Regulation of glucose homeostasis:investigation of novel polyphenols

我的主要研究项目是研究包括激素在内的不同刺激如何控制骨骼肌的葡萄糖代谢。我的重点是了解被激活并控制葡萄糖运输和代谢的细胞内信号通路，并找到调节这些信号通路的食物成分、营养食品或功能食品。胰岛素是一种胰腺激素，在骨骼肌葡萄糖运输和代谢中起着重要作用。胰岛素与骨骼肌细胞膜上发现的胰岛素受体结合，激活磷脂酰肌醇-3激酶(PI3K)/Akt信号通路，导致细胞内储存的葡萄糖转运蛋白(GLUT4)转位到质膜，从而增加骨骼肌对葡萄糖的摄取和代谢。PI3K-Akt信号通路的缺陷或损伤导致胰岛素不能作用于骨骼肌组织，这种情况称为胰岛素抵抗。骨骼肌细胞中的另一个信号通路--AMP激活的蛋白激酶(AMPK)通路的激活也导致肌肉葡萄糖摄取和代谢的增加。AMP激活的蛋白激酶(AMPK)是一种丝氨酸/苏氨酸激酶，起细胞能量感受器的作用，并随着AMP/ATP比率的增加而激活。重要的是，骨骼肌AMPK被运动/收缩和各种化合物激活，包括用于治疗血糖水平升高和胰岛素抵抗的药物二甲双胍。我在控制葡萄糖摄取和代谢的细胞内信号机制方面所做的工作，促使我寻找能够调节这些细胞内途径的化合物。最近，我们发现有证据表明，迷迭香提取物中存在的一些多酚可以影响这些信号通路，改变葡萄糖代谢，从而可能对胰岛素抵抗有利。拟议研究计划的长期目标是阐明迷迭香提取物和迷迭香提取物多酚对骨骼肌糖代谢的作用机制。这些目标将使用培养中的肌肉细胞(体外)和骨骼肌胰岛素抵抗的动物模型来解决。拟议的研究将有助于确定迷迭香提取物中存在的活性药物成分(API)，并使用这些API来研究与胰岛素抵抗有关的基本细胞机制。许多加拿大人患有胰岛素抵抗。我的研究重点是研究这些条件的细胞机制，并找到酚类化合物来修饰它们，这将为加拿大社会带来巨大的好处。

My main research program investigates how different stimuli including hormones control skeletal muscle glucose metabolism. My focus is to understand the intracellular signaling pathways that are activated and control glucose transport and metabolism and to find food components, nutraceuticals, or functional foods that modulate these signaling pathways. Insulin is a pancreatic hormone that plays an important role in skeletal muscle glucose transport and metabolism. Insulin binds to its receptor found on the plasma membrane of skeletal muscle cells and activates the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway causing translocation of intracellularly stored glucose transporter proteins (GLUT4) to the plasma membrane resulting in increased skeletal muscle glucose uptake and metabolism. Defects or impairments in the PI3K-Akt signaling pathway lead to inability of insulin to act on skeletal muscle tissue, a condition termed insulin resistance. Activation of another signaling cascade, the AMP-activated protein kinase (AMPK) cascade in skeletal muscle cells also leads to increased muscle glucose uptake and metabolism. The AMP-activated protein kinase (AMPK) is a serine/threonine kinase that functions as a cellular energy sensor and becomes activated in response to increased AMP/ATP ratio. Importantly, skeletal muscle AMPK is activated by exercise/contraction, and various compounds including the drug metformin which is used to treat individuals with increased blood glucose levels, and insulin resistance. My work on the intracellular signaling mechanisms controlling glucose uptake and metabolism has led me to search for compounds that can modulate these intracellular pathways. Recently we found evidence that some polyphenols that are present in rosemary extract can influence these signaling pathways and alter glucose metabolism in ways that might be beneficial in conditions of insulin resistance. The long term goals of the proposed research program are to elucidate the mechanism of action of rosemary extract and rosemary extract polyphenols on skeletal muscle glucose metabolism. These goals will be addressed using muscle cells in culture (in vitro) and animal models of skeletal muscle insulin resistance. The proposed studies will help determine the active pharmaceutical ingredients (APIS) present in rosemary extract and use these APIs to investigate fundamental cellular mechanisms involved in insulin resistance. Many Canadians suffer from insulin resistance. My research focused on investigating the cellular mechanism of these conditions and finding phenolic compounds to modify them will provide huge benefit to the Canadian society.