Molecular scanning of insulin receptor substrate-1 (IRS-1) revealed several amino acid substitutions. The most common IRS-1 variant, a Gly to Arg(972) change, is more prevalent among type 2 diabetic patients. In this study we overexpressed wild-type and Arg(972)IRS-1 variant in L6 skeletal muscle cells and examined the functional consequences of this polymorphism on insulin metabolic signaling. L6 cells expressing Arg(972)-IRS-1 (L6-Arg(972)) showed a decrease in insulin-stimulated IRS-l-associated phosphatidylinositol 3-binase (PI 3-kinase) activity compared with L6 cells expressing wild-type IRS-1(L6-WT) as a consequence of decreased binding of p85 subunit of PI S-kinase to IRS-1. L6-Ar-972 exhibited a decrease in both basal and insulin-stimulated glucose transport due to a reduction in the amount of both GLUT1 and GLUT4 translocated to the plasma membrane. Both basal and insulin-stimulated Akt phosphorylations were decreased in L6-Arg(972) compared with L6-WT. Basal glycogen synthase kinase-3 (GSK-3) activity was increased in L6-Arg(972) compared with L6-WT, and insulin-induced inactivation of GSK-3 was also reduced in L6-Arg(972). This change was associated with a significant decrease in insulin-stimulated glucose incorporation into glycogen and glycogen synthase activity in L6-Arg(972) compared with L6-WT. These results indicate that the Arg(972)-IRS-1 polymorphism impairs the ability of insulin to stimulate glucose transport, glucose transporter translocation, and glycogen synthesis by affecting the PI 3-kinase/Akt/GSK-3 signaling pathway. The present data indicate that the polymorphism at codon 972 of IRS-1 may contribute to the in vivo insulin resistance observed in carriers of this variant.

Hribal, M., Federici, M., Porzio, O., Lauro, D., Borboni, P., Accili, D., et al. (2000). The Gly -> Arg(972) amino acid polymorphism in insulin receptor substrate-1 affects glucose metabolism in skeletal muscle cells. THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM, 85(5), 2004-2013 [10.1210/jc.85.5.2004].

The Gly -> Arg(972) amino acid polymorphism in insulin receptor substrate-1 affects glucose metabolism in skeletal muscle cells

FEDERICI, MASSIMO;PORZIO, OTTAVIA;LAURO, DAVIDE;BORBONI, PATRIZIA;LAURO, RENATO;SESTI, GIORGIO
2000

Abstract

Molecular scanning of insulin receptor substrate-1 (IRS-1) revealed several amino acid substitutions. The most common IRS-1 variant, a Gly to Arg(972) change, is more prevalent among type 2 diabetic patients. In this study we overexpressed wild-type and Arg(972)IRS-1 variant in L6 skeletal muscle cells and examined the functional consequences of this polymorphism on insulin metabolic signaling. L6 cells expressing Arg(972)-IRS-1 (L6-Arg(972)) showed a decrease in insulin-stimulated IRS-l-associated phosphatidylinositol 3-binase (PI 3-kinase) activity compared with L6 cells expressing wild-type IRS-1(L6-WT) as a consequence of decreased binding of p85 subunit of PI S-kinase to IRS-1. L6-Ar-972 exhibited a decrease in both basal and insulin-stimulated glucose transport due to a reduction in the amount of both GLUT1 and GLUT4 translocated to the plasma membrane. Both basal and insulin-stimulated Akt phosphorylations were decreased in L6-Arg(972) compared with L6-WT. Basal glycogen synthase kinase-3 (GSK-3) activity was increased in L6-Arg(972) compared with L6-WT, and insulin-induced inactivation of GSK-3 was also reduced in L6-Arg(972). This change was associated with a significant decrease in insulin-stimulated glucose incorporation into glycogen and glycogen synthase activity in L6-Arg(972) compared with L6-WT. These results indicate that the Arg(972)-IRS-1 polymorphism impairs the ability of insulin to stimulate glucose transport, glucose transporter translocation, and glycogen synthesis by affecting the PI 3-kinase/Akt/GSK-3 signaling pathway. The present data indicate that the polymorphism at codon 972 of IRS-1 may contribute to the in vivo insulin resistance observed in carriers of this variant.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/09 - Medicina Interna
Settore M-EDF/01 - Metodi e Didattiche delle Attivita' Motorie
Settore MED/13 - Endocrinologia
Settore MED/50 - Scienze Tecniche Mediche Applicate
English
Con Impact Factor ISI
amino acid; arginine; glucose; glucose transporter; glycine; glycogen; glycogen synthase; glycogen synthase kinase 3; insulin; insulin receptor substrate 1; phosphatidylinositol 3 kinase; AKT1 protein, human; glucose transporter 1; glucose transporter 4; insulin receptor; insulin receptor substrate 1 protein; insulin receptor substrate-1 protein; muscle protein; oncoprotein; phosphoprotein; protein kinase B; protein serine threonine kinase; protein tyrosine kinase; recombinant protein; SLC2A1 protein, human; SLC2A4 protein, human; amino acid substitution; article; cell membrane; codon; controlled study; enzyme activity; glucose metabolism; glucose transport; glycogen synthesis; human; human cell; insulin metabolism; insulin resistance; muscle cell; non insulin dependent diabetes mellitus; priority journal; protein phosphorylation; animal; biosynthesis; cell line; drug effect; genetic polymorphism; genetic transfection; genetic variability; genetics; kinetics; metabolism; phosphorylation; skeletal muscle; 1-Phosphatidylinositol 3-Kinase; Amino Acid Substitution; Animals; Arginine; Cell Line; Cell Membrane; Glucose; Glucose Transporter Type 1; Glucose Transporter Type 4; Glycine; Glycogen; Humans; Insulin; Kinetics; Monosaccharide Transport Proteins; Muscle Proteins; Muscle, Skeletal; Phosphoproteins; Phosphorylation; Polymorphism, Genetic; Protein-Serine-Threonine Kinases; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Receptor, Insulin; Recombinant Proteins; Transfection; Variation (Genetics)
Hribal, M., Federici, M., Porzio, O., Lauro, D., Borboni, P., Accili, D., et al. (2000). The Gly -> Arg(972) amino acid polymorphism in insulin receptor substrate-1 affects glucose metabolism in skeletal muscle cells. THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM, 85(5), 2004-2013 [10.1210/jc.85.5.2004].
Hribal, M; Federici, M; Porzio, O; Lauro, D; Borboni, P; Accili, D; Lauro, R; Sesti, G
Articolo su rivista
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/53036
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 84
  • ???jsp.display-item.citation.isi??? 80
social impact