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Defective insulin signaling in placenta from pregnancies complicated by gestational diabetes mellitus

¹ Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne and Mercy Perinatal Research Centre, 4th Floor/163 Studley Road, Heidelberg 3084, Victoria, Australia² Translational Proteomic, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia³ Department of Obstetrics and Gynaecology, Medical University of Graz, Graz, Austria

(Correspondence should be addressed to M Colomiere; Email: m.colomiere{at}pgrad.unimelb.edu.au)

Objective: Studies in adipose tissue and skeletal muscle suggest that impaired insulin action is due to defects in the insulin signaling pathway and may play a role in the pathophysiology of insulin resistance associated with gestational diabetes mellitus (GDM) and obesity. The present study tested the hypothesis that endogenous expression levels in the human term placenta of insulin signaling components are altered in placental tissue from GDM women in comparison with normal controls and maternal obesity.

Design and methods: Placental tissue was collected from normal, diet-controlled GDM, and insulin-controlled GDM in both non-obese and obese women (n=6–7 per group). Western blotting and quantitative RT-PCR was performed to determine the level of expression in the insulin signaling pathway.

Results: There was a significant increase in insulin receptor (IR) substrate (IRS)-1 protein expression with a concurrent decrease in IRS-2 protein expression in non-obese women with insulin-controlled GDM compared with diet-controlled GDM and normal controls. Furthermore, a decrease in both protein and mRNA expression of phosphatidyl-inositol-3-kinase (PI3-K) p85 and glucose transporter (GLUT)-4 was observed in non-obese and obese women with insulin controlled GDM compared with normal controls. When comparing non-obese to obese patients, significant decreases in mRNA expression of IR-β, PI3K p85 and GLUT-4 was found in obese patients.

Conclusion: Our results suggest that post receptor defects are present in the insulin signaling pathway in placenta of women with pregnancies complicated by diabetes and obesity. In addition, expression studies demonstrate post receptor alterations in insulin signaling possibly under selective maternal regulation and not fetal regulation.