Modulation of Human Myocardial Metabolism by GLP-1

描述(申请人提供)：缺血性心脏病是糖尿病患者最常见的死亡原因。在氧气供应有限的情况下，最大化心脏对葡萄糖的利用可能是有利的，因为葡萄糖是最高效的氧气燃料，这种方法可能对糖尿病患者特别有利。胰升糖素样肽(GLP)-1是一种肠源性多肽，通过作用于朗格汉斯的胰岛来改善葡萄糖代谢。GLP-1的胰腺外作用也已被描述，包括增强心肌葡萄糖代谢的直接作用，这与对全身代谢的影响不同。因此，GLP-1有可能在治疗上用于调节心肌燃料的选择，在优先使用葡萄糖燃料有利的情况下提供益处。支持这一潜在应用的数据包括体外研究、整体器官研究、整体动物研究和原则验证人体研究。在临床试验中进一步评估这种方法的一个重要障碍是缺乏人类的定量数据来指导使用GLP-1作为心肌燃料选择调节剂的剂量选择。此外，在2型糖尿病中，GLP-1抵抗被识别(即，与对照组相比，对系统新陈代谢的作用减少)。因此，在非糖尿病对照组和2型糖尿病受试者中，GLP-1在心脏中的作用也可能不同。这项建议的目的是提供健康对照受试者和肥胖2型糖尿病受试者的定量剂量反应数据，以支持评估GLP-1对心脏病治疗应用的研究设计。这将使用正电子发射断层扫描(PET)来完成，它允许对心脏代谢的多个参数进行定量测量，因此是进行这些测量的理想工具。我们将研究瘦身健康的非糖尿病受试者(目标1)和肥胖的2型糖尿病受试者(目标2)。在每组研究中，每组10名受试者将在输注0(生理盐水对照)、0.5、1.5和4.0pmol/kg/min GLP-1(每名受试者一项研究)的过程中进行研究。心脏代谢将使用正电子发射计算机断层扫描(PET)进行测量，使用双示踪方法可以测量心肌葡萄糖摄取(主要终点)以及总氧化率和心肌血流(次要终点)。与循环代谢产物和调节激素的测量相结合，我们将对GLP-1对人类心肌代谢的作用进行迄今为止最全面的评估。每种剂量的效果将与生理盐水对照组进行比较，此外，我们将结合所有数据并使用非线性曲线拟合来得出GLP-1对心肌葡萄糖摄取的敏感性(ED50)和最大反应。AIMS 1和AIMS 2的结果将结合在一起，以便直接比较非糖尿病对照组和2型糖尿病受试者之间的剂量反应。 公共卫生相关性：建议的研究对于量化和更好地了解GLP-1对患有和不患有2型糖尿病的人类心肌代谢的影响是必要的。这将为进一步的临床研究评估GLP-1在急性心肌缺血治疗中的使用提供合理的剂量选择，这可能对糖尿病患者特别有益。

DESCRIPTION (provided by applicant): Ischemic heart disease is the most common cause of death among patients with diabetes. Maximizing the use of glucose by the heart under limited oxygen availability can be advantageous, since glucose is the most oxygen-efficient fuel, and this approach may be particularly advantageous in patients with diabetes. Glucagon-like peptide (GLP)-1 is a gut-derived peptide that improves glucose metabolism by actions in the pancreatic islets of Langerhans. Extrapancreatic actions of GLP-1 have also been described, including direct actions to augment myocardial glucose metabolism that are distinct from effects on systemic metabolism. Therefore it is possible that GLP-1 could be used therapeutically to modulate myocardial fuel selection, conferring benefits where preferential use of glucose fuel is advantageous. Data in support of this potential application includes in vitro, whole organ, whole animal and proof-of-principle human studies. One important barrier to the further evaluation of this approach in clinical trials is a lack of quantitative data in humans to guide dose selection for the use of GLP-1 as a modulator of myocardial fuel selection. Further, in type 2 diabetes GLP-1 resistance is recognized (i.e. actions on systemic metabolism are reduced compared to controls). Therefore GLP-1 effects in the heart may also differ between nondiabetic control and type 2 diabetic subjects. The objective of this proposal is to provide quantitative dose-response data in healthy control subjects and obese type 2 diabetic subjects, in support of the design of studies evaluating therapeutic applications of GLP-1 to heart disease. This will be accomplished using Positron Emission Tomography (PET), which allows quantitative measurement of multiple parameters of cardiac metabolism and is therefore an ideal tool for undertaking these measurements. We will study lean healthy non-diabetic subjects (Aim 1) and obese type 2 diabetic subjects (Aim 2). In each set of studies, four groups of 10 subjects will be studied during infusions of 0 (saline control), 0.5, 1.5, and 4.0 pmol/kg/min GLP-1 (one study per subject). Cardiac metabolism will be measured using PET, using a dual- tracer approach which allows measurement of myocardial glucose uptake (the primary endpoint) along with total oxidation rate and myocardial perfusion (secondary endpoints). In concert with measures of circulating metabolites and regulatory hormones, we will produce the most comprehensive assessment of actions of GLP- 1 on myocardial metabolism in humans to date. Effects of each dose will be compared to the saline control, plus we will combine all data and use nonlinear curve-fitting to derive sensitivity (ED50) and maximal responses for GLP-1 effects on myocardial glucose uptake. Results from Aims 1 and 2 will be combined to allow direct comparison of the dose-response between nondiabetic control and type 2 diabetic subjects. PUBLIC HEALTH RELEVANCE: The proposed studies are necessary to quantify and better understand the effects of GLP-1 on myocardial metabolism in humans with and without type 2 diabetes. This will allow rational dose selection for further clinical studies evaluating the use of GLP-1 in the management of acute myocardial ischemia, which may be of particular benefit for people with diabetes