title: Insulin-like growth factor binding protein-3 induces insulin resistance in adipocytes in vitro and in rats in vivo.
abstract: Insulin-like growth factor binding protein (IGFBP)-3 binds to IGF and modulates their actions and also possesses intrinsic activities. We investigated its effects on insulin action and found that when IGFBP-3 was added to fully differentiated 3T3-L1 adipocytes in culture, insulin-stimulated glucose transport was significantly inhibited to 60% of control in a time- and dose-dependent manner. Tumor necrosis factor (TNF)-alpha treatment also inhibited glucose transport to the same degree as IGFBP-3 and, in addition, increased IGFBP-3 levels 3-fold. Co-treatment with TNF-alpha and IGFBP-3 antisense partially prevented the inhibitory effect of TNF-alpha on glucose transport, indicating a role for IGFBP-3 in cytokine-induced insulin resistance. Insulin-stimulated phosphorylation of the insulin receptor was markedly decreased by IGFBP-3 treatment. IGFBP-3 treatment suppressed adiponectin expression in 3T3-L1 adipocytes. Infusion of IGFBP-3 to Sprague-Dawley rats for 3 h decreased peripheral glucose uptake by 15% compared with controls as well as inhibiting glycogen synthesis. Systemic administration of IGFBP-3 to rats for 7 d resulted in a dramatic 40% decrease in peripheral glucose utilization and glycogen synthesis. These in vitro and in vivo findings demonstrate that IGFBP-3 has potent insulin-antagonizing capability and suggest a role for IGFBP-3 in cytokine-induced insulin resistance and other mechanisms involved in the development of type-2 diabetes.
authors.affiliation: Department of Pediatrics, Ewha Womans University, Seoul, 120-750 Korea.
authors.forename: Hae Soon
authors.initials: HS
authors.lastname: Kim
authors.forename: Omar
authors.initials: O
authors.lastname: Ali
authors.forename: Melanie
authors.initials: M
authors.lastname: Shim
authors.forename: Kuk-Wha
authors.initials: KW
authors.lastname: Lee
authors.forename: Patricia
authors.initials: P
authors.lastname: Vuguin
authors.forename: Radhika
authors.initials: R
authors.lastname: Muzumdar
authors.forename: Nir
authors.initials: N
authors.lastname: Barzilai
authors.forename: Pinchas
authors.initials: P
authors.lastname: Cohen
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D052242:Adiponectin / Q000037:antagonists & inhibitors; D000818:Animals; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D052242:Adiponectin; D018972:Insulin-Like Growth Factor Binding Protein 3; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D011972:Receptor, Insulin; D005947:Glucose