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

Figure 2

Cell signalling in insulin resistance in the human foetoplacental vasculature. Insulin activates insulin receptors A (IR-A) and B (IR-B) leading to recruitment and activation of insulin receptor substrates 1 and 2 (IRS1/2) and Src homology 2 domain-containing transforming protein 1 type A of 42 and 56 kDa (SHcA42/56). IR-A activation causes preferential activation of SHcA42/56, which triggers signalling through the growth factor receptor-bound protein 2 (Grb2) ending in increased (⇧) activity of the 44 and 42 kDa mitogen-protein kinases (p44/42^mapk) and c-Jun N-terminal kinases (JNK). IR-B activation causes preferential activation of IRS^1/2 triggering signalling by the p85α regulatory subunit of phosphatidylinositol 3 kinase (PI3K p85α). Activation of this subunit of PI3K decreases (⇩) the protein kinase B/Akt (Akt) activity ending in reduced endothelial nitric oxide (NO) synthase (eNOS) activity and NO generation. Reduced Akt activity also results in lower activity of the mammalian target of rapamycin (mTOR) activity, which turns into reduced activity of the adenosine monophosphate protein kinase (AMPK). Reduced AMPK activity is also caused by the reduced plasma level of adiponectin (an AMPK-activator) thus releasing AMPK-inhibition of mTOR facilitating activation of this molecule. This phenomenon potentially (?) increases mTOR-activated signalling through p70 S6 kinase 1 (S6 K1) thus reducing IRS1/2 signalling. The increased extracellular level of leptin and tumour necrosis factor α (TNFα) results in JNK activation. The possibility that JNK increases the inhibitor phosphorylation of IRS1/2 (Ser³¹²) reducing insulin signalling (?) is likely. All in concert, these mechanisms lead to a state of lower response to insulin of the human foetoplacental vasculature (insulin resistance). Blue arrows denote activation. Red arrows denote inhibition.