CYCLOTRON PRODUCED ISOTOPES IN BIOLOGY AND MEDICINE-PROJECT 3

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 在美国，糖尿病的患病率在过去30年中急剧增加。 绝大多数病例为胰岛素抵抗或2型糖尿病（T2 DM）。 T2 DM患病率的快速增加与肥胖症（及其对胰岛素敏感性的伴随影响）的急剧增加相平行。 心血管疾病是T2 DM患者死亡的主要原因，动脉粥样硬化约占80%。 T2 DM患者易患心血管疾病，特别是动脉粥样硬化的原因是多因素的。 胰岛素抵抗、高血糖、血脂异常、高凝状态、肥胖和高血压等称为“代谢综合征”的集合是导致冠状动脉粥样硬化增加的主要原因。 然而，即使没有冠状动脉粥样硬化累及冠状动脉内膜的证据，心肌内皮依赖性血管舒张功能的显著异常也可以表现出来。 此外，有越来越多的证据表明，真正的糖尿病心肌病-左心室收缩和舒张功能障碍的存在，发生在没有伴随冠状动脉疾病。 事实上，糖尿病的存在显着增加了老年男性和女性充血性心力衰竭的风险。 因此，T2 DM患者心血管疾病的临床表现很复杂。 也就是说，越来越多的证据表明全身和心肌底物代谢异常导致了T2 DM患者中观察到的心血管异常。 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改变的研究扩展到T2 DM患者心肌底物代谢和功能与全身底物代谢的关系。在T2 DM实验模型中获得的大量证据和我们自己在T1 DM患者中的数据表明，脂肪酸可用性（以NEFA和TG的形式）增加在T2 DM患者心肌脂肪酸代谢增加和葡萄糖代谢降低以及随后左心室舒张功能下降中起着核心作用。 为了验证我们的假设，即达到血糖控制的目标水平和降低血浆NEFA和TG水平与心肌对脂肪酸代谢的依赖性的更大下降和心肌舒张功能的更大改善相关，而不是仅为达到血糖控制的目标水平而设计的治疗策略，我们的具体目标是： 1A：为了评估降低血浆NEFA对T2 DM患者的影响，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（过氧化物酶体增殖物激活受体-γ）激动剂ROSI对全身底物代谢以及心肌底物代谢和功能的影响。 1B：为了评估降低血浆TG对T2 DM患者的影响，我们将确定在MET +/-其他非噻唑烷二酮口服药物（MET）方案中添加缓释烟酸药物NI对全身底物代谢和心肌底物代谢和功能的影响。 我们将进行一系列实验，利用PET（正电子发射断层扫描）定量心肌基质代谢，超声心动图测量左心室收缩和舒张功能，稳定同位素测量全身脂肪酸和葡萄糖动力学在T2 DM患者。 将在三个组中获得测量值;仅接受MET的组、接受MET和ROSI的组以及接受MET和NI的组。 当与项目2的结果结合时，在T2 DM患者中观察到的全身和心肌底物代谢对特定干预措施的响应变化将与接受相同干预措施的啮齿动物模型中的基因表达变化相关。 该数据可能为通过纳入旨在减少NEFA向心脏输送的治疗来实现T2 DM治疗的范式转变提供支持。 该项目的成功完成将为T2 DM对外周底物代谢、心肌底物代谢和左心室（LV）功能的影响之间的联系提供关键见解。 证明减少脂肪酸输送导致心肌对脂肪酸代谢的依赖性降低和LV功能改善，将为积极降低血浆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。 该项目的数据可能有助于刺激旨在降低T2 DM患者血浆脂肪酸利用率的新型疗法的开发。 此外，它可以为更大规模的研究提供基础，以评估旨在降低血浆脂肪酸利用率的治疗（单独使用或与主要针对T2 DM患者血糖控制的治疗联合使用）的临床疗效。

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.