Diabetes and obesity during pregnancy alter insulin signalling and glucose transporter expression in maternal skeletal muscle and subcutaneous adipose tissue

Abstract

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 (nZ6-8 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) p85a, 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 p85a 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.

NOD1 expression is increased in the adipose tissue of women with gestational diabetes

“…Collectively, these results indicate that NOD1 activation may facilitate the infiltration of leukocytes into adipose tissue, leading to adipose inflammation, a key feature of GDM pregnancies (Lappas 2013a, Oliva et al 2013. Moreover, NOD1-mediated release of pro-inflammatory cytokines from adipose tissue may directly contribute to the insulin resistance that is evident in pregnancies complicated by GDM (Catalano et al 2002, Colomiere et al 2010. In keeping with this, the data presented in this paper indicates that NOD1 activation induces attenuation of insulin signalling, which leads to suppression of insulin-induced glucose uptake.…”

“…In women with GDM, expression of GLUT4 (SLC2A4) gene and subsequent glucose uptake are lower in adipose tissue (Garvey et al 1993, Colomiere et al 2010. Given that NOD1 expression was higher in adipose tissue obtained from women with GDM, the next aim of this study was to determine the effect of the NOD1 ligand iE-DAP on insulin signalling in adipose tissue from pregnant women.…”

“…There is now some evidence that metabolic endotoxemia originating from the diet or the environment disrupts the balance between the immune and the metabolic systems (Cani et al 2007) which may lead to GDM. Thus, it is possible that this increase in bacteria may activate NOD1, leading to the increased inflammation and insulin resistance observed in women with GDM (Garvey et al 1993, Colomiere et al 2010, Lappas 2013a, Oliva et al 2013. Indeed, it has recently been shown that dietinduced modification of the gut flora with probiotics can ameliorate the insulin resistance and glucose homoeostasis of pregnant women (Laitinen et al 2009).…”

“…Thus, NOD1 may be one of the mechanisms causing the peripheral insulin resistance observed in GDM (Garvey et al 1993, Colomiere et al 2010). In agreement, other studies have also shown an important role for NOD1 in insulin action.…”

“…For example, maternal adipose tissue's insulin resistance, an important adaptation that occurs in the later part of pregnancy, is even more pronounced in women with GDM (Catalano et al 2002, Colomiere et al 2010, resulting in greater foetal substrate availability and thus enhanced adiposity (Lain & Catalano 2007). Maternal adipose tissue also synthesises and secretes a number of inflammatory mediators, which are dysregulated in obese and GDM pregnancies, that have been shown to correlate with foetal adiposity (Kautzky-Willer et al 1997, Krauss et al 2002, Radaelli et al 2006.…”