Grzelkowska K, Dardevet D, Balage M, Grizard J
Unité d'Etude du Métabolisme Azoté, Institut National de la Recherche Agronomique, 63122 Ceyrat, France.
J Endocrinol. 1999 Jan;160(1):137-45. doi: 10.1677/joe.0.1600137.
Insulin resistance in 3-day streptozotocin (STZ)-treated rats was manifested by the lack of antiproteolytic action of insulin as well as by a reduction of its stimulatory effect on protein synthesis (-60% compared with the control group) in epitrochlearis muscle incubated in vitro. In the present study, we have investigated the diabetes-associated alterations in the insulin signalling cascade, especially the phosphatidylinositol-3 kinase (PI-3 kinase)/p70 S6 kinase (p70(S6K)) pathway, in rat skeletal muscle. LY 294002, a specific inhibitor of PI-3 kinase, markedly decreased the basal rate of protein synthesis and completely prevented insulin-mediated stimulation of this process both in control and diabetic rats. Thus, PI-3 kinase is required for insulin-stimulated muscle protein synthesis in diabetic rats as in the controls. Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), had no effect on the basal rate of protein synthesis in either of the experimental groups. In control rats, the stimulatory action of insulin on muscle protein synthesis was diminished by 36% in the presence of rapamycin, whereas in diabetic muscles this reduction amounted to 68%. The rapamycin-sensitive pathway makes a relatively greater contribution to the stimulatory effect of insulin on muscle protein synthesis in diabetic rats compared with the controls, due presumably to the preferential decrease in the rapamycin-insensitive component of protein synthesis. Neither basal nor insulin-stimulated p70(S6K) activity, a signalling element lying downstream of mTOR, were modified by STZ-diabetes.
在经3天链脲佐菌素（STZ）处理的大鼠中，胰岛素抵抗表现为胰岛素缺乏抗蛋白水解作用，以及在体外培养的肱三头肌中其对蛋白质合成的刺激作用降低（与对照组相比降低60%）。在本研究中，我们调查了大鼠骨骼肌中与糖尿病相关的胰岛素信号级联变化，特别是磷脂酰肌醇-3激酶（PI-3激酶）/p70 S6激酶（p70(S6K)）途径。PI-3激酶的特异性抑制剂LY 294002显著降低了蛋白质合成的基础速率，并完全阻止了胰岛素介导的这一过程的刺激作用，无论是在对照大鼠还是糖尿病大鼠中。因此，与对照组一样，PI-3激酶是糖尿病大鼠中胰岛素刺激肌肉蛋白质合成所必需的。雷帕霉素是哺乳动物雷帕霉素靶蛋白（mTOR）的抑制剂，对两个实验组的蛋白质合成基础速率均无影响。在对照大鼠中，在雷帕霉素存在的情况下，胰岛素对肌肉蛋白质合成的刺激作用降低了36%，而在糖尿病肌肉中，这种降低达到了68%。与对照组相比，雷帕霉素敏感途径对糖尿病大鼠中胰岛素对肌肉蛋白质合成的刺激作用贡献相对更大，这可能是由于蛋白质合成中雷帕霉素不敏感成分的优先减少。STZ诱导的糖尿病既未改变基础状态下的p70(S6K)活性，也未改变胰岛素刺激后的p70(S6K)活性，p70(S6K)是位于mTOR下游的信号元件。
