Department of Obstetrics and Gynaecology, Mercy Perinatal Research Centre, Mercy Hospital for Women, University of Melbourne, 4th Floor, 163 Studley Road, Heidelberg 3084, Victoria, Australia.
J Mol Endocrinol. 2010 Apr;44(4):213-23. doi: 10.1677/JME-09-0091. Epub 2009 Dec 2.
Severe insulin resistance is a defining attribute of gestational diabetes mellitus (GDM). It is postulated that alterations in the insulin-signalling pathway and subsequent glucose disposal are the underlying cause of insulin resistance in patients with GDM. The purpose of this study was to profile the insulin-signalling pathway and intermediates in insulin-sensitive tissues. Subcutaneous adipose tissue and skeletal muscle were collected from normal glucose-tolerant (NGT) and insulin-controlled GDM in both non-obese and obese cohorts (n=6-8 per subgroup). Expression studies of the insulin-signalling pathway were performed using western blotting and quantitative reverse transcription-PCR. This study demonstrated altered mRNA expression of insulin receptor substrate (IRS)-1, IRS-2, glucose transporter (GLUT)-1, GLUT-4 and glycogen synthase kinase (GSK)-3 isoforms genes in adipose tissue in GDM women in comparison to NGT pregnant controls. In skeletal muscle, insulin-controlled GDM was associated with decreased IRS-1, phosphatidylinositol-3-kinase (PI3-K) p85alpha, GLUT-1 and -4, GSK-3 isoforms and phosphoinositide-dependent kinase-1. Both adipose tissue and skeletal muscle from women with GDM displayed decreased IRS-1 and GLUT-4 and increased PI3-K p85alpha protein expression. Both skeletal muscle and adipose tissue from obese women demonstrated lower GLUT-1 and -4 mRNA expression and diminished GLUT-4 protein expression in skeletal muscle only. Collectively, our results suggest that diabetes and obesity during pregnancy cause defects in insulin-signalling transduction in adipose tissue and skeletal muscle and may be the underlying cause of GDM.
严重的胰岛素抵抗是妊娠期糖尿病（GDM）的一个明确特征。据推测，胰岛素信号通路的改变以及随后的葡萄糖处置是 GDM 患者胰岛素抵抗的根本原因。本研究的目的是分析胰岛素信号通路和胰岛素敏感组织中的中间产物。从糖耐量正常（NGT）和经胰岛素控制的非肥胖和肥胖 GDM 患者（每组 6-8 例）的皮下脂肪组织和骨骼肌中采集样本。使用 Western blot 和定量逆转录 PCR 进行胰岛素信号通路的表达研究。本研究表明，与 NGT 妊娠对照组相比，GDM 女性的脂肪组织中胰岛素受体底物（IRS）-1、IRS-2、葡萄糖转运体（GLUT）-1、GLUT-4 和糖原合酶激酶（GSK）-3 同工型基因的 mRNA 表达发生改变。在骨骼肌中，经胰岛素控制的 GDM 与 IRS-1、磷酸肌醇-3-激酶（PI3-K）p85alpha、GLUT-1 和 -4、GSK-3 同工型和磷酸肌醇依赖性激酶-1 的减少有关。GDM 女性的脂肪组织和骨骼肌均表现出 IRS-1 和 GLUT-4 的减少以及 PI3-K p85alpha 蛋白表达的增加。肥胖女性的骨骼肌和脂肪组织均表现出较低的 GLUT-1 和 -4 mRNA 表达，仅在骨骼肌中 GLUT-4 蛋白表达减少。总之，我们的结果表明，妊娠期间的糖尿病和肥胖会导致脂肪组织和骨骼肌中胰岛素信号转导缺陷，这可能是 GDM 的根本原因。
