L-365,260 br Materials and methods br Results br
Materials and methods
Discussion Regardless of obvious beneficial effects of GC on acceleration of foetal lung and cardiomyocytes maturation (Kamath-Rayne et al., 2012; Rog-Zielinska et al., 2015), the current study revealed that GC exposure during late pregnancy induces IR and altered foetal outcome. This finding is in line with previous studies in animals (O’Regan et al., 2004; Gomes et al., 2014) as well as in humans (Di Dalmazi et al., 2012). However, IR which is the predominant mechanism involved in the diabetogenic effects of GC based therapy is an independent risk factor for CVD and has been strongly associated with vascular inflammation (Paneni et al., 2013). From the findings of this study, it is observed that GC exposure in pregnant rats resulted in IR that is accompanied by reduced body weight gain, increased liver weight, decreased visceral adiposity and uterine fat suggesting that the IR induced by gestational GC exposure is independent of body weight gain, visceral and uterine fat accumulation that is expected in pregnancy but associated with liver inflammation and hypertrophy. However, the reduced body weight may be as a result of reduced food intake as observed in this study. Decreased body weight and food intake shown in this study are consistent with previous study that reported that gestational GC exposure led to weight loss (Gomes et al., 2014) and reduced food intake in animal studies (Holness and Sugden, 2001). In addition, gestational GC-induced adverse birth outcome in the present study is in consonance with previous findings in experimental animals (Schwitzgebel et al., 2009). Adverse prenatal environment such as exposure to excess GC have been reported to lead to metabolic imprinting including intrauterine growth restriction (IUGR) characterized by low birth weight and negative impact on the placenta that is needed to sustain foetal growth which are predictive of increased development of CMD such as IR, type 2 diabetes, obesity and hypertension in later life of offsprings (Seckl, 2004; Cunningham et al., 2010). The observed glucose intolerance and elevated fasting blood glucose in this study is in consonance with earlier study (Ferris and Kahn, 2012). These have been the common features of GC exposure and are not unexpected. Previous researches that reported IR during GC exposure have shown controversy concerning insulinemia. Insulin level can be decreased (Jeong et al., 2001) or increased (Protzek et al., 2016) or unaltered (Quarta et al., 2017) during GC treatment, however, our finding in this study shows that GC exposure during late L-365,260 led to hyperinsulinemia that is associated with impaired pancreatic β-cell function. However, various reports exists that hyperinsulinemia elicit inflammation and elevate levels of markers of oxidative stress (Paneni et al., 2013) which is in line with the findings of GC-induced systemic and hepatic oxidative stress and inflammation in the present study. Hepatic inflammation was further confirmed microscopically by histology (Fig. 7). In essence, this present study suggests that the resulting IR induced by GC exposure in pregnancy is associated with compensatory hyperinsulinemia and impaired pancreatic β-cell function. However, as it has been shown in other studies, it is noteworthy that the predominant mechanism responsible for glucose intolerance induced by GC is associated with increased hepatic glucose output, reduced glucose uptake by insulin-responsive tissues (skeletal muscles and adipose tissue) and an impaired disposition index; the proper insulin secretion to match with the reduced peripheral insulin sensitivity (Rafacho et al., 2014; Pasieka and Rafacho, 2016). Evidence exist that hyperuricemia has been reported in individuals with CMD and it is an independent predictor of CVD such as stroke and myocardial infarction (Chaudhary et al., 2013). Also, there are evidences showing the association between elevated uric acid and IR (Krishnan et al., 2012). IR can individually result in inflammation and similarly, there are reports that elevated uric acid also has pro-inﬂammatory effects that interfere with glucose uptake in skeletal muscles and peripheral tissues (Zoccali et al., 2006). However, hyperuricaemia induces vascular inflammation by increasing reactive oxidative species production which in turn lowers nitric oxide concentrations in endothelial cells (Gersch et al., 2008) or by directly reducing endothelial nitric oxide bioavailability in humans as well as in in vitro and in vivo animal studies (Kang et al., 2005; Khosla et al., 2005). Importantly, it is known that nitric oxide generated by endothelial cells plays a major role in the maintenance of vascular homeostasis and reports have shown that reduction in nitric oxide bioavailability which occurs during IR (Muniyappa and Sowers, 2013) and oxidative stress conditions (Khosla et al., 2005) promotes vascular inflammation and atherosclerosis. Hence, the findings of the present study that gestational GC exposure resulted in elevated oxidative stress levels, increased pro-inflammatory biomarkers such as hyperuricaemia, and reduced nitric oxide is of utmost importance suggesting the increased risk of developing vascular inflammation and endothelial dysfunction.