Akt/mTOR Role in Human Foetoplacental Vascular Insulin Resistance in Diseases of Pregnancy

Figure 3

Potential involvement of Akt/mTOR in insulin resistance in the human foetoplacental unit from diseases of pregnancy. Pregestational maternal obesity (PGMO), gestational diabetes mellitus (GDM), and preeclampsia are diseases of pregnancy where the human foetoplacental endothelial function is reduced. The response of the placenta to insulin results from activation of insulin receptor A (IR-A) via preferential signalling through Src homology 2 domain-containing transforming protein 1 type A (IR-A/SHcA) and insulin receptor B (IR-B) via preferential signalling through insulin receptor substrates (IR-B/IRSs). The effect of PGMO (represented as orange bars), GDM (represented as green bars), and PE (represented as blue bars) in the cell signalling triggered by insulin causes an increase (+) or a decrease (−) in the expression and activity of the indicated associated signalling molecules for each pathology. The defective action of insulin is also documented for a reduced (⇩) activity of protein kinase B/Akt (Akt) due to signalling molecules that are reported for PGMO and early onset PE (EOPE), a phenomenon that is less clear (?) in GDM pregnancies. Reduced Akt activity results in reduced expression and activity of the mammalian target of rapamycin (mTOR) and its signalling in cells from PGMO, with a not clear mechanism (?) in GDM and PE. These changes result in reduced activation of the endothelial nitric oxide (NO) synthase (eNOS) activity leading to lower NO generation in PGMO and EOPE but increased eNOS activity in GDM and late onset PE (LOPE). These mechanisms lead to a reduced Akt/mTOR signalling cascade in response to insulin (insulin resistance) in the foetoplacental vasculature. This condition’s outcome is a reduced vasodilation with several other adverse foetal outcomes and higher risk of developing adulthood diseases. PI3K: phosphatidylinositol 3 kinase; AMPK: adenosine monophosphate kinase; SK61: p70 S6 kinase 1; TNFα: tumour necrosis factor α; PDK1: human 3-phosphoinositide-dependent protein kinase 1; JNK: c-Jun N-terminal kinases. Specific signalling mechanisms for each molecule shown are described in the text. The magnitude of the bars represents the degree of involvement of the diseases of pregnancy at the corresponding mechanism.