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: 8234308
• 负责人: DONGMIN LIU
• 金额: $ 39.28万
• 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/8234308
• 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. PUBLIC HEALTH RELEVANCE: Diabetes mellitus is a growing health problem, which presently affects 23.6 million or 7.8% of the American population, and this number is projected to double by 2025. Loss of insulin secreting ?-cell mass through apoptosis is central to the development of both type 1 and type 2 diabetes. The results of this research, which is aimed at identifying and characterizing natural agents that are capable of protecting ?-cells from death, may allow us to develop low-cost alternative treatment for this disease.

描述（由申请人提供）：这项研究的远距离目标是识别和表征可以有效预防2型糖尿病（T2D）的天然药物。 T2D是慢性胰岛素抵抗和损失？细胞质量和功能的结果。因此，一种同时防止胰岛素抵抗并保护功能的方法？ - 细胞质量可能是预防T2D的更有效策略。 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老鼠。值得注意的是，染料木黄酮与Kaempferol结合使用，对中年肥胖糖尿病小鼠的血糖控制产生有效的附加作用。我们在这个年龄时使用了小鼠，因为T2D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防止T2D的巨大潜力。该应用的目的是确定染料黄酮和kaempferol发挥抗糖尿病作用的分子机制。这项赠款的中心假设是，染料木黄酮和kaempferol的饮食内部同时保留功能吗？ - 细胞质量并提高胰岛素敏感性，从而在预防T2D方面发挥了添加作用。 AIM＃1将通过G蛋白偶联受体GPR30介导的G？S的激活以及随后刺激CAMP/PKA/CREB和PI3K/AKT途径来确定染料木黄酮是否可以预防？细胞凋亡。分离的小鼠和人类胰岛将用于识别染料木黄酮靶向的信号分子。具体而言，将利用GPR30缺陷型小鼠以及遗传学和药理学探针探索这些途径是否介导？细胞中染料木黄酮的抗凋亡作用。 AIM＃2将探索Genastein，Kaempferol的影响， 或在胰腺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基本分子机制上的结合。我们将首先 使用具有GPR30的糖尿病小鼠来确定染料木黄酮是否通过该受体改善了葡萄糖稳态和？细胞生存和质量。然后，我们将测试Kaempferol是否促进了能量代谢和胰岛素敏感性，以及这些作用是否是通过激活AMPK的激活来介导的，AMPK是细胞能量稳态的主要调节剂和T2D的潜在治疗靶标。预计这笔赠款的完成将定义新机制，通过这些机制，染料木黄酮和kaempferol发挥了抗糖尿病作用，这可能有可能导致使用这些低成本自然化合物的预防糖尿病的糖尿病，美国和全球种植的公共卫生问题的互补或替代（CAM）策略的发展。 公共卫生相关性：糖尿病是一个日益严重的健康问题，目前影响2360万或7.8％的美国人口，预计到2025年，这一数字将增加一倍。胰岛素分泌的损失是通过细胞凋亡的细胞质量？质量是1型和2型糖尿病的发展至关重要。这项研究的结果旨在识别和表征能够保护能够保护的天然药物吗？ - 可能使我们能够为这种疾病开发低成本的替代治疗方法。