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

• 批准号: 8427297
• 负责人: DONGMIN LIU
• 金额: $ 38.05万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8427297
• 关键词: 5' -AMP-activated protein kinase; Affect; Age; American; Apoptosis; Apoptotic; Blood; CREB1 gene; Cell Death; Cell Survival; Cell membrane; Cell physiology; Cells; 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; Kaempferols; 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; Protein Subunits; 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

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 ?-cell mass and function. Therefore, a method to simultaneously prevent insulin resistance and protect functional ?-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 ?-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 ?-cell mass and improves insulin sensitivity, thereby exerting the additive effect in preventing T2D. Aim #1 will determine whether genistein protects against ?-cell apoptosis through the G-protein coupled receptor GPR30-mediated activation of G?s, 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 ?-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 ?-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 AMPK??, 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（由申请人提供）：本研究的长期目标是识别和表征可以有效预防2型糖尿病（T2 D）的天然药物。2型糖尿病是慢性胰岛素抵抗和？细胞质量和功能。因此，一种方法，同时防止胰岛素抵抗和保护功能？细胞团可能是预防T2 D的更有效策略。我们首次发现大豆和一些中草药中存在的染料木黄酮直接保护胰腺？在糖尿病小鼠中，银杏叶中的黄酮醇可抑制细胞凋亡，并改善高血糖，而不影响胰岛素敏感性，而银杏叶中的黄酮醇山奈酚可改善肥胖小鼠的胰岛素敏感性和葡萄糖稳态。值得注意的是，染料木黄酮与山奈酚组合对中年肥胖糖尿病小鼠的血糖控制产生有效的累加效应。我们使用这个年龄的小鼠，因为T2 D通常发生在人类的中年和老年。这些令人兴奋的发现证明了使用这些天然化合物有效预防T2 D的巨大潜力。本申请的目的是确定染料木黄酮和山奈酚发挥抗糖尿病作用的分子机制。这项研究的中心假设是，膳食摄入的染料木素和山奈酚同时保留了功能性？细胞质量和改善胰岛素敏感性，从而在预防T2 D中发挥累加效应。目标#1将确定染料木黄酮是否能防止？细胞凋亡通过G蛋白偶联受体GPR 30介导的G？s，随后刺激cAMP/PKA/CREB和PI 3 K/Akt通路。分离的小鼠和人胰岛将用于鉴定染料木黄酮靶向的信号分子。具体而言，GPR 30缺陷小鼠和遗传和药理学探针将被用来探索这些途径是否介导染料木黄酮的抗凋亡作用？细胞目的#2将探索染料木黄酮，山奈酚， 或两者的组合对胰腺β-细胞功能、能量代谢和胰岛素敏感性以及体内这些作用的潜在分子机制的影响。我们将首先 使用GPR 30缺陷型糖尿病小鼠来确定染料木黄酮是否改善葡萄糖稳态和？细胞存活率和质量。然后，我们将测试山奈酚是否促进能量代谢和胰岛素敏感性，以及这些作用是否通过激活AMPK？？，细胞能量稳态的主要调节剂和T2 D的潜在治疗靶点。完成这项资助有望确定染料木黄酮和山奈酚发挥抗糖尿病作用的新机制，这可能会导致开发使用这些低成本天然化合物预防糖尿病的补充或替代（CAM）策略，糖尿病是美国和世界范围内一个主要且日益严重的公共卫生问题。