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)-␣ 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-␣ and IGFBP-3 antisense partially prevented the inhibitory effect of TNF-␣ 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. (Pediatr Res 61: 159-164, 2007)

Maternal serum insulin-like growth factor-binding protein-3 (IGFBP-3) at 11–13 weeks in preeclampsia

“…41,42 Evidence from both in vitro and in vivo studies suggest that increased levels of IGFBP-3 are associated with hyperglycaemia, metabolic syndrome and increased insulin resistance. [43][44][45][46] Consequently, our finding of an increase in serum IGFBP-3 from the first-trimester of pregnancy in cases that subsequently develop late-PE appears to provide further evidence in support of the association between increased insulin resistance and late-PE.…”

Circulating Insulin-Like Growth Factor-Binding Protein 3 Levels, Independent of Insulin-Like Growth Factor 1, Associate with Truncal Fat and Systolic Blood Pressure in South Asian and White European Preschool Children

“…These IGFBP-3 associations were therefore a direct independent effect and not the result of co-linearity with weight indices. This has not previously been reported, but there is some evidence from animal studies and in vitro experiments for the direct role of IGFBP-3 on energy metabolism, and adipose tissue structure and function [34,35,36,37,38]. Whereas IGF-1 has insulin-like effects, promotes lipogenesis and energy storage, and has vascular protective actions [39], IGFBP-3 has effects by binding IGF-1 and also independently modulates carbohydrate and lipid metabolism, possibly through its actions on toxic fat depots [36].…”

Total and high molecular weight adiponectin are elevated in patients with Laron syndrome despite marked obesity

“…It may be attributed to loss of a direct suppression of adiponectin synthesis or secretion by GH, as the GH receptor is expressed in adipocytes, or alternatively to repression by IGF1 or IGF binding protein-3 (IGFBP-3), known to be deficient in LS (2,47). Indeed, suppressive effects of GH and IGFBP-3 on adipocyte secretion of adiponectin are supported by recent in vitro and ex vivo studies (45,48). Unlike GH and IGFBP-3, in vitro studies did not support an inhibitory effect of IGF1 on adiponectin secretion (49).…”