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• W2915564229 startingPage "556571" @default.
• W2915564229 abstract "ABSTRACT Hyperinsulinemia is often viewed as a compensatory mechanism for insulin resistance, but recent studies have shown that high levels of insulin may also contribute to insulin resistance. The precise mechanisms by which hyperinsulinemia contributes to insulin resistance remain poorly defined. To understand the direct effects of prolonged exposure to excess insulin in muscle cells, we incubated differentiated C2C12 myotubes with 200 nM insulin for 16 hours, followed by a 6-hour period of serum starvation, before examining insulin signaling. Using this model, we found that prolonged high insulin treatment significantly increased the phosphorylation of insulin receptor and AKT but not ERK. After serum starvation, acute AKT and ERK signaling stimulated by 0.2 - 20 nM insulin were attenuated. Total and surface insulin receptor protein levels are significantly downregulated by hyperinsulinemia, which resulted in an inhibition of acute insulin signaling. Mechanistically, we found that both isoforms of insulin receptor mRNA were reduced by hyperinsulinemia and implicated the transcription factor FOXO1. Interestingly, 6h serum starvation reversed the effects of high insulin on basal phosphorylation of insulin receptor, AKT and FOXO1 and insulin receptor transcription. Finally, we validated our results in vivo, by determining that insulin receptor levels in mouse skeletal muscle were negatively correlated with circulating insulin. Together, our findings shed light on the mechanisms underlying hyperinsulinemia-induced insulin resistance in muscle cells, which are likely to be relevant in the pathogenesis of type 2 diabetes." @default.
• W2915564229 created "2019-03-02" @default.
• W2915564229 creator A5008510522 @default.
• W2915564229 creator A5032884032 @default.
• W2915564229 creator A5055826409 @default.
• W2915564229 date "2019-02-21" @default.
• W2915564229 modified "2023-09-23" @default.
• W2915564229 title "Modulation of Insr and insulin receptor signaling by hyperinsulinemia in vitro and in vivo" @default.
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• W2915564229 hasPublicationYear "2019" @default.
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