MULTI-TISSUE MULTI-TRACER METABOLIC PHENOTYPING OF DIABETES WITH PRE-CLINICAL PET

描述（由申请人提供）：2型糖尿病（T2D）是全身代谢紊乱的结果，主要表现为外周组织（如肝脏、肌肉和脂肪组织）胰岛素作用受损。鉴于健康中底物代谢的高度相互关联和协调的性质，以及它在T2D中的失败，目前的研究需要一个综合的体内“系统生物学”策略来研究肥胖和糖尿病胰岛素抵抗病因中的体内多组织代谢改变。临床前PET的独特之处在于多个组织在视场（FOV）中。这种实现提供了通过多示踪剂实验和示踪剂动力学数学模型进行非侵入性多组织定量成像和代谢表型分析的机会。考虑到这一点，并考虑到我们量化啮齿动物心肌底物代谢的经验，我们假设采用类似的方法将提供肝脏、肌肉和脂肪组织底物代谢的定量测量。本提案中考虑的代谢示踪剂包括用于FA氧化和甘油三酯合成（储存）的[11C]棕榈酸酯，用于脂肪酸氧化的18FTHA；[11C]葡萄糖用于葡萄糖氧化和糖原合成，18FDG用于葡萄糖利用，[11C]乳酸作为糖异生的潜在成像标记物。鉴于肝脏的双输入功能，在Specific Aim 1中，我们将验证和优化一种算法，以重建肝脏底物代谢多示踪成像中的肝脏双输入功能。有了肝脏的双输入功能，在Specific Aim 2中，我们通过增强代谢反应动态范围的干预，构建并验证了18FDG、[11C]葡萄糖、[11C]乳酸、[11C]棕榈酸酯、[11C]醋酸酯和18FTHA代谢的室室模型。在本研究中，我们构建并验证了示踪剂的区室模型，并通过多组织多示踪剂时间过程代谢表型分析来评估和表征T2D发病机制中的代谢紊乱。体内代谢表型将与表达阵列分析相结合，以将基因组学改变与代谢紊乱联系起来。我们预计，这项工作的成功完成将提供一个整合的体内代谢表型平台，将转基因/敲除动物疾病模型中的基因组改变与T2D研究中的多组织代谢紊乱联系起来。此外，拟议的工作将有助于表征T2D与心血管疾病之间的相互作用，以及提案中强调的其他方面。同样重要的是，我们预计从这项工作中获得的策略和见解将转化为临床应用。

DESCRIPTION (provided by applicant): Type 2 Diabetes (T2D) is a result of systemic disturbances in metabolism characterized mainly by impaired insulin action in peripheral tissues such as liver, muscle, and adipose tissue. In light of the highly interconnected and coordinated nature of substrate metabolism in health, and its failure in T2D, current research necessitates an integrated in-vivo "systems biology" strategy to investigate in-vivo multi-tissue metabolic alterations in the etiology of insulin resistance in obesity and diabetes. Pre-clinical PET is unique in that multiple tissues are in the field-of-view (FOV). This realization affords the opportunity to perform non-invasive multi-tissue quantitative imaging and metabolic phenotyping through multi-tracer experiments coupled with mathematical models of tracer kinetics. With that in mind and given our experience in quantifying myocardial substrate metabolism in rodents, we hypothesize that employing a similar approach will provide quantitative measures of substrate metabolism in liver, muscle, and adipose tissue. The metabolic tracers considered in this proposal include [11C]Palmitate for FA oxidation and triglycerides synthesis (storage), 18FTHA for fatty acid oxidation; [11C]Glucose for glucose oxidation and glycogen synthesis, 18FDG for glucose utilization, and [11C]Lactate as a potential imaging marker for gluconeogenesis. Given the dual-input function to the liver, in Specific Aim 1 we will validate and optimize an algorithm to reconstruct the liver dual-input function in multi- tracer imaging of hepatic substrate metabolism. With the liver dual input function at hand, in Specific Aim 2 we construct and validate compartmental models of 18FDG, [11C]Glucose, [11C]Lactate, [11C]Palmitate, [11C]Acetate, and 18FTHA metabolism through interventions that enhance the dynamic range of metabolic response. Having constructed and validated compartmental models for the tracers in this proposal, we assess and characterize metabolic disturbances in the pathogenesis of T2D by performing multi-tissue multi-tracer time-course metabolic phenotyping. In-vivo metabolic phenotyping will be coupled with expression array analysis to correlate genomics alterations to metabolic disturbances. We anticipate that successful completion of the proposed work will provide an integrated in-vivo metabolic phenotyping platform linking genomic alterations in transgenetic/knockout animal models of disease to multi-tissue metabolic disturbances in the study of T2D. In addition, the proposed work will facilitate characterization of the interplay between T2D and cardiovascular disease, among others highlighted in the proposal. Equally important, we anticipate that strategy and insights derived from this work will be translated to clinical applications. PUBLIC HEALTH RELEVANCE: Type 2 Diabetes (T2D) is a complex disease affecting more than 150 million people worldwide, and a large increase in these numbers is expected within the coming years. Recent epidemiological and experimental evidence suggests that there is a close link between the etiology of obesity and T2D, thus confounding the bleak outlook for T2D. A common feature to both obesity and T2D is insulin resistance. In the setting of insulin resistance, multiple-tissues including liver, muscle, and adipose tissue, fail to regulate glucose and fatty acid metabolism. Given this coordinated failure in regulating metabolism, new strategies are needed to characterize substrate metabolism non-invasively in multiple systems. We propose to develop and validate an integrated strategy to perform metabolic imaging in multi-tissues using multiple metabolic tracers in conjunction with pre-clinical Positron Emission Tomography (PET). Pre-clinical PET is unique in that multiple tissues are in the field-of-view (FOV). This realization affords the opportunity to perform non-invasive multi-tissue quantitative imaging to assess metabolism through multi-tracer experiments coupled with mathematical models to quantify metabolism. The tracers we will consider in this proposal include tracers involved in fatty acid metabolism, glucose metabolism, and lactate metabolism. We anticipate that the proposed strategy will aid in characterizing the progression of T2D, the study of the interplay between diabetes and cardiovascular disease-a leading cause of death among diabetic patients-as well as other diseases and conditions highlighted in the proposal.