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.

项目概要 这是一个竞争性修订申请，旨在支持我们资助的项目 R01 DK112700 的扩展 “骨骼肌和脂肪组织的动态 PET 成像，探索下外周的机制 非裔美国女性的葡萄糖摄取。（AAW）我们的项目旨在扩大我们对非裔美国女性的葡萄糖摄取的了解。 导致种族差异（非裔美国人与白种人）风险的代谢差异 这一竞争性修订将使我们能够将研究方案的范围扩大到 这些研究很重要，因为 AAW 和 HW 几乎是西班牙裔女性的两倍。 与白人女性 (CW) 相比，患 2 型糖尿病 (T2DM) 的风险更大。 这些种族差异背后的原因尚不清楚，但胰岛素敏感性 (IS) 较低是一个主要风险因素 与 T2DM 的发展相比，在健康、非肥胖 AA 和 H 儿童和成人中观察到 已发表的数据表明胰岛素在某些方面存在内在的生理差异。 AAW 和 HW 中较低的外周 GU 受到刺激可能具有潜在的严重后果。 临床后果，因为这可能会由于长期需要代偿而导致 β 细胞紧张 胰岛素分泌，导致患 T2DM 的风险更大。 鉴定导致胰岛素刺激 GU 减少的特定组织和生化途径 具有重要的积极临床意义；即针对衰退部位的干预措施 瘦 AAW 和 HW 中的 IS 可以降低肥胖女性随后的 IR，从而降低患 我们当前 R01 的具体目标涉及两个假设：1) 降低胰岛素使用率。 刺激的葡萄糖转运是 AAW 中胰岛素刺激的 GU 减少的基础；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。 通过这种扩展，我们将包括以下方面的研究： 此外，还将包括一个新的目标，以探索对这些种族负责的其他机制。 为了帮助实现这一新目标，我们聘请了埃默里大学和乔治亚州的研究人员。 在液相色谱/质谱 (LC/MS) 代谢组学和 通过有限的靶向代谢物分析，我们发现特定的神经酰胺， 二酰基甘油和酰基肉碱与白种人的胰岛素敏感性有关。 总之，AAW 和 HW 中外周 GU 的减少似乎是 T2DM 的早期危险因素。 第一项研究证明了特定的代谢步骤，即脂肪组织的贡献和 骨骼肌，以及 AAW 和 HW 中下外周 GU 的潜在机制。 提供对针对 AAW 和下外周 GU 潜在机制的治疗的见解 HW，重要的是可以用来减少与肥胖相关的胰岛素抵抗和糖尿病。