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  • The observed glucose intolerance and elevated fasting

    2022-06-23

    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 gestation 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 Trimidox 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. Also, our data from this study indicate that gestational GC exposure altered hematological and hemorheological parameters, however reports exist that altered blood rheological markers are associated with atherosclerosis and CVD (Tzoulaki et al., 2007). Also, the platelet to lymphocyte ratio (PLR) has been recently reported to be a reliable marker of inflammation and resulting atherothrombotic CVD events (Koseoglu et al., 2015). Hence, the findings in this present study that gestational GC exposure caused altered hematological markers that are associated with increased blood viscosity. Interestingly, in the current study is that gestational GC exposure led to increased endoglin that is associated with impaired glucose homeostasis. The finding of La Sala and coworkers that hyperglycemia upregulates endoglin expression and release in diabetes (La Sala et al., 2015), further corroborate the report of the current study and suggest a connection between endoglin and glucose homeostasis. Although, endoglin is required for normal angiogenesis during foetal development as endoglin null embryos die at 10–11.5 days due to vascular and cardiac abnormalities (Arthur et al., 2000; Li et al., 2003). Several studies have reported elevated endoglin in numerous vascular pathological events, including active site of inflamed tissues, atherosclerosis, in response to arterial injury (Sánchez-Elsner et al., 2002), in wound healing (Torsney et al., 2002), preeclampsia, systemic sclerosis or tumor angiogenesis (Ten Dijke et al., 2008; Wipff et al., 2008) and endometriosis (Fujishita et al., 1999). Several published studies have reported that endoglin negatively regulates TGF-β-mediated signalling in quiescent endothelium (Lebrin et al., 2004) and is involved in endothelial proliferation in response to an injury (Lopez-Novoa and Bernabeu, 2010) and in the inflammation (Rossi et al., 2013).