Rossetti L, Barzilai N, Chen W, Harris T, Yang D, Rogler C E
Division of Endocrinology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
J Biol Chem. 1996 Jan 5;271(1):203-8. doi: 10.1074/jbc.271.1.203.
The physiological role of circulating insulin-like growth factor-II (IGF-II) in adult humans is poorly understood. We recently generated an IGF-II transgenic murine model of persistent IGF-II production (plasma IGF-II approximately 30-fold increased above normal) through over-expression of the transgene driven by the major urinary protein promoter (Rinderknecht, E., and Humbel, R. E. (1978) J. Biol. Chem. 269, 13779-13784). To determine whether in vivo insulin action is improved in these transgenic mice, we performed euglycemic insulin (18 milliunits/kg.min) clamp studies in conscious IGF-II transgenic and in age- and weight-matched control mice. Plasma glucose and insulin concentrations were significantly lower in the IGF-II transgenic compared with both control grouoff Despite decreased plasma glucose concentration, basal hepatic glucose production (HGP) and glucose clearance were increased. During the insulin clamp studies in IGF-II transgenic mice compared with control mice (a) the rates of glucose infusion and glucose uptake were increased by approximately by 65 and approximately 55%, respectively; (b) glycolysis was increased by approximately 12% while glycogen synthesis was approximately 2-fold higher; (c) while the suppression of plasma free fatty acid was similar, the increment in plasma lactate concentration was significantly higher; (d) although HGP was similarly inhibited by insulin, phosphoenolpyruvate gluconeogenesis was enhanced and accounted for a larger portion of HGP (64% versus approximately 40% in control mice). Our data suggest that the persistence of circulating IGF-II in adult mice to levels commonly observed in adult humans (50-70 nM) causes a marked improvement in peripheral (skeletal muscle) insulin action, which is not due to changes in body composition. These results suggest that circulating IGF-II may exert a regulatory role on insulin sensitivity and body composition in humans.
循环胰岛素样生长因子-II（IGF-II）在成年人体内的生理作用尚不清楚。我们最近通过由主要尿蛋白启动子驱动的转基因过表达，建立了一种持续产生IGF-II的转基因小鼠模型（血浆IGF-II比正常水平增加约30倍）（林德克内希特，E.，和洪贝尔，R. E.（1978年）《生物化学杂志》269，13779 - 13784）。为了确定这些转基因小鼠体内胰岛素作用是否得到改善，我们在清醒的IGF-II转基因小鼠以及年龄和体重匹配的对照小鼠中进行了正常血糖胰岛素（18毫单位/千克·分钟）钳夹研究。与两个对照组相比，IGF-II转基因小鼠的血浆葡萄糖和胰岛素浓度显著降低。尽管血浆葡萄糖浓度降低，但基础肝葡萄糖生成（HGP）和葡萄糖清除率增加。与对照小鼠相比，在IGF-II转基因小鼠的胰岛素钳夹研究期间：（a）葡萄糖输注率和葡萄糖摄取率分别增加了约65%和约55%；（b）糖酵解增加了约12%，而糖原合成增加了约2倍；（c）虽然血浆游离脂肪酸的抑制相似，但血浆乳酸浓度的增加显著更高；（d）尽管胰岛素对HGP的抑制相似，但磷酸烯醇丙酮酸糖异生增强，并且在HGP中占更大比例（64%对对照小鼠中的约40%）。我们的数据表明，成年小鼠体内循环IGF-II持续到成年人类常见的水平（50 - 70 nM）会导致外周（骨骼肌）胰岛素作用显著改善，这并非由于身体组成的变化。这些结果表明，循环IGF-II可能对人类的胰岛素敏感性和身体组成发挥调节作用。
