Insulin-like growth factor binding protein-3 induces insulin resistance in adipocytes in vitro and in rats in vivo.
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.
Kim
Hae Soon
HS
Department of Pediatrics, Ewha Womans University, Seoul, 120-750 Korea.
Ali
Omar
O
Shim
Melanie
M
Lee
Kuk-Wha
KW
Vuguin
Patricia
P
Muzumdar
Radhika
R
Barzilai
Nir
N
Cohen
Pinchas
P
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
D052242:Adiponectin; D018972:Insulin-Like Growth Factor Binding Protein 3; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D011972:Receptor, Insulin; D005947:Glucose