Traditional Chinese medicine (TCM) herbal formulae can be valuable therapeutic strategies and drug discovery resources. However, the active ingredients and action mechanisms of most TCM formulae remain unclear. Therefore, the identification of potent ingredients and their actions is a major challenge in TCM research. In this study, we used a network pharmacology approach we previously developed to help determine the potential antidiabetic ingredients from the traditional Ge-Gen-Qin-Lian decoction (GGQLD) formula. We predicted the target profiles of all available GGQLD ingredients to infer the active ingredients by clustering the target profile of ingredients with FDA-approved antidiabetic drugs. We also applied network target analysis to evaluate the links between herbal ingredients and pharmacological actions to help explain the action mechanisms of GGQLD. According to the predicted results, we confirmed that a novel antidiabetic ingredient from Puerariae Lobatae radix (Ge-Gen), 4-Hydroxymephenytoin, increased the insulin secretion in RIN-5F cells and improved insulin resistance in 3T3-L1 adipocytes. The network pharmacology strategy used here provided a powerful means for identifying bioactive ingredients and mechanisms of action for TCM herbal formulae, including Ge-Gen-Qin-Lian decoction. 1. Introduction Type 2 diabetes (T2D), or noninsulin-dependent diabetes mellitus, is a common complex disease with an increasing prevalence worldwide. In 2012 it was estimated that more than 371 million people have diabetes and that T2D constitutes over 90% of diabetic patients [1]. Furthermore, epidemiological survey analysis suggests that the prevalence of diabetes is accelerating [2]. T2D is characterized by high blood glucose levels due to insufficient insulin secretion, insulin resistance, and impaired insulin action [3]. T2D is influenced by lifestyle factors, such as age, pregnancy, and obesity, but has a strong genetic predisposition [4]. Multiple genes are involved in genetic susceptibility, each making a small contribution to T2D risk [5, 6]. Alterations in multiple signaling pathways, for example, JAK-STAT, MAPK, VEGF, PPAR, P13K, and Wnt were implicated in the pathogenesis of the disease [7–9]. Treatments aimed at controlling high-level blood glucose, as well as therapies that prevent diabetic complications, have all shown specific therapeutic activity in T2D patients, such as metformin, alpha-glucosidase inhibitors, sulfonylureas, thiazolidinediones (TZDs), and insulin injections [10]. However, these treatments have shown limited efficacy and are
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