PMI-5011 and Insulin Action

胰岛素抵抗是代谢综合征的一个重要病理生理学特征，与心血管危险因素共存和动脉粥样硬化加速密切相关。通过药理学手段改善胰岛素抵抗的策略代表了临床医学的传统方法。然而，由于公众广泛使用膳食补充剂，使用植物性药物的营养补充剂， 有效地增加胰岛素敏感性代表了一个非常有吸引力的和新的方法，为未来的研究，旨在干预代谢综合征的发展。不幸的是，关于植物补充剂对代谢综合征的影响存在相当大的争议，因为关于植物药改善体内胰岛素作用或胰岛素作用的细胞方面的测量的人类数据很少。然而，我们提供 在体外和体内模型中的几条证据表明植物性药物可以调节葡萄糖代谢的细胞内途径。具体来说，我们提供的证据表明，俄罗斯龙蒿（龙蒿L）的醇提取物称为PMI-5011，可能会增加体内胰岛素的作用，并确定了几个新的细胞内途径，可以解释的效果。因此，本项目的总体目标是审查 具体的植物，PMI-5011，在体内胰岛素作用，并阐明潜在的细胞作用机制。为了实现我们的目标，我们将使用PMI-5011及其生物活性成分进行体外和体内实验，旨在通过全身，细胞和分子方法评估胰岛素敏感性和葡萄糖代谢途径。我们假设，在动物模型和代谢紊乱的受试者中， 综合征，膳食补充PMI-5011将通过增加非氧化葡萄糖处置来改善全身胰岛素介导的葡萄糖摄取（即胰岛素敏感性）（目的1）。这种全身葡萄糖处置的增加将是由于通过胰岛素受体的增强的细胞信号传导和骨骼肌脂质代谢的调节（目的2）。在目标3中，我们将进行早期人体研究，以评估安全性、毒性、剂量反应和人体条件下的拟议机制。

Insulin resistance is a key pathophysiologic feature of the "metabolic syndrome" and is strongly associated with co-existing cardiovascular risk factors and accelerated atherosclerosis. Strategies to improve insulin resistance by pharmacological means have represented the traditional approach for clinical medicine. However, because of the widespread use of dietary supplements by the general public, nutritional supplementation with the use of botanicals that effectively increase insulin sensitivity represent a very attractive and novel approach for future studies designed to intervene in the development of metabolic syndrome. Unfortunately, considerable controversy exists regarding the effect of botanical supplements on the metabolic syndrome as there is a paucity of data in humans in regard to the effect of botanicals to improve measures of insulin action in vivo or on cellular aspects of insulin action. However, we provide several lines of evidence in both in vitro and in vivo models to suggest that botanicals may modulate intracellular pathways of glucose metabolism. Specifically, we provide evidence that an alcoholic extract of Russian Tarragon (Artemisia dracunculus L) referred to as PMI-5011, may increase insulin action in vivo and have identified several novel intracellular pathways that may explain the effect. Thus, this project's overall objective is to examine the role of a specific botanical, PMI-5011, on insulin action in vivo and to elucidate potential cellular mechanism(s) of action. To accomplish our goal, we will conduct both in vitro and in vivo experiments with PMI-5011 and its bioactive components that are designed to assess insulin sensitivity and pathways of glucose metabolism with whole-body, cellular, and molecular approaches. We hypothesize that in both animal models and in subjects with the metabolic syndrome, dietary supplementation with PMI-5011 will improve whole-body insulin-mediated glucose uptake (i.e. insulin sensitivity) by increasing non-oxidative glucose disposal (Aim 1). This increase in whole body glucose disposal will be due to enhanced cellular signaling through the insulin receptor and modulation of skeletal muscle lipid metabolism (Aim 2). In Aim 3 we will conduct early phase human studies to evaluate safety, toxicity, dose response and proposed mechanisms in the human condition.