Tomas F M, Knowles S E, Owens P C, Chandler C S, Francis G L, Read L C, Ballard F J
CSIRO Division of Human Nutrition, Adelaide, South Australia.
Biochem J. 1992 Feb 15;282 ( Pt 1)(Pt 1):91-7. doi: 10.1042/bj2820091.
The administration of insulin-like growth factor-I (IGF-I) via subcutaneously implanted osmotic pumps partially reversed a catabolic state produced by the co-administration of 20 micrograms of dexamethasone/day to 150 g male rats. Marked dose-dependent effects on body weight and nitrogen retention were produced, with the highest IGF-I dose, 695 micrograms/day, giving a 6 g increase in body weight over 7 days, compared with a 19 g loss in the dexamethasone-only group and an 18 g gain in pair-fed controls. Two IGF-I analogues that bind poorly to IGF-binding proteins, the truncated form, des(1-3)IGF-I, and a variant with an N-terminal extension as well as arginine at residue 3, LR3IGF-I, were approx. 2.5-fold more potent than IGF-I. The response with LR3IGF-I was particularly striking because this peptide binds 3-fold less well than IGF-I to the type 1 IGF receptor. The increased potencies of the IGF-I variants may relate to the substantially increased plasma levels of IGF-binding proteins, particularly IGFBP-3, produced by the combined treatment of dexamethasone with IGF-I or the variants. These binding proteins would be expected to decrease the transfer of IGF-I, but not that of the variants, from blood to tissue sites of action. Measurements of muscle protein synthesis at the end of the treatment period and muscle protein breakdown by 3-methylhistidine (3MH) excretion throughout the experiment indicated coordinate anabolic effects of the IGF peptides on both processes. Thus 3MH excretion was decreased at the highest IGF-I dose from 83.5 +/- 4.2 (S.E.M.) mumol/kg per 7 days to 65.1 +/- 2.2, compared with 54.9 +/- 1.2 in the pair-fed controls. Part of this response in 3MH excretion may have reflected a decrease in gut protein breakdown, because IGF-I and especially the IGF analogues increased the gut weight by up to 45%. Notwithstanding the effects on protein synthesis and breakdown, the fractional carcass weights remained low in the IGF-treated groups, although the increase in total carcass weight reflected nitrogen rather than fat gain. The dexamethasone-induced changes in liver, spleen and heart weight were restored towards normal by the IGF treatment. The experiment demonstrates the potential of IGF-I treatment of catabolic states and especially the value of modified forms of growth factors that bind weakly to IGF-binding proteins.
通过皮下植入渗透泵给予胰岛素样生长因子-I（IGF-I），可部分逆转每日给150 g雄性大鼠联合注射20微克地塞米松所产生的分解代谢状态。对体重和氮潴留产生了明显的剂量依赖性效应，IGF-I最高剂量组（695微克/天）在7天内体重增加了6 g，而仅注射地塞米松的组体重减轻了19 g，配对喂养对照组体重增加了18 g。两种与IGF结合蛋白结合能力较差的IGF-I类似物，截短形式的des(1-3)IGF-I和在第3位残基处有N端延伸以及精氨酸的变体LR3IGF-I，其效力约为IGF-I的2.5倍。LR3IGF-I的反应尤为显著，因为该肽与1型IGF受体的结合能力比IGF-I低3倍。IGF-I变体效力的增加可能与地塞米松与IGF-I或变体联合治疗所产生的IGF结合蛋白（尤其是IGFBP-3）血浆水平大幅升高有关。预计这些结合蛋白会减少IGF-I从血液到组织作用部位的转运，但不会减少变体的转运。治疗期结束时对肌肉蛋白质合成的测量以及整个实验过程中通过3-甲基组氨酸（3MH）排泄来测量肌肉蛋白质分解，结果表明IGF肽对这两个过程都有协同的合成代谢作用。因此，在IGF-I最高剂量组，3MH排泄量从每7天83.5±4.2（标准误）微摩尔/千克降至65.1±2.2，而配对喂养对照组为54.9±1.2。3MH排泄量的这种反应部分可能反映了肠道蛋白质分解的减少，因为IGF-I尤其是IGF类似物使肠道重量增加了多达45%。尽管对蛋白质合成和分解有影响，但IGF治疗组的胴体重量分数仍然较低，尽管胴体总重量的增加反映的是氮增加而非脂肪增加。IGF治疗使地塞米松诱导的肝脏、脾脏和心脏重量变化恢复正常。该实验证明了IGF-I治疗分解代谢状态的潜力，尤其是与IGF结合蛋白结合较弱的生长因子修饰形式的价值。
