Dynamic PET imaging in skeletal muscle and adipose tissue to explore mechanisms of lower peripheral glucose uptake in African American Women

骨骼肌和脂肪组织动态 PET 成像探索非洲裔美国女性外周葡萄糖摄取较低的机制

• 批准号: 10165182
• 负责人: James P DeLany
• 金额: $ 70.96万
• 依托单位: ADVENTHEALTH ORLANDO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165182
• 关键词: Abdomen; Address; Adipose tissue; Adult; African American; Beta Cell; Biochemical; Biochemical Pathway; Biological Assay; Biopsy; Caucasians; Ceramides; Child; Clinical; Collection; Data; Development; Diabetes Mellitus; Diglycerides; Endocannabinoids; Exhibits; Fiber; Funding; GLUT4 gene; Glucose; Glucose Clamp; Hispanics; Image; Insulin; Insulin Resistance; Intervention; Lead; Liver; Measures; Metabolic; Mitochondria; Muscle; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Peripheral; Phosphorylation; Physiological; Plasma; Play; Positron-Emission Tomography; Protocols documentation; Publishing; Research; Research Personnel; Risk; Risk Factors; Role; Site; Skeletal Muscle; Thigh structure; Thinness; Tissues; Universities; Visceral; Woman; acylcarnitine; adipokines; biceps brachii muscle; blood glucose regulation; clinically relevant; design; diabetes risk; experience; glucose transport; glucose uptake; hexokinase; in vivo; insight; insulin secretion; insulin sensitivity; kinetic model; liquid chromatography mass spectrometry; men; metabolomics; racial difference; racial disparity; subcutaneous; therapeutic target; vastus lateralis

Project Summary This is a competitive revision application to support the expansion of our funded project, R01 DK112700 “Dynamic PET imaging in skeletal muscle and adipose tissue to explore mechanisms of lower peripheral glucose uptake in African American Women.” (AAW) Our project was designed to expand our understanding of the metabolic differences responsible for the racial disparity (African American compared to Caucasian) in risk for diabetes. This competitive revision will allow us to expand the scope of our research protocol to include Hispanic women (HW). These studies are important because AAW and HW exhibit nearly a two-fold greater risk of developing type 2 diabetes (T2DM) compared to Caucasian women (CW). Reasons behind these racial disparities are not understood, but lower insulin sensitivity (IS), a major risk factor for development of T2DM, is observed in healthy, non-obese AA and H children and adults compared to matched Caucasians. Published data indicate an intrinsic physiologic difference in some aspect(s) of insulin- stimulated GU in peripheral tissues. The lower peripheral GU in AAW and HW could have potentially serious clinical consequences, as this may lead to a strain on the β-cells due to the long term need for compensatory insulin secretion, resulting in greater risk for development of T2DM. The identification of specific tissues and biochemical pathways that underlie reduced insulin-stimulated GU would have important positive clinical relevance; that is that interventions that target the site of the decreased IS in lean AAW and HW could decrease subsequent IR in obese women, and thus lessen the risk for the development of T2DM. The specific aims of our current R01 address two hypotheses: 1) a lower rate of insulin- stimulated glucose transport underlies the reduction in insulin-stimulated GU in AAW; and 2) insulin-stimulated GU into adipose tissue is an important site of decreased insulin sensitivity in AAW. In addition, we will explore potential mechanisms responsible for these racial differences. With this expansion we will include studies in HW. In addition, a new aim will be included to explore additional mechanisms responsible for these racial differences. To assist with this new aim, we have engaged investigators from Emory University and Georgia Tech with extensive experience in liquid chromatography/ mass spectrometry (LC/MS) metabolomic and lipidomic analyses. Using, limited targeted metabolite analyses, we have shown that specific ceramides, diacylglycerols, and acylcarnitines are associated with insulin sensitivity in Caucasians. In summary, decreased peripheral GU in AAW and HW appears to be an early risk factor of T2DM. This will be the first study to demonstrate specific metabolic steps that are altered, the contribution of adipose tissue and skeletal muscle, and potential mechanisms underlying lower peripheral GU in AAW and HW. Our findings will provide insights into therapeutics that target mechanisms underlying lower peripheral GU specific to AAW and HW, which importantly may be implemented to decrease obesity-related insulin resistance and diabetes.

项目摘要 这是一项竞争性修订申请，旨在支持我们资助的项目R01 DK112700的扩展 “骨骼肌和脂肪组织中的动态宠物成像，以探索下周围的机制 非裔美国人妇女的葡萄糖吸收。”（AAW）我们的项目旨在扩大我们对 造成种族差异的代谢差异（非裔美国人与白种人相比）的风险 用于糖尿病。这种竞争性修订将使我们能够将研究协议的范围扩展到 包括西班牙裔妇女（HW）。这些研究很重要，因为AAW和HW暴露了几乎两倍 与高加索妇女（CW）相比，患2型糖尿病（T2DM）的风险更大。 这些种族分布背后的原因尚不清楚，但较低的胰岛素敏感性（IS）是主要的危险因素 为了开发T2DM，在健康的非肥胖AA和H儿童和成人中观察到 匹配的高加索人。已发布的数据表明胰岛素的某些方面存在内在的生理差异 在外周组织中刺激GU。 AAW和HW中的下部外围GU可能具有严重性 临床后果，因为这可能会导致β细胞的压力，因为长期需要代码 胰岛素分泌，导致T2DM发展的风险更大。 鉴定特定的组织和生化途径，这些途径是胰岛素刺激的GU的基础 具有重要的积极临床相关性；那就是针对改进现场的干预措施 在瘦小的AAW中，HW可能会减少肥胖妇女的随后IR，从而降低 T2DM的开发。我们当前R01的具体目的提到了两个假设：1）胰岛素 - 较低的速率 刺激的葡萄糖转运是AAW中胰岛素刺激的GU的减少。 2）胰岛素刺激 GU进入脂肪组织是AAW中胰岛素敏感性降低的重要部位。此外，我们将探索 导致这些种族差异的潜在机制。通过这种扩展，我们将在 HW。此外，还将包括一个新的目标，以探索负责这些种族的其他机制 差异。为了帮助实现这一新目标，我们聘请了埃默里大学和佐治亚州的调查员 具有丰富液相色谱/质谱法（LC/ MS）代谢组和代谢组的技术丰富经验 脂质组分析。使用有限的目标代谢物分析，我们已经表明特定的神经酰胺， 二酰基甘油和酰基肉碱与高加索人的胰岛素敏感性有关。 总而言之，AAW和HW中的外围GU的改善似乎是T2DM的早期危险因素。这将是 首次研究发生了变化的特定代谢步骤的研究，脂肪组织和 骨骼肌和AAW和HW中较低外围GU的潜在机制。我们的发现会 提供有关治疗的见解，该治疗的目标是针对AAW和AAW和 HW，重要的是可以实施，以减少与肥胖相关的胰岛素耐药性和糖尿病。