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. 2019 Nov 20;10:788. doi: 10.3389/fendo.2019.00788

Figure 1.

Figure 1

The role of insulin signaling and insulin resistance in MetS and skin diseases. Insulin binds to insulin receptor (IR) and phosphorylates insulin receptor substrates (IRS-1, IRS-2) and Shc, which activates the two main insulin signaling pathways: the phosphatidylinositol-3-kinase (PI3K)/Akt pathway and the mitogen-activated protein kinases (MAPK)/Ras pathway. Under insulin resistance and compensatory hyperinsulinemia condition, insulin not only binds to IR, but also binds to IGF-receptors and stimulates the proliferation of keratinocytes and fibroblasts. Moreover, insulin resistance and compensatory hyperinsulinemia could decrease the expression of insulin-like growth factor binding proteins (IGFBPs), thus increasing biological active IGF-1 and resulting in the development of hyperkeratosis and papillomatosis, which are demonstrated as the possible pathogenesis of acanthosis nigricans. As for acne vulgaris and hidradenitis suppurativa, western diet and puberty increase PI3K/Akt signaling and activate mTORC1. mTOR causes the serine/threonine phosphorylation of IRS by activating S6K and reduces its ability to be phosphorylated on tyrosine residues, which results in invalid insulin signaling and insulin resistance. mTORC1 also promotes lipid synthesis via activating the transcription factor sterol regulatory element binding protein 1 (SREBP-1) and inducing the expression of acetyl CoA carboxylase (ACC), which is the rate-limiting enzyme of fatty acid synthesis. In psoriasis, overactivation of PI3K and Akt phosphorylates FOXO and leads to its nuclear export, thus promoting cell proliferation by suppressing its function of activating cell cycle inhibitors (p27KIP1 and p21) and repressing cell cycle activators (cyclin D1/D2), which contributes to proliferation of keratinocytes. Moreover, in psoriatic condition, growth factors and relevant cytokines (IL-17A, TNF-α, and IL-1β) in psoriasis activate mTOR and then promote keratinocyte hyperproliferation and inhibiting differentiation. In the MAPK/Ras pathway, ERK1/2 could activate upstream MEK, reduce Akt phosphorylation, and contribute to insulin resistance. Furthermore, p-ERK1/2 have been identified to be increased in psoriatic skin, which results in the abnormal and proliferation and differentiation of keratinocytes.