糖皮质激素对人皮下脂肪组织中胰岛素信号传导的调节作用。
Glucocorticoid modulation of insulin signaling in human subcutaneous adipose tissue.
作者信息
Gathercole Laura L, Bujalska Iwona J, Stewart Paul M, Tomlinson Jeremy W
机构信息
Institute of Biomedical Research, Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TT, United Kingdom.
出版信息
J Clin Endocrinol Metab. 2007 Nov;92(11):4332-9. doi: 10.1210/jc.2007-1399. Epub 2007 Aug 21.
CONTEXT
Glucocorticoid (GC) excess is characterized by central obesity, insulin resistance, and in some cases, type 2 diabetes. However, the impact of GC upon insulin signaling in human adipose tissue has not been fully explored.
OBJECTIVE
We have examined the effect of GC upon insulin signaling in both human sc primary preadipocyte cultures and a novel human immortalized sc adipocyte cell line (Chub-S7) and contrasted this with observations in primary cultures of human skeletal muscle.
DESIGN AND SETTING
This is an in vitro study characterizing the impact of GC upon insulin signaling in human tissues.
PATIENTS
Biopsy specimens were from healthy volunteers who gave their full and informed written consent.
INTERVENTIONS
Combinations of treatments, including GC, RU38486, and wortmannin, were used.
MAIN OUTCOME MEASURES
Insulin signaling cascade gene and protein expression and insulin-stimulated glucose uptake were determined.
RESULTS
In human adipocytes, pretreatment with GC induced a dose-dependent [1.0 (control); 1.2 +/- 0.1 (50 nm); 2.2 +/- 0.2 (250 nm), P < 0.01 vs. control; 3.4 +/- 0.2 (1000 nm), P < 0.001 vs. control] and time-dependent [1.0 (1 h); 3.2 +/- 2.0 (6 h); 9.1 +/- 5.9 (24 h), P < 0.05 vs. 1 h; 4.5 +/- 2.2 (48 h)] increase in insulin-stimulated protein kinase B/akt phosphorylation. In addition, whereas insulin receptor substrate (IRS)-1 protein expression did not change, IRS-1 tyrosine phosphorylation increased. Furthermore, GC induced IRS-2 mRNA expression (2.8-fold; P < 0.05) and increased insulin-stimulated glucose uptake [1.0 (control) 1.8 +/- 0.1 (insulin) vs. 2.8 +/- 0.2 (insulin + GC); P < 0.05]. In contrast, in primary cultures of human muscle, GC decreased insulin-stimulated glucose uptake [1.0 (control) 1.9 +/- 0.2 (insulin) vs. GC 1.3 +/- 0.1 (insulin + GC); P < 0.05].
CONCLUSIONS
We have demonstrated tissue-specific regulation of insulin signaling by GC. Within sc adipose tissue, GCs augment insulin signaling, yet in muscle GCs cause insulin resistance. We propose that enhanced insulin action in adipose tissue increases adipocyte differentiation, thereby contributing to GC-induced obesity.
背景
糖皮质激素（GC）过量的特征为中心性肥胖、胰岛素抵抗，在某些情况下还会引发2型糖尿病。然而，GC对人体脂肪组织中胰岛素信号传导的影响尚未得到充分研究。
目的
我们研究了GC对人皮下原代前脂肪细胞培养物和一种新型人永生化皮下脂肪细胞系（Chub-S7）中胰岛素信号传导的影响，并将其与人体骨骼肌原代培养物中的观察结果进行对比。
设计与环境
这是一项体外研究，旨在表征GC对人体组织中胰岛素信号传导的影响。
患者
活检标本来自给予充分知情书面同意的健康志愿者。
干预措施
使用了包括GC、RU38486和渥曼青霉素在内的多种治疗组合。
主要观察指标
测定胰岛素信号级联基因和蛋白表达以及胰岛素刺激的葡萄糖摄取。
结果
在人脂肪细胞中，GC预处理诱导胰岛素刺激的蛋白激酶B/akt磷酸化呈剂量依赖性增加[1.0（对照）；1.2±0.1（50 nM）；2.2±0.2（250 nM），与对照相比P<0.01；3.4±0.2（1000 nM），与对照相比P<0.001]和时间依赖性增加[1.0（1小时）；3.2±2.0（6小时）；9.1±5.9（24小时），与1小时相比P<0.05；4.5±2.2（48小时）]。此外，虽然胰岛素受体底物（IRS）-1蛋白表达未改变，但IRS-1酪氨酸磷酸化增加。此外，GC诱导IRS-2 mRNA表达（2.8倍；P<0.05）并增加胰岛素刺激的葡萄糖摄取[1.0（对照），1.8±0.1（胰岛素）对2.8±0.2（胰岛素+GC）；P<0.05]。相比之下，在人体肌肉原代培养物中，GC降低了胰岛素刺激的葡萄糖摄取[1.0（对照），1.9±0.2（胰岛素）对GC 1.3±0.1（胰岛素+GC）；P<0.05]。
结论
我们证明了GC对胰岛素信号传导的组织特异性调节。在皮下脂肪组织中，GC增强胰岛素信号传导，但在肌肉中GC导致胰岛素抵抗。我们提出，脂肪组织中增强的胰岛素作用增加了脂肪细胞分化，从而导致GC诱导的肥胖。
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