Earlier studies have reported contrasting findings

Earlier studies have reported contrasting findings on the effect of GC exposure on DPP-4 activity such as diminished DPP-4 activity on cultured human dermal fibroblasts (Sorrell et al., 2003), increased DPP-4 activity in thymocyte of male rats (Kraml et al., 2003) and unaltered circulating DPP-4 activity in asthmatic patients (Van Der Velden et al., 1999). However, it is interesting to note that the diabetogenic effect of GC exposure during late pregnancy was accompanied by elevated DPP-4 activity in this study. The report of Quarta and coworkers support the involvement of DPP-4 in GC-induced gluco-metabolic dysfunction because mice treated with glucagon-like peptide-1 (GLP-1) had improved glucose homeostasis while GC-exposed mice had impaired glucose homeostasis (Quarta et al., 2017). Elevated DPP-4 activity has been strongly associated with diabetes mellitus, IR (Röhrborn et al., 2015), metabolic syndrome (Lamers et al., 2011) and inflammation (Zhong et al., 2015). However, report has it that GC exposure increases DPP-4activity in thymocyte homogenates (Kraml et al., 2003) but to the best of our knowledge, this is the first study that report elevated DPP-4 activity in GC-exposed rats during late pregnancy. However, one of the most remarkable findings from this study is that gestational GC exposure in female rats caused elevated DPP-4 activity suggesting that the glucose dysregulation induced by gestational GC exposure is DPP-4 dependent in female rats. Glycogen synthase kinase-3 (GSK-3), a multi-tasking and housekeeping enzyme that has widespread influences on many cellular functions, plays an important role in Eltrombopag metabolism, however, it is constitutively active in resting cells (Guo et al., 2016). It constitutes part of the insulin signalling pathway and has been reported to be involved in the pathogenesis of IR and diabetes mellitus (Nikoulina et al., 2000). Nevertheless, there has been conflicting documents on the role of GSK-3 in GC-induced IR. There are reports that GC-induced IR can either be associated or not associated with GSK-3 (Ruzzin et al., 2005; Vaughan et al., 2015) although GC has been reported to induce pancreatic β-cell apoptosis through GSK-3-dependent pathway that was accompanied by oxidative stress (Guo et al., 2016). Another study showed that GSK-3 is involved in oxidative stress-induced GC insensitivity in chronic obstructive pulmonary disease patients (Ngkelo et al., 2015). Furthermore, the role of GSK-3 in the pathogenesis of inflammation has been widely documented as it accompanies inflammatory conditions such as diabetes mellitus, mood disorders, Alzheimer’s disease, cancer (Jope et al., 2007), and has been associated with atherothrombotic CVD events. However, another interesting finding in this study is that gestational GC exposure in rats decreases GSK-3 which is contrary to our previous finding where nicotine-/or COC-treatment in female rats led to increased GSK-3 accompanied with glucose deregulation and elevated circulating GC. In the same study, decreased GSK-3 was associated with improved gluco-metabolic function (Michael and Olatunji, 2017). Therefore, the finding of the current study suggest that the development of gluco-metabolic dysfunction in this animal model of gestational GC-induced IR is through GSK-3-independent but endoglin-/DPP-4-dependent pathway in female rats.