Bioactives in Blueberries and Insulin Resistance

蓝莓中的生物活性物质和胰岛素抵抗

• 批准号: 8384431
• 负责人: April Stull
• 金额: $ 12.47万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384431
• 关键词: 1-Phosphatidylinositol 3-Kinase; 5' -AMP-activated protein kinase; Address; Adipocytes; Adipose tissue; Adverse event; Animals; Anthocyanins; Antioxidants; Area; Biological; Biological Factors; Blueberries; Botanicals; Canada; Cell Culture Techniques; Ceramides; Clinical; Clinical Data; Clinical Trials; Complementary and alternative medicine; Consumption; Data; Development; Dietary Supplementation; Disease; Effectiveness; Euglycemic Clamping; Fatty acid glycerol esters; Folk Remedy; Fractionation; Fruit; Funding; Glucose Clamp; Goals; Health; Health Benefit; Hepatic; Human; In Vitro; Individual; Insulin; Insulin Receptor; Insulin Resistance; Intervention; Intracellular Signaling Proteins; Knowledge; Laboratories; Learning; Liver; Measures; Mentors; Metabolic; Methodology; Modeling; Molecular and Cellular Biology; Mus; Muscle Fibers; Myoblasts; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral Administration; Palmitates; Pathway interactions; Personal Satisfaction; Pharmacological Treatment; Phosphorylation; Phytochemical; Placebos; Population; Prediabetes syndrome; Property; Proteins; Public Health; Publishing; Quality of life; Reporting; Research; Research Personnel; Rodent; Site; Skeletal Muscle; Supplementation; Techniques; Testing; Therapeutic; Therapeutic Intervention; Tissues; Training; Treatment Efficacy; Work; base; blood glucose regulation; career; career development; dietary supplements; feeding; glucose disposal; glucose production; glucose uptake; improved; in vivo; insight; insulin sensitivity; insulin signaling; novel; pre-clinical; research study; response

DESCRIPTION (provided by applicant): Insulin resistance is a key pathophysiologic feature of pre-diabetes and a major contributor to the progression towards overt type 2 diabetes mellitus (T2DM). For many years, increased consumption of bioactives in blueberries (BB) has been a folk remedy in Canada for treating T2DM. Preliminary data in the applicant's laboratory found that dietary supplementation with BB for six weeks was well tolerated and increased whole-body insulin sensitivity in humans with pre-diabetes when compared to the placebo group. However, cellular mechanisms of action underlying the biological response of BB in improving insulin sensitivity were not evaluated previously. Therefore, the overall research objective in the application is to determine the underlying cellular mechanism(s) of action and therapeutic efficacy of BB and its bioactive component(s) in modulating insulin sensitivity in target tissues i vitro and in vivo. To attain the overall objective, the working hypothesis will be tested that BB wll improve insulin sensitivity by modulating glucose uptake and intracellular proteins in the insulin-dependent (i.e., Insulin receptor (IR), insulin receptor substrate (IRS), phosphatidylinositol-3 kinase (PI-3K), and Akt)) and -independent (i.e., AMP-activated protein kinase (AMPK)) pathways in target tissues in vitro and in vivo. The hypothesis will be addressed through the following Specific Aims: 1) determine cellular mechanism(s) by which whole BB enhances insulin sensitivity in insulin sensitive tissues in vitro (i.e., adipose and skeletal muscle cell cultures), 2) isolate and identify the bioactive component(s) in BB and their mechanism(s) of action by which insulin sensitivity is enhanced in insulin sensitive tissues in vitro, and 3) evaluate the therapeutic efficacy and tissue-specific site of action (i.e., liver, adipose tissue, and/or skeletal muscle) of whole BB and BB bioactive component(s) on ameliorating insulin sensitivity in mice using the hyperinsulinemic-euglycemic clamp. During this mentored career development, Dr. Stull will acquire detailed input from her mentors with relevant expertise and work to increase her versatility as a clinical researcher by learning new techniques and methodologies related to [molecular and cellular biology, botanical characterization, and animal biomethodology. Dr. Stull's long-term goal is to become an independent translational CAM investigator and leader in the study of complementary and alternative medicine with an emphasis in botanical dietary supplementation and its impact on insulin resistance. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it will provide new insights on the effectiveness of phytochemicals found in a common fruit (i.e., blueberries) on glucose control and insulin sensitivity, which would potentially benefit the health quality of life, and well-being of an insulin-resistant population. Most importantly, the findings from this application will enable consumers to make more informed decisions about the use of bioactives in blueberries to treat insulin resistance in individuals with pre-diabetes or type 2 diabetes.

描述（由申请人提供）：胰岛素抵抗是糖尿病前期的一个关键病理生理学特征，也是进展为明显的 2 型糖尿病 (T2DM) 的主要因素。多年来，增加食用蓝莓 (BB) 中的生物活性物质一直是加拿大治疗 T2DM 的民间疗法。申请人实验室的初步数据发现，与安慰剂组相比，患有糖尿病前期的人在膳食中补充 BB 六周的耐受性良好，并且提高了全身胰岛素敏感性。然而，之前并未评估 BB 在改善胰岛素敏感性方面的生物反应的细胞作用机制。 因此，本申请的总体研究目标是确定 BB 及其生物活性成分在体外和体内调节靶组织胰岛素敏感性的潜在细胞作用机制和治疗功效。为了实现总体目标，将测试工作假设，即 BB 将通过调节胰岛素依赖性的葡萄糖摄取和细胞内蛋白（即胰岛素受体 (IR)、胰岛素受体底物 (IRS)、磷脂酰肌醇 3 激酶）来提高胰岛素敏感性。 (PI-3K) 和 Akt)) 和体外和体内靶组织中独立的 (即 AMP 激活的蛋白激酶 (AMPK)) 途径。该假设将通过以下具体目标得到解决：1) 确定整个 BB 在体外增强胰岛素敏感性组织（即脂肪和骨骼肌细胞培养物）中胰岛素敏感性的细胞机制，2) 分离和鉴定生物活性BB 中的成分及其在体外胰岛素敏感性组织中增强胰岛素敏感性的作用机制，以及 3) 评估治疗效果和组织特异性作用部位（即肝脏、使用高胰岛素正常血糖钳改善小鼠胰岛素敏感性的完整 BB 和 BB 生物活性成分的脂肪组织和/或骨骼肌。在这一受指导的职业发展过程中，Stull 博士将从具有相关专业知识的导师那里获得详细的意见，并通过学习与[分子和细胞生物学、植物学表征和动物生物方法学]相关的新技术和方法来提高她作为临床研究人员的多功能性。 Stull 博士的长期目标是成为补充和替代医学研究的独立转化 CAM 研究者和领导者，重点研究植物膳食补充剂及其对胰岛素抵抗的影响。 公共健康相关性：拟议的研究与公共健康相关，因为它将提供关于常见水果（即蓝莓）中发现的植物化学物质对血糖控制和胰岛素敏感性的有效性的新见解，这可能有利于生活的健康质量，和胰岛素抵抗人群的福祉。最重要的是，该应用的研究结果将使消费者能够就使用蓝莓中的生物活性物质治疗糖尿病前期或 2 型糖尿病患者的胰岛素抵抗做出更明智的决定。