Huppertz C, Schwartz C, Becker W, Horn F, Heinrich P C, Joost H G
Institut für Pharmakologie und Toxikologie, RWTH Aachen, Germany.
Diabetologia. 1996 Dec;39(12):1432-9. doi: 10.1007/s001250050595.
The effects of insulin, insulin-like growth factor (IGF)-I, platelet-derived growth factor (PDGF), interleukin (IL)-6 and interferon-gamma on 2-deoxyglucose uptake and insulin receptor substrate (IRS)-1 phosphorylation were compared in 3T3-L1 cells at confluence and after differentiation to the adipocyte-like phenotype. Insulin and IGF-I produced the expected stimulation of glucose transport and tyrosine phosphorylation of IRS-1 in both confluent and differentiated cells. In contrast, IL-6 and interferon-gamma failed to stimulate glucose transport or IRS-1 phosphorylation, although a marked stimulation of the JAK/STAT pathways as shown by acute-phase response factor (APRF)/Stat3 or Stat1 activation was observed in fibroblasts (IL-6, interferon-gamma) and adipocytes (IL-6). PDGF-AA and PDGF-BB stimulated glucose transport in confluent, undifferentiated cells to the same extent as insulin (approximately six-fold stimulation), but produced only a small portion of the effect of insulin in differentiated cells. Similarly, mRNA levels and autophosphorylation of PDGF receptors were much lower in differentiated cells than in confluent fibroblasts. In contrast to insulin and IGF-I, PDGF failed to stimulate tyrosine phosphorylation of IRS-1. All effects of insulin, IGF-I, and PDGF on glucose transport were inhibited by Wortmannin; the half-maximally inhibiting concentration (IC50) of Wortmannin was increased by insulin. These data demonstrate distinct signalling potentials of the investigated receptors, and indicate that the IL-6 and interferon-gamma controlled JAK/STAT pathways lack the potential to stimulate glucose transport. IRS-1 does not appear to be involved in the PDGF receptor-mediated effects, whereas activation of phosphatidylinositol (PI) 3-kinase is a crucial event in all pathways leading to stimulation of glucose transport.
在3T3-L1细胞汇合时以及分化为脂肪细胞样表型后，比较了胰岛素、胰岛素样生长因子（IGF）-I、血小板衍生生长因子（PDGF）、白细胞介素（IL）-6和干扰素-γ对2-脱氧葡萄糖摄取及胰岛素受体底物（IRS）-1磷酸化的影响。胰岛素和IGF-I在汇合细胞和分化细胞中均产生了预期的葡萄糖转运刺激以及IRS-1的酪氨酸磷酸化。相比之下，IL-6和干扰素-γ未能刺激葡萄糖转运或IRS-1磷酸化，尽管在成纤维细胞（IL-6、干扰素-γ）和脂肪细胞（IL-6）中观察到急性期反应因子（APRF）/Stat3或Stat1激活所显示的JAK/STAT途径的显著激活。PDGF-AA和PDGF-BB在汇合的未分化细胞中刺激葡萄糖转运的程度与胰岛素相同（约六倍刺激），但在分化细胞中仅产生胰岛素作用的一小部分。同样，分化细胞中PDGF受体的mRNA水平和自身磷酸化程度远低于汇合的成纤维细胞。与胰岛素和IGF-I相反，PDGF未能刺激IRS-酪氨酸磷酸化。胰岛素、IGF-I和PDGF对葡萄糖转运的所有作用均被渥曼青霉素抑制；渥曼青霉素的半数最大抑制浓度（IC50）因胰岛素而增加。这些数据证明了所研究受体具有不同的信号转导潜能，并表明IL-6和干扰素-γ控制的JAK/STAT途径缺乏刺激葡萄糖转运的潜能。IRS-1似乎不参与PDGF受体介导的效应，而磷脂酰肌醇（PI）3激酶的激活是所有导致葡萄糖转运刺激的途径中的关键事件。
