Figure 1 The insulin signalling pathway

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Figure 1 The insulin signalling pathway Figure 1 | The insulin signalling pathway. a | Activation of insulin signalling pathways. Insulin binding activates the insulin receptor and leads to the recruitment of insulin receptor substrate (IRS) isoforms and subsequent activation of the phosphatidylinositol 3-kinase (PI3K)–Akt pathway, which regulates glucose and lipid metabolism, protein biosynthesis, cell survival and apoptosis. Insulin-induced activation of the Ras–mitogen-activated protein kinase (MAPK) pathway increases cell proliferation. b | Negative regulation of insulin signalling pathways. Hyperglycaemia, hyperinsulinaemia, high plasma free fatty acid (FFA) levels and inflammation activate serine/threonine kinases, adaptor proteins and phosphatases either directly or via lipid intermediates, mitochondrial dysfunction or the induction of endoplasmic reticulum (ER) stress. Activation of these negative regulators results in a chronically reduced cellular response to insulin. aPKC, atypical protein kinase C; AS160, Akt substrate 160 kDa; FoxO, forkhead box O; Grb, growth factor receptor-bound protein; GSK3, glycogen synthase kinase 3; IKK, IκB kinase; JNK, c-Jun N-terminal kinase; mTORC, mTOR complex; PDK1, phosphatidylinositide- dependent protein kinase 1; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PKC, protein kinase C; PPA, protein phosphatase A; PTEN, phosphatase and tensin homologue; PTP1B, protein-tyrosine phosphatase 1B; p85, PI3K 85 kDa regulatory subunit α; p110, PI3K 110 kDa catalytic subunit α; Raf-1, RAF proto-oncogene serine/threonine-protein kinase; SHIP, SH2 domain-containing inositol phosphatase; SOCS, suppressor of cytokine signalling; SOS, son of sevenless homologue 1; S6K1, ribosomal protein S6 kinase β1. Artunc, F. et al. (2016) The impact of insulin resistance on the kidney and vasculature Nat. Rev. Nephrol. doi:10.1038/nrneph.2016.145