CYCLOTRON PRODUCED ISOTOPES IN BIOLOGY AND MEDICINE-PROJECT 3

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。在美国，糖尿病的患病率在过去30年里急剧增加。绝大多数病例是胰岛素抵抗或2型糖尿病(T2 DM)。T2 DM患病率的快速增加与肥胖症的急剧增加(及其对胰岛素敏感性的影响)同步。心血管疾病是T2 DM患者的主要死亡原因，动脉粥样硬化约占患者总数的80%。T2 DM患者对心血管疾病特别是动脉粥样硬化易感的原因是多因素的。胰岛素抵抗、高血糖、血脂异常、高凝、肥胖和高血压等一系列被称为代谢综合征的疾病在很大程度上导致冠状动脉粥样硬化的增加。然而，即使没有证据表明心外膜参与冠状动脉粥样硬化，心肌内皮细胞依赖的血管扩张能力也可能出现显著的异常。此外，有越来越多的证据表明真正的糖尿病心肌病--在没有合并冠状动脉病变的情况下出现左室收缩和舒张期功能障碍。事实上，糖尿病的存在显著增加了老年男性和女性充血性心力衰竭的风险。因此，T2 DM患者的心血管疾病的临床表现是复杂的。也就是说，有越来越多的证据表明，全身和心肌基质代谢的异常是导致T2 DM患者心血管异常的原因之一。本研究的主要目的是将我们对1型糖尿病(T1 DM)患者心肌底物代谢和功能的研究扩展到T2 DM患者心肌底物代谢和功能与全身底物代谢的关系的研究。在T2 DM的实验模型和我们自己在T1 DM患者中的数据中获得的大量证据表明，在T2 DM患者中，脂肪酸可获得性(以NEFA和TG的形式)的增加对于T2 DM患者心肌脂肪酸代谢的增加和葡萄糖代谢的降低以及随后的左室舒张功能的下降起着中心作用。为了验证我们的假设，即同时达到血糖控制的目标水平并降低血浆NEFA和TG水平，将与仅为达到血糖控制目标水平而设计的治疗策略相比，更大程度地降低心肌对脂肪酸代谢的依赖，以及更大程度地改善心肌舒张期功能，我们的具体目标是：1A：为了评估降低T2 DM患者血浆NEFA的影响，我们将确定在二甲双胍(MET)+/-其他非噻唑烷二酮口服药物(MET)方案中添加PPARy(过氧化体增殖物激活受体-γ)激动剂ROSI对全身基质代谢及心肌基质代谢和功能的影响。1B：为了评估T2 DM患者降低血浆甘油三酯(TG)的效果，我们将确定在MET+/-其他非噻唑烷二酮口服药物(MET)方案中加入缓释烟酸制剂NI对全身基质代谢以及对心肌基质代谢和功能的影响。我们将开展一系列实验，利用正电子发射断层扫描(PET)定量检测T2 DM患者的心肌基质代谢，超声放射学测量左室收缩和舒张期功能，稳定同位素测量全身脂肪酸和葡萄糖动力学。测量将分成三组：仅使用MET的测量，使用MET和ROSI的测量，以及使用MET和NI的测量。当结合项目2的结果时，在人类2型糖尿病患者中观察到的特定干预措施导致的全身和心肌基质代谢的变化将与经历相同干预的啮齿动物模型中基因表达的变化联系在一起。这一数据可能会通过纳入旨在减少NEFA进入心脏的治疗方法，为T2 DM治疗模式的转变提供支持。该项目的成功完成将为了解T2 DM对外周基质代谢、心肌基质代谢和左心室(LV)功能的影响之间的联系提供关键的见解。减少脂肪酸输送导致减少心肌对脂肪酸代谢的依赖，改善左心功能，这将为积极降低Plamsa、NEFA和TG的必要性提供强有力的证据。此外，可以获得关于降低NEFA相对于TG的相对优点的信息。来自该项目的数据可能有助于刺激旨在降低T2 DM患者血浆脂肪酸供应的新疗法的开发。此外，这可能为更大规模的研究提供基础，以评估旨在降低T2 DM患者血浆脂肪酸可获得性的治疗的临床效果，无论是单独还是与主要针对血糖控制的治疗相结合。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the United States, the prevalence of diabetes mellitus has increased dramatically over the past 30 years. The vast majority of cases are insulin-resistant or type 2 diabetes mellitus (T2DM). This rapid increase in the prevalence of T2DM parallels the dramatic increase in obesity (and its attendant effects on insulin sensitivity). Cardiovascular disease is the leading cause of death in patients with T2DM, with atherosclerosis accounting for approximately 80% of the cases. The reason for suseceptibility of T2DM patients to cardiovascular disease in general and atherosclerosis in particular, is multifactorial. The cluster of insulin resistance, hyperglycemia, dyslipidemia, hypercoagubility, obesity and hypertension known as the "metabolic sydrome" is largely responsible for the increase in coronary atherosclerosis. However, even when evidence of epicarial involvement of coronary atherosclerosis is not present, significant abnormalities in myocardial endothelial-dependent vasodilator capacity can manifest. Moreover, there is increaseing evidence for true diabetic cardiomyopathy - The presence of left ventricular systolic and diastolic dysfunction that occurs in the absence of concomitant coronary artery disease. Indeed, the presence of diabetes mellitus significantly increases the risk for congestive heart failure in both older men and women. Consequently, the clinical picture of cardiovascular disease in the T2DM patient is complex. That being said, there is a burgeoning body of evidence to suggest that abnormalities in both whole-body and myocardial substrate metabolism are contributing to the cardiovascular abnormalities observed in T2DM patients. The primary objective is to extend our studies of the alterations in myocardial substrate metabolism and function in patients with type 1 diabetes mellitus (T1DM), to the study of myocardial substrate metabolism and function in relation to whole-body substrate metabolism in patients with T2DM. There is a wealth of evidence obtained in experimental models of T2DM and our own data in patients wih T1DM that suggests a central role for increased fatty acid availability (in the form of NEFA and TG) for the increase in myocardial fatty acid metabolism and the decrease in glucose metabolism and subsequent decline in left ventricular diastolic function in patients with T2DM. To test our hypothesis that reaching both a targeted level of glycemic contorl and lowering plasma NEFA and TG levels will be associated with a greater decline in the dependence of the myocardium on fatty acid metabolism and a greater improvement in myocardial diastolic function than treatment strategies designed solely to reach target level of glycemic control, our specific aims are: 1A: To assess the impact of lowering plasma NEFA in patients with T2DM, we will determine the effect of adding the PPARy (peroxisome proliferator activated receptor-gamma) agonist ROSI to a regimen of metformin (MET) +/- other non-thiazolidinedione oral agents (MET) on whole body substrate metabolism and on myocardial substrate metabolism and function. 1B: To assess the impact of lowering plasma TG in patients with T2DM, we will determine the effect of adding an extended-release niacin agent, NI to a regimen of MET +/- other non-thiazolidinedione oral agents (MET) on whole-body substrate metabolism and on myocardial substrate metabolism and function. We will perform a series of experiments that utilize PET (positron emission tomography) quantification of myocardial substrate metabolism, echocradiographic measurements of left ventricular systolic and diastolic function and stable isotopic measurement of whole-body fatty acid and glucose kinetics in T2DM patients. The measurements will be obtained in three groups; those on MET alone, those on MET and ROSI, and those on MET and NI. When combined with the results from Project 2, alterations in whole-body and myocardial substrate metabolism in response to specific interventions observed in humans with T2DM will be linked to changes in gene expression in the rodent models undergoing the same interventions. This data may potentially provide support for a paradigm shift in the treatment of T2DM through the incorporation of therapies designed to decrease NEFA delivery to the heart. Successful completion of this project should provide key insights into the link between the effects of T2DM on peripheral substrate metabolism, myocardial substrate metabolism and left ventricular (LV) function. Demonstration that reduced fatty acid delivery results in less myocardial dependence on fatty acid metabolism and improved LV function will provide strong evidence for the need for aggressive lowering of plamsa NEFA and TG. Furthermore, information may be obtained about the relative merits of lowering NEFA as opposed to TG. Data from this project may help stimulate the development of novel therapeutics designed to decrease plasma fatty acid availability in patients with T2DM. Moreover, it may provide the basis for larger studies to evaluate the clinical efficacy of therapies designed to lower plasma fatty acid availability either alone or in combination with therapies targeted primarily to glycemic control in patients with T2DM.