-Recent studies suggest that insulin-like growth factor-binding protein-2 (IGFBP-2) affects both growth and metabolism. Whereas negative growth effects are primarily due to negative interference with IGF-I, the mechanisms for metabolic interference of IGFBP-2 are less clear. As we demonstrate, overexpression of IGFBP-2 in transgenic mice is correlated with a decelerated clearance of blood glucose after oral administration. IGFBP-2 carries an integrin-binding domain (RGD motif), which has been shown to also mediate IGF-independent effects. We thus asked if higher serum levels of IGFBP-2 without an intact RGD motif would also partially block blood glucose clearance after oral glucose application. In fact, transgenic mice overexpressing mutated IGFBP-2 with higher levels of IGFBP-2 carrying an RGE motif instead of an RGD were not characterized by decelerated glucose clearance. Impaired glucose tolerance was correlated with lower levels of GLUT4 present in plasma membranes isolated from muscle tissues after glucose challenge. At the same time, activation of TBC1D1 was depressed in mice overexpressing wild-type but not mutated IGFBP-2. Although we do not have reason to assume altered activation of IGF-I receptor or PDK1/Akt activation in both models, we have identified increased levels of integrin-linked kinase and focal adhesion kinase dependent on the presence of the RGD motif. From our results we conclude that impaired glucose clearance in female IGFBP-2 transgenic mice is dependent on the presence of the RGD motif and that translocation of GLUT4 in the muscle may be regulated by IGFBP-2 via RGDdependent mechanisms.WITH THE EPIDEMIC INCREASE of metabolic diseases worldwide, a better understanding of metabolic control in vivo is required. The insulin-like growth factor (IGF) system is known to have metabolic effects, and IGF-I is capable of improving cellular defects present in type 2 diabetes (T2D) (25). In addition, IGF-binding proteins (IGFBPs) have well-recognized metabolic but also therapeutic potential due to IGF-dependent or -independent effects (12, 37). Beyond all other IGFBPs, metabolic effects of IGFBP-1 and IGFBP-2 have received a detailed discussion recently (A. Hoeflich and V. C. Russo, unpublished data). IGFBP-2 is reduced in obesity and further suppressed in obese subjects with T2D (9). IGFBP-2 has also been identified as a marker of the metabolic syndrome (11). Interestingly, serum IGFBP-2 levels correlated positively with insulin sensitivity and negatively with fat mass in young adult subjects (6). IGFBP-2 was identified in sheep as a mediator of leptin effects and insulin sensitivity in muscles (38). In mice, Wheatcroft et al. (36) have demonstrated that IGFBP-2 protects against the development of age-related glucose intolerance, insulin resistance, and hypertension. IGFBP-2 contains an RGD sequence motif in addition to heparin-binding domains located in the linker domain or in the COOH-terminal region, respectively (8). The RGD motif of IGFBP-2 seems to particularly mediate IGF-independent effe...

SummaryImpaired growth is often associated with an extension of lifespan. However, the negative correlation between somatic growth and life expectancy is only true within, but not between, species. This can be observed because smaller species have, as a rule, a shorter lifespan than larger species. In insects and worms, reduced reproductive development and increased fat storage are associated with prolonged lifespan. However, in mammals the relationship between the dynamics of reproductive development, fat metabolism, growth rate, and lifespan are less clear. To address this point, female transgenic mice that were overexpressing similar levels of either intact (D‐mice) or mutant insulin‐like growth factor‐binding protein‐2 (IGFBP‐2) lacking the Arg‐Gly‐Asp (RGD) motif (E‐ mice) were investigated. Both lines of transgenic mice exhibited a similar degree of growth impairment (−9% and −10%) in comparison with wild‐type controls (C‐mice). While in D‐mice, sexual maturation was found to be delayed and life expectancy was significantly increased in comparison with C‐mice, these parameters were unaltered in E‐mice in spite of their reduced growth rate. These observations indicate that the RGD‐domain has a major influence on the pleiotropic effects of IGFBP‐2 and suggest that somatic growth and time of sexual maturity or somatic growth and life expectancy are less closely related than thought previously.

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