Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulin-dependent diabetes mellitus

• Published in: Proceedings of the National Academy of Sciences - PNAS 1997-04, Vol.94 (8), p.4171-4175
• Main Authors: Rondinone, C.M. (University of Goteborg, Sweden.), Wang, L.M, Lonnroth, P, Wesslau, C, Pierce, J.H, Smith, U
• Format: Article
• Language: English
• Subjects: ACTIVIDAD ENZIMATICA; ACTIVITE ENZYMATIQUE; Adipocytes; Adipocytes - metabolism; Animals; Antibodies; Biological Sciences; Body mass index; Cells, Cultured; Cellular biology; CELLULE; CELULAS; CIRCULACION SANGUINEA; CIRCULATION SANGUINE; CONTENIDO PROTEICO; CONTROL HORMONAL; CONTROLE HORMONAL; DIABETE; DIABETES; Diabetes mellitus; Diabetes Mellitus, Type 2 - metabolism; FOSFORILACION; GENERO HUMANO; GENRE HUMAIN; GLUCOSA; GLUCOSE; Humans; Insulin; Insulin Receptor Substrate Proteins; Insulin resistance; INSULINA; INSULINE; Intracellular Signaling Peptides and Proteins; Mice; NUTRIENTES; Pharmacology; Phosphatidylinositol 3-Kinases; Phosphoproteins - metabolism; PHOSPHORYLATION; Phosphotransferases (Alcohol Group Acceptor) - metabolism; PROTEINAS AGLUTINANTES; PROTEINE DE LIAISON; Proteins; Receptors; Signal Transduction; SINTESIS DE PROTEINAS; SUBSTANCE NUTRITIVE; SYNTHESE PROTEIQUE; TEJIDO ADIPOSO; TENEUR EN PROTEINES; TIROSINA; TISSU ADIPEUX; TRANSFERASAS; TRANSFERASE; Type 1 diabetes mellitus; Type 2 diabetes mellitus; TYROSINE
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.94.8.4171

The large docking protein IRS-1 is a major substrate for the insulin receptor and other tyrosine kinases. It plays a key role in eliciting many of insulin's actions, including binding and activation of phosphatidylinositol (PI) 3-kinase and the subsequent increase in glucose transport. Gene disruption of IRS-1 in mice is associated with an impaired insulin-stimulated glucose disposal in vivo and glucose transport in vitro, but the survival of the animals and residual insulin sensitivity is dependent on the presence of the alternative docking protein IRS-2. We examined the expression and function of IRS-1 and IRS-2 in adipocytes from healthy and diabetic individuals. Cells from subjects with non-insulin-dependent diabetes mellitus (NIDDM), but not with insulin-dependent diabetes mellitus, had an impaired insulin effect and a marked reduction (70 +/- 6%) in the expression of IRS-1 protein, whereas IRS-2 was unchanged. In normal cells, IRS-1 was the main docking protein for the binding and activation of insulin-stimulated PI 3-kinase; IRS-2 was also functional but required a higher insulin concentration for a similar binding and activation of PI 3-kinase. In contrast in NIDDM cells with a low IRS-1 content, IRS-2 became the main docking protein. These findings may provide important reasons for the insulin resistance in NIDDM