Modulation of Human Myocardial Metabolism by GLP-1

描述（由申请人提供）：缺血性心脏病是糖尿病患者最常见的死亡原因。在有限的氧气可用性下最大化心脏对葡萄糖的使用可能是有利的，因为葡萄糖是最有效的氧气燃料，并且这种方法在患有糖尿病的患者中可能特别有利。胰高血糖素样肽（GLP）-1是一种肠源性肽，通过在胰岛中的作用改善葡萄糖代谢。还描述了GLP-1的胰腺外作用，包括增加心肌葡萄糖代谢的直接作用，这与对全身代谢的作用不同。因此，GLP-1可能在治疗上用于调节心肌燃料选择，在优先使用葡萄糖燃料是有利的情况下赋予益处。支持这一潜在应用的数据包括体外、整个器官、整个动物和原理验证人体研究。在临床试验中进一步评价这种方法的一个重要障碍是缺乏人体定量数据来指导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，确认GLP-1抵抗（即与对照相比，对全身代谢的作用降低）。因此，GLP-1在心脏中的作用在非糖尿病对照和2型糖尿病受试者之间也可能不同。本提案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，以支持评价GLP-1治疗心脏病应用的研究设计。这将使用正电子发射断层扫描（PET）来完成，PET允许定量测量心脏代谢的多个参数，因此是进行这些测量的理想工具。我们将研究瘦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，将在0（生理盐水对照）、0.5、1.5和4.0 pmol/kg/min GLP-1输注期间研究4组10例受试者（每例受试者一项研究）。将使用PET测量心脏代谢，使用双示踪剂方法，允许测量心肌葡萄糖摄取（主要终点）沿着总氧化率和心肌灌注（次要终点）。结合循环代谢物和调节激素的测量，我们将对GLP- 1对人体心肌代谢的作用进行迄今为止最全面的评估。将每种剂量的效应与生理盐水对照进行比较，并且我们将联合收割机所有数据并使用非线性曲线拟合来推导GLP-1对心肌葡萄糖摄取效应的灵敏度（ED 50）和最大响应。将合并目标1和2的结果，以直接比较非糖尿病对照和2型糖尿病受试者之间的剂量反应。 公共卫生相关性：拟议的研究对于量化和更好地了解GLP-1对患有和不患有2型糖尿病的人的心肌代谢的影响是必要的。这将为进一步的临床研究提供合理的剂量选择，以评估GLP-1在急性心肌缺血管理中的应用，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