diagnosis of diabetes mellitus, recruited from the community.
Baseline higher 5α-reductase (5αR) activity, but not 11β-hydroxysteroid dehydrogenase type 1 activity, was predictive of increased fasting insulin at final visit (11.4 compared with 7.4 mU/l in subjects with lower 5αR activity, P<0.05), area under the curve insulin response to oral glucose tolerance test (176.7 compared with 89.1 mU/l.h, P<0.01), and homeostasis model assessment (HOMA2-IR; 1.3 compared with 0.8, P<0.01). Higher total glucocorticoid production was associated with abnormal glucose tolerance and increased BMI. During this study, systolic blood pressure increased (equivalent to ∼1 mmHg/year), as did plasma sodium levels; this evidence of increased mineralocorticoid activity was associated with increased aldosterone metabolites and decreased 11β-hydroxysteroid dehydrogenase type 2 activity.
Increased 5αR activity and glucocorticoid secretion rate over time are linked with the development of metabolic disease, and may represent targets for therapeutic intervention, which merits further study.
控制局部组织类固醇代谢的酶的失调与肥胖和胰岛素抵抗的发病机制有关；然而，尚未研究糖皮质激素代谢的纵向变化。本研究旨在评估糖皮质激素代谢在胰岛素抵抗和肥胖发展中的作用，并确定代谢性疾病未来发展的生物标志物。
这是一项为期 5 年的前瞻性纵向观察研究。
对 57 名无糖尿病既往诊断的肥胖和超重社区患者进行了 24 小时尿液采集，以连续分析尿糖皮质激素和盐皮质激素代谢物。
基线时较高的 5α-还原酶（5αR）活性（而非 11β-羟类固醇脱氢酶 1 型活性）可预测最终访视时空腹胰岛素升高（5αR 活性较低的受试者为 11.4 比 7.4 mU/l，P<0.05）、口服葡萄糖耐量试验胰岛素反应的曲线下面积（176.7 比 89.1 mU/l.h，P<0.01）和稳态模型评估（HOMA2-IR；1.3 比 0.8，P<0.01）。总糖皮质激素生成增加与葡萄糖耐量异常和 BMI 增加有关。在此期间，收缩压升高（相当于每年增加约 1mmHg），血浆钠水平也升高；这种醛固酮活性增加的证据与醛固酮代谢物增加和 11β-羟类固醇脱氢酶 2 活性降低有关。
随着时间的推移，5αR 活性和糖皮质激素分泌率的增加与代谢性疾病的发展有关，可能代表治疗干预的靶点，值得进一步研究。
