Prolonged Exposure to Insulin Inactivates Akt and Erk1/2 and Increases Pancreatic Islet and INS1E β-Cell Apoptosis

Chronic hyperinsulinemia, in vivo, increases the resistance of peripheral tissues to insulin by desensitizing insulin signaling. Insulin, in a heterologous manner, can also cause IGF-1 resistance. The aim of the current study was to investigate whether insulin-mediated insulin and IGF-1 resistance develops in pancreatic beta-cells and whether this resistance results in beta-cell decompensation. Chronic exposure of rat islets or INS1E beta-cells to increasing concentrations of insulin decreased Akt(S473) phosphorylation in response to subsequent acute stimulation with 10 nM insulin or IGF-1. Prolonged exposure to high insulin levels not only inhibited Akt(S473) phosphorylation, but it also resulted in a significant inhibition of the phosphorylation of P70S6 kinase and Erk(1/2) phosphorylation in response to the acute stimulation by glucose, insulin, or IGF-1. Decreased activation of Akt, P70S6K, and Erk(1/2) was associated with decreased insulin receptor substrate 2 tyrosine phosphorylation and insulin receptor beta-subunit abundance; neither IGF receptor beta-subunit content nor its phosphorylation were affected. These signaling impairments were associated with decreased SERCA2 expression, perturbed plasma membrane calcium current and intracellular calcium handling, increased endoplasmic reticulum stress markers such as eIF2 alpha(S51) phosphorylation and Bip (GRP78) expression, and increased islet and beta-cell apoptosis. We demonstrate that prolonged exposure to high insulin levels induces not only insulin resistance, but in a heterologous manner causes resistance to IGF-1 in rat islets and insulinoma cells resulting in decreased cell survival. These findings suggest the possibility that chronic exposure to hyperinsulinemia may negatively affect beta-cell mass by increasing beta-cell apoptosis. Copyright (C) 2019 Endocrine Society