Department of Clinical and Experimental Medicine, Diabetes and Integrative Systems Biology, Linköping University, SE58185 Linköping, Sweden.
J Biol Chem. 2011 Jul 22;286(29):26028-41. doi: 10.1074/jbc.M110.188987. Epub 2011 May 13.
Type 2 diabetes is a metabolic disease that profoundly affects energy homeostasis. The disease involves failure at several levels and subsystems and is characterized by insulin resistance in target cells and tissues (i.e. by impaired intracellular insulin signaling). We have previously used an iterative experimental-theoretical approach to unravel the early insulin signaling events in primary human adipocytes. That study, like most insulin signaling studies, is based on in vitro experimental examination of cells, and the in vivo relevance of such studies for human beings has not been systematically examined. Herein, we develop a hierarchical model of the adipose tissue, which links intracellular insulin control of glucose transport in human primary adipocytes with whole-body glucose homeostasis. An iterative approach between experiments and minimal modeling allowed us to conclude that it is not possible to scale up the experimentally determined glucose uptake by the isolated adipocytes to match the glucose uptake profile of the adipose tissue in vivo. However, a model that additionally includes insulin effects on blood flow in the adipose tissue and GLUT4 translocation due to cell handling can explain all data, but neither of these additions is sufficient independently. We also extend the minimal model to include hierarchical dynamic links to more detailed models (both to our own models and to those by others), which act as submodules that can be turned on or off. The resulting multilevel hierarchical model can merge detailed results on different subsystems into a coherent understanding of whole-body glucose homeostasis. This hierarchical modeling can potentially create bridges between other experimental model systems and the in vivo human situation and offers a framework for systematic evaluation of the physiological relevance of in vitro obtained molecular/cellular experimental data.
2 型糖尿病是一种代谢疾病，它会深刻影响能量平衡。该疾病涉及多个水平和子系统的故障，其特征是靶细胞和组织中的胰岛素抵抗（即细胞内胰岛素信号受损）。我们之前曾使用迭代的实验理论方法来阐明原代人脂肪细胞中的早期胰岛素信号事件。与大多数胰岛素信号研究一样，该研究基于体外实验检查细胞，并且此类研究与人类的体内相关性尚未系统地检查。在此，我们开发了脂肪组织的分层模型，该模型将人原代脂肪细胞中细胞内胰岛素对葡萄糖转运的控制与全身葡萄糖稳态联系起来。实验和最小建模之间的迭代方法使我们能够得出结论，不可能将通过分离的脂肪细胞实验确定的葡萄糖摄取量扩大到与体内脂肪组织的葡萄糖摄取曲线相匹配。但是，一个模型除了包括胰岛素对脂肪组织血流的影响以及由于细胞处理引起的 GLUT4 易位，还可以解释所有数据，但这两种添加物都不能独立地完成。我们还将最小模型扩展到包括与更详细模型（包括我们自己的模型和其他人的模型）的分层动态链接，这些模型充当可以打开或关闭的子模块。由此产生的多层次分层模型可以将不同子系统的详细结果合并为对全身葡萄糖稳态的一致理解。这种分层建模有可能在其他实验模型系统和体内人类环境之间架起桥梁，并为系统评估体外获得的分子/细胞实验数据的生理学相关性提供了框架。
