Please use this identifier to cite or link to this item: http://repositorio.unicamp.br/jspui/handle/REPOSIP/196578
Type: Artigo de periódico
Title: Regulation Of Insulin Signalling By Hyperinsulinaemia: Role Of Irs-1/2 Serine Phosphorylation And The Mtor/p70 S6k Pathway.
Author: Ueno, M
Carvalheira, J B C
Tambascia, R C
Bezerra, R M N
Amaral, M E
Carneiro, E M
Folli, F
Franchini, K G
Saad, M J A
Abstract: Several epidemiological studies have suggested an association between chronic hyperinsulinaemia and insulin resistance. However, the causality of this relationship remains uncertain. We performed chronic hyperinsulinaemic-euglycaemic clamps and delineated, by western blotting, an IR/IRSs/phosphatidylinositol 3-kinase(PI[3]K)/Akt pathway in insulin-responsive tissues of hyperinsulinaemic rats. IRS-1/2 serine phosphorylation, IR/protein tyrosine phosphatase 1B (PTP1B) association, and mammalian target of rapamycin (mTOR)/p70 ribosomal S6 kinase (p70 S6K) activity were also evaluated in the liver, skeletal muscle and white adipose tissue of hyperinsulinaemic animals. We found that chronic hyperinsulinaemic rats have insulin resistance and reduced levels of glycogen content in liver and muscle. In addition, we demonstrated an impairment of the insulin-induced IR/IRSs/PI3K/Akt pathway in liver and muscle of chronic hyperinsulinaemic rats that parallels increases in IRS1/2 serine phosphorylation, IR/PTP1B association and mTOR activity. Despite a higher association of IR/PTP1B, there was an increase in white adipose tissue of chronic hyperinsulinaemic rats in IRS-1/2 protein levels, tyrosine phosphorylation and IRSs/PI3K association, which led to an increase in basal Akt serine phosphorylation. No increases in IRS-1/2 serine phosphorylation and mTOR activity were observed in white adipose tissue. Rapamycin reversed the insulin resistance and the changes induced by hyperinsulinaemia in the three tissues studied. Our data provide evidence that chronic hyperinsulinaemia itself, imposed on normal rats, appears to have a dual effect, stimulating insulin signalling in white adipose tissue, whilst decreasing it in liver and muscle. The underlying mechanism of these differential effects may be related to the ability of hyperinsulinaemia to increase mTOR/p70 S6K pathway activity and IRS-1/2 serine phosphorylation in a tissue-specific fashion. In addition, we demonstrated that inhibition of the mTOR pathway with rapamycin can prevent insulin resistance caused by chronic hyperinsulinaemia in liver and muscle. These findings support the hypothesis that defective and tissue-selective insulin action contributes to the insulin resistance observed in hyperinsulinaemic states.
Subject: Adipose Tissue
Animals
Body Weight
Energy Intake
Epididymis
Glucose Clamp Technique
Glycolysis
Insulin
Insulin Receptor Substrate Proteins
Insulin Resistance
Intracellular Signaling Peptides And Proteins
Male
Phosphoproteins
Phosphorylation
Phosphoserine
Protein Kinases
Rats
Rats, Wistar
Ribosomal Protein S6 Kinases, 70-kda
Tor Serine-threonine Kinases
Rights: fechado
Identifier DOI: 10.1007/s00125-004-1662-6
Address: http://www.ncbi.nlm.nih.gov/pubmed/15692808
Date Issue: 2005
Appears in Collections:Unicamp - Artigos e Outros Documentos

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