Moon Byoung, Kwan Jamie Jun-Mae, Duddy Noreen, Sweeney Gary, Begum Najma
Diabetes Research Laboratory, Winthrop University Hospital, Mineola, New York 11501, USA.
Am J Physiol Endocrinol Metab. 2003 Jul;285(1):E106-15. doi: 10.1152/ajpendo.00457.2002. Epub 2003 Mar 4.
Elevated levels of resistin have been proposed to cause insulin resistance and therefore may serve as a link between obesity and type 2 diabetes. However, its role in skeletal muscle metabolism is unknown. In this study, we examined the effect of resistin on insulin-stimulated glucose uptake and the upstream insulin-signaling components in L6 rat skeletal muscle cells that were either incubated with recombinant resistin or stably transfected with a vector containing the myc-tagged mouse resistin gene. Transfected clones expressed intracellular resistin, which was released in the medium. Incubation with recombinant resistin resulted in a dose-dependent inhibition of insulin-stimulated 2-deoxyglucose (2-DG) uptake. The inhibitory effect of resistin on insulin-stimulated 2-DG uptake was not the result of impaired GLUT4 translocation to the plasma membrane. Furthermore, resistin did not alter the insulin receptor (IR) content and its phosphorylation, nor did it affect insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation, its association with the p85 subunit of phosphatidylinositol (PI) 3-kinase, or IRS-1-associated PI 3-kinase enzymatic activity. Insulin-stimulated phosphorylation of Akt/protein kinase B-alpha, one of the downstream targets of PI 3-kinase and p38 MAPK phosphorylation, was also not affected by resistin. Expression of resistin also inhibited insulin-stimulated 2-DG uptake when compared with cells expressing the empty vector (L6Neo) without affecting GLUT4 translocation, GLUT1 content, and IRS-1/PI 3-kinase signaling. We conclude that resistin does not alter IR signaling but does affect insulin-stimulated glucose uptake, presumably by decreasing the intrinsic activity of cell surface glucose transporters.
高水平的抵抗素被认为会导致胰岛素抵抗，因此可能是肥胖与2型糖尿病之间的一个关联因素。然而，其在骨骼肌代谢中的作用尚不清楚。在本研究中，我们检测了抵抗素对胰岛素刺激的葡萄糖摄取以及L6大鼠骨骼肌细胞中上游胰岛素信号成分的影响，这些细胞要么与重组抵抗素孵育，要么用含有myc标签的小鼠抵抗素基因的载体进行稳定转染。转染的克隆表达细胞内抵抗素，并释放到培养基中。与重组抵抗素孵育导致胰岛素刺激的2-脱氧葡萄糖（2-DG）摄取呈剂量依赖性抑制。抵抗素对胰岛素刺激的2-DG摄取的抑制作用不是由于葡萄糖转运蛋白4（GLUT4）向质膜转位受损所致。此外，抵抗素没有改变胰岛素受体（IR）的含量及其磷酸化，也没有影响胰岛素刺激的胰岛素受体底物（IRS）-1酪氨酸磷酸化、其与磷脂酰肌醇（PI）3-激酶p85亚基的结合或IRS-1相关的PI 3-激酶酶活性。胰岛素刺激的PI 3-激酶下游靶点之一的Akt/蛋白激酶B-α磷酸化以及p38丝裂原活化蛋白激酶（MAPK）磷酸化也不受抵抗素影响。与表达空载体（L6Neo）的细胞相比，抵抗素的表达也抑制了胰岛素刺激的2-DG摄取，而不影响GLUT4转位、GLUT1含量和IRS-1/PI 3-激酶信号传导。我们得出结论，抵抗素不会改变IR信号，但会影响胰岛素刺激的葡萄糖摄取，可能是通过降低细胞表面葡萄糖转运蛋白的内在活性来实现的。
