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）：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 (T2D) 的天然药物。 T2D 是慢性胰岛素抵抗以及β细胞质量和功能丧失的结果。因此，同时预防胰岛素抵抗和保护功能性β细胞量的方法可能是预防T2D的更有效策略。我们首次发现，大豆和一些中草药中存在的异黄酮金雀异黄酮可以直接保护胰腺β细胞免于凋亡并改善高血糖，而不影响糖尿病小鼠的胰岛素敏感性，而银杏叶中存在的黄酮醇山奈酚可以改善胰岛素敏感性肥胖小鼠的敏感性和葡萄糖稳态。值得注意的是，金雀异黄素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附加作用。我们使用这个年龄段的小鼠，因为 T2D 通常发生在人类中老年。这些令人兴奋的发现证明了利用这些天然化合物有效预防 T2D 的巨大潜力。本申请的目的是确定金雀花素和山奈酚发挥抗糖尿病作用的分子机制。这项资助的中心假设是，膳食中摄入金雀花素和山奈酚可以同时保留功能性β细胞质量并提高胰岛素敏感性，从而在预防 T2D 方面发挥附加作用。目标 #1 将确定金雀异黄素是否通过 G 蛋白偶联受体 GPR30 介导的 G?s 激活以及随后的 cAMP/PKA/CREB ​​和 PI3K/Akt 途径的刺激来防止 ? 细胞凋亡。分离的小鼠和人类胰岛将用于鉴定金雀异黄素靶向的信号分子。具体而言，将利用GPR30缺陷小鼠以及遗传和药理学探针来探索这些途径是否介导金雀异黄素在γ细胞中的抗凋亡作用。目标 #2 将探索金雀花素、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这些体内作用的潜在分子机制的影响。我们首先会 使用 GPR30 缺陷的糖尿病小鼠来确定金雀异黄酮是否通过该受体改善葡萄糖稳态以及 β 细胞存活和质量。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，以及这些作用是否是通过 AMPK 的激活介导的，AMPK 是细胞能量稳态的主要调节剂，也是 T2D 的潜在治疗靶点。这项拨款的完成预计将确定金雀花素和山奈酚发挥抗糖尿病作用的新机制，这可能会导致使用这些低成本天然化合物预防糖尿病的补充或替代（CAM）策略的开发，美国和世界范围内一个重大且日益严重的公共卫生问题。 公共健康相关性：糖尿病是一个日益严重的健康问题，目前影响着 2360 万美国人，即 7.8% 的美国人口，预计到 2025 年这一数字将翻一番。通过细胞凋亡导致分泌胰岛素的 β 细胞数量减少是糖尿病发展的核心1 型和 2 型糖尿病。这项研究的目的是鉴定和表征能够保护β细胞免于死亡的天然药物，其结果可能使我们能够开发出针对这种疾病的低成本替代疗法。