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 β-cells and whether this resistance results in β-cell decompensation. Chronic exposure of rat islets or INS1E β-cells to increasing concentrations of insulin decreased AktS473 phosphorylation in response to subsequent acute stimulation with 10 nM insulin or IGF-1. Prolonged exposure to high insulin levels not only inhibited AktS473 phosphorylation, but it also resulted in a significant inhibition of the phosphorylation of P70S6 kinase and Erk1/2 phosphorylation in response to the acute stimulation by glucose, insulin, or IGF-1. Decreased activation of Akt, P70S6K, and Erk1/2 was associated with decreased insulin receptor substrate 2 tyrosine phosphorylation and insulin receptor β-subunit abundance; neither IGF receptor β-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 eIF2α S51 phosphorylation and Bip (GRP78) expression, and increased islet and β-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 β-cell mass by increasing β-cell apoptosis.
Pubmed ID: 30697602 RIS Download
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View all literature mentionsThis monoclonal targets RPS6KB2
View all literature mentionsThis polyclonal targets RPS6KB2
View all literature mentionsThis monoclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis monoclonal targets Actin, Cardiac
View all literature mentionsThis monoclonal targets ATP2A2/SERCA2 (D51B11) Rabbit mAb
View all literature mentionsThis monoclonal targets eIF2alpha (Ser51)
View all literature mentionsThis polyclonal targets Caspase-3
View all literature mentionsThis unknown targets Annexin V
View all literature mentionsThis polyclonal targets MAPK1, MAPK3
View all literature mentionsThis unknown targets Epitope maps to carboxy terminus of IGF-!R of human origin. Specific for IGF-IRbeta, Non-reactive with IGF-Iralpha
View all literature mentionsThis polyclonal targets RPS6KB1, RPS6KB2
View all literature mentionsThis polyclonal targets INSR
View all literature mentionsThis monoclonal targets Phospho-Tyrosine Mouse mAb (P-Tyr-100)
View all literature mentionsThis polyclonal targets AKT3
View all literature mentionsThis polyclonal targets Akt1/2 (N-19)
View all literature mentionsThis monoclonal targets Actin, Cardiac
View all literature mentionsThis unknown targets Annexin V
View all literature mentionsThis polyclonal targets Caspase-3
View all literature mentionsThis monoclonal targets Phospho-Tyrosine Mouse mAb (P-Tyr-100)
View all literature mentionsThis unknown targets Epitope maps to carboxy terminus of IGF-!R of human origin. Specific for IGF-IRbeta, Non-reactive with IGF-Iralpha
View all literature mentionsThis monoclonal targets eIF2alpha (Ser51)
View all literature mentionsThis polyclonal targets INSR
View all literature mentionsThis monoclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis monoclonal targets ATP2A2/SERCA2 (D51B11) Rabbit mAb
View all literature mentionsThis polyclonal targets MAPK1, MAPK3
View all literature mentionsThis polyclonal targets RPS6KB1, RPS6KB2
View all literature mentionsThis polyclonal targets Akt1/2 (N-19)
View all literature mentionsThis polyclonal targets AKT3
View all literature mentions