Identification and molecular characterization of anti-diabetic flavonoids

抗糖尿病黄酮类化合物的鉴定和分子表征

基本信息

批准号：
8820798
负责人：
DONGMIN LIU
金额：
$ 37.92万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8820798
关键词：
5&apos -AMP-activated protein kinase Affect Age American Apoptosis Apoptotic Beta Cell Blood CREB1 gene Cell Death Cell Survival Cell membrane Cell physiology Chinese Herbs Chronic Cyclic AMP Cyclic AMP-Dependent Protein Kinases Development Diabetes Mellitus Diabetes prevention Diabetic mouse Diet Dietary intake Disease Energy Metabolism Flavonoids Flavonols G-Protein-Coupled Receptors GTP-Binding Proteins Genetic Genistein Ginkgo biloba Goals Grant Health Homeostasis Human Hyperglycemia Hypoglycemia Individual Insulin Insulin Resistance Isoflavones Lead Mediating Metabolic Metabolic Diseases Methods Molecular Molecular Mechanisms of Action Mus Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Outcome Pancreas Pathway interactions Peripheral Population Prevention strategy Preventive Public Health Research Role Screening procedure Signal Pathway Signaling Molecule Soybeans Structure of beta Cell of islet Test Result Testing Therapeutic Time Tissues Work alternative treatment blood glucose regulation cost diabetic fatty acid oxidation glucose uptake glycemic control improved in vivo innovation insulin sensitivity islet kaempferol middle age novel prevent receptor therapeutic target tool type I and type II diabetes

项目摘要

DESCRIPTION (provided by applicant): The long-range goal of this research is to identify and characterize natural agents that can effectively prevent type 2 diabetes (T2D). T2D is a result of chronic insulin resistance and loss of β-cell mass and function. Therefore, a method to simultaneously prevent insulin resistance and protect functional β-cell mass could be a more effective strategy to prevent T2D. We discovered for the first time that genistein, an isoflavone present in soybean and some Chinese herbs, directly protect pancreatic β-cells from apoptosis and ameliorates hyperglycemia without affecting insulin sensitivity in diabetic mice, while kaempferol, a flavonol present in gingko biloba, improves insulin sensitivity and glucose homeostasis in obese mice. Notably, genistein in combination with kaempferol produces a potent additive effect on blood glycemic control in middle-aged obese diabetic mice. We used mice at this age because T2D usually occurs at middle and older age in humans. These exciting findings demonstrate a great potential for using these natural compounds to effectively prevent T2D. The goal of this application is to determine molecular mechanisms by which genistein and kaempferol exert an anti-diabetic effect. The central hypothesis of this grant is that dietary intae of both genistein and kaempferol simultaneously preserves functional β-cell mass and improves insulin sensitivity, thereby exerting the additive effect in preventing T2D. Aim #1 will determine whether genistein protects against β-cell apoptosis through the G-protein coupled receptor GPR30-mediated activation of Gαs, and subsequent stimulation of the cAMP/PKA/CREB and PI3K/Akt pathways. Isolated mouse and human islets will be used to identify the signaling molecules targeted by genistein. Specifically, GPR30-deficient mice and genetic and pharmacological probes will be utilized to explore whether these pathways mediate the anti-apoptotic action of genistein in β-cells. Aim #2 will explore the effects of genistein, kaempferol, or a combination of both on pancreatic beta-cell function, energy metabolism, and insulin sensitivity as well as the underlying molecular mechanisms for these actions in vivo. We will first use GPR30-deificent diabetic mice to determine whether genistein improves glucose homeostasis and β-cell survival and mass via this receptor. We will then test whether kaempferol promotes energy metabolism and insulin sensitivity and whether these effects are mediated via activation of AMPKα, a master regulator of cellular energy homeostasis and potential therapeutic target for T2D. Completion of this grant is expected to define novel mechanisms by which genistein and kaempferol exert the anti-diabetic effects, which may potentially lead to the development of complementary or alternative (CAM) strategies using these low-cost natural compounds for the prevention of diabetes, a major and growing public health problem in the U.S. and worldwide.

描述（由申请人证明）：远程是识别和表征可以有效预防PE 2糖尿病的天然药物（T2D）。因此，甲旋性防止IND保护功能性β细胞质量可能是我们首次发现的更有效的策略。肥胖小鼠的葡萄糖稳态对中年肥胖小鼠的血糖控制作用。。受体GPR30介导的αs激活，随后刺激CAMP/PKA/CREB和PI3K/AKT途径。染料木黄酮在β细胞中的作用。或β细胞功能，能量代谢和胰岛素以及基本的分子机电作用的结合使用GPR30有效的糖尿病小鼠来确定染料木黄酮是否不稳态稳态和β细胞存活和质量是否会通过该受体进行测试。对于T2D。