Gavete M L, Martín M A, Alvarez C, Escrivá F
Instituto de Bioquímica (Consejo Superior de Investigaciones Centíficas-Universidad Complutense de Madrid), Facultad de Farmacia, Universidad Complutense, Ciudad Universitaria, 28040 Madrid, Spain.
Endocrinology. 2005 Aug;146(8):3368-78. doi: 10.1210/en.2004-1658. Epub 2005 May 19.
Restriction of protein calories during stages of immaturity has a major influence on glucose metabolism and increases the risk of type 2 diabetes in adulthood. However, it is known that reduction of food intake alleviates insulin resistance. We previously demonstrated an improved insulin-induced glucose uptake in skeletal muscle of chronically undernourished adult rats. The purpose of this work was to investigate whether this condition is present during suckling, a period characterized by physiological insulin resistance as well as elucidate some of the underlying mechanisms. With this aim, 10-d-old pups from food-restricted dams were studied. We showed that undernourished suckling rats are glucose normotolerants, despite their depressed insulin secretion capacity. The content of the main glucose transporters in muscle, GLUT-4 and GLUT-1, was not affected by undernutrition, but fractionation studies showed an improved insulin-stimulated GLUT-4 translocation. p38MAPK protein, implicated in up-regulation of intrinsic activity of translocated GLUT-4, was increased. These changes suggest an improved insulin-induced glucose uptake associated with undernutrition. Insulin receptor content as well as that of both regulatory and catalytic phosphoinositol 3-kinase subunits was increased by food restriction. Insulin receptor substrate-1-associated phosphoinositol 3-kinase activity after insulin was enhanced in undernourished rats, as was phospho-glycogen synthase kinase-3, in line with insulin hypersensitivity. Surprisingly, protein tyrosine phosphatase-1B association with insulin receptor was also increased by undernutrition. These adaptations to a condition of severely limited nutritional resources might result in changes in the development of key tissues and be detrimental later in life, when a correct amount of nutrients is available, as the thrifty phenotype hypothesis predicts.
在未成熟阶段限制蛋白质热量对葡萄糖代谢有重大影响，并增加成年后患2型糖尿病的风险。然而，已知减少食物摄入量可减轻胰岛素抵抗。我们之前证明，长期营养不良的成年大鼠骨骼肌中胰岛素诱导的葡萄糖摄取有所改善。这项工作的目的是研究在哺乳期这种情况是否存在，哺乳期的特点是存在生理性胰岛素抵抗，并阐明一些潜在机制。为此，研究了来自食物受限母鼠的10日龄幼崽。我们发现，营养不良的哺乳大鼠尽管胰岛素分泌能力降低，但对葡萄糖具有正常耐受性。肌肉中主要葡萄糖转运蛋白GLUT-4和GLUT-1的含量不受营养不良影响，但分级分离研究显示胰岛素刺激的GLUT-4转位有所改善。与转位的GLUT-4内在活性上调有关的p38MAPK蛋白增加。这些变化表明营养不良与胰岛素诱导的葡萄糖摄取改善有关。食物限制增加了胰岛素受体含量以及调节性和催化性磷酸肌醇3激酶亚基的含量。营养不良的大鼠胰岛素刺激后胰岛素受体底物-1相关的磷酸肌醇3激酶活性增强，磷酸化糖原合酶激酶-3也是如此，这与胰岛素超敏反应一致。令人惊讶的是，营养不良也增加了蛋白酪氨酸磷酸酶-1B与胰岛素受体的结合。正如节俭表型假说所预测的那样，这些对营养资源严重受限状况的适应性变化可能会导致关键组织发育的改变，并在以后生命中当有适量营养物质时产生不利影响。
