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

项目摘要 这是一个竞争性修订申请，以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成像探讨低位外周的发病机制 非裔美国女性的葡萄糖摄取情况。(Aaw)我们的项目旨在扩大我们对 导致风险种族差异(非裔美国人与高加索人)的代谢差异 治疗糖尿病。这一竞争性修订将使我们能够将研究方案的范围扩大到 包括西班牙裔妇女(HW)。这些研究很重要，因为AAW和HW表现出近两个方面的 与高加索女性(CW)相比，患2型糖尿病(T2 DM)的风险更高。 这些种族差异背后的原因尚不清楚，但胰岛素敏感性(IS)较低是一个主要的风险因素。 在健康、非肥胖的AA和H儿童和成人中观察到与T2 DM的发生 和高加索人匹配。已公布的数据表明，胰岛素的某些方面存在内在生理差异(S)- 刺激外周组织中的GU。AAW和HW中较低的外周GU可能有潜在的严重 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，导致发生T2 DM的风险更大。 胰岛素刺激谷氨酸减少的特定组织和生化途径的鉴定 将具有重要的积极临床意义；即针对减少的部位的干预 精瘦的AAW和HW可以降低肥胖女性随后的IR，从而降低 2型糖尿病的发展。我们目前的R01的具体目标解决了两个假设：1)较低的胰岛素比率- 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胰岛素敏感性降低的重要部位。此外，我们还将探索 造成这些种族差异的潜在机制。随着这一扩展，我们将包括以下研究 HW。此外，将包括一个新目标，以探索应对这些种族问题负责的其他机制 不同之处。为了帮助实现这一新目标，我们聘请了来自埃默里大学和佐治亚州的调查人员 在液-质联用(LC/MS)代谢物和 脂肪组学分析。使用有限的靶向代谢物分析，我们已经证明了特定的神经酰胺， 在高加索人中，二酰甘油和酰肉碱与胰岛素敏感性有关。 综上所述，AAW和HW患者外周GU减少似乎是T2 DM的早期危险因素。这将是 这是第一项证明特定代谢步骤被改变的研究，脂肪组织和 骨骼肌，以及在AAW和HW中导致外周GU降低的潜在机制。我们的发现将 提供针对AAW和AAW特有的较低外周GU潜在机制的治疗见解 HW，重要的是它可能被实施来降低肥胖相关的胰岛素抵抗和糖尿病。

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.