Cardiometabolic effects of genetically decreased dipeptidyl peptidase-4 (DPP4)

项目摘要/摘要 心血管疾病是2型糖尿病患者发病率和死亡率的主要原因。 (T2 DM)。确定T2 DM治疗的心血管效应具有重要的临床意义。人类遗传学 可能是一种策略，为T2 DM治疗的长期效果和联系T2 DM的机制提供见解 和心血管风险。二肽基肽酶4(DPP4)抑制剂用于治疗T2 DM和 减少可能有代谢或心血管作用的底物的降解，如类胰高血糖素 肽-1(GLP-1)、神经肽、CXCL12、脑利钠肽和P物质。 通过GLP-1效应改善血糖动力学的好处，DPP4抑制剂也与 因心力衰竭住院的风险增加(如在萨格列汀期间)，可能与阴性有关 神经肽、CXCL12和P物质对DPP4心血管效应的影响 抑制作用仍然有限，因为DPP4抑制剂的最长心血管结局试验只有三次 好几年了。我们在宾夕法尼亚医学生物库的个人中的初步数据显示，基因负担 分析罕见的功能变异丧失，DPP4功能丧失与心脏显著相关 失败了。对DPP4功能丧失的个体进行表型分析将提供对可能的 这一发现的机制以及人类DPP4活性和抗原减少的长期影响。 我们假设遗传性DPP4功能丧失与代谢参数的改善有关 而且还与心力衰竭和相关的生物标志物/成像有关。我们会在《宾夕法尼亚医学会》中指认个人 DPP4功能缺失的生物库和Mayo临床生物库及其配对对照和招募 进行表型研究。我们还将招募参与者参加一项试点临床试验，以评估 DPP4杂合子个体由于药理上的DPP4抑制而丧失功能。 候选人拥有一支强大的多学科指导团队，拥有以患者为导向的研究专家， 遗传学、内分泌学、心脏病学(晚期心力衰竭)、数学建模/生物统计学，以及 代谢组学/蛋白质组学。候选人将在获奖期间获得必要的技能和专业知识 研究领域：遗传学，一种基于遗传学的临床试验招募方法， 胰岛素敏感性和胰岛素分泌、高级生物统计学和领导技能。这将有助于 实现成为独立学术内科医生-科学家所需里程碑的候选人 擅长使用遗传学和临床试验方法来回答T2 DM和 代谢、心血管风险和相关治疗。

Project Summary/Abstract Cardiovascular disease is the leading cause of morbidity and mortality for patients with type 2 diabetes (T2DM). Determining cardiovascular effects of T2DM therapies is of clinical importance. Human genetics may be a strategy to provide insights to long-term effects of T2DM therapies and mechanisms linking T2DM and cardiovascular risk. Dipeptidyl peptidase 4 (DPP4) inhibitors are used for the treatment of T2DM and decrease degradation of substrates with possible metabolic or cardiovascular effects such as glucagon like peptide-1 (GLP-1), neuropeptides, CXCL12, brain natriuretic peptide, and substance P. Although they have the benefit of improving glucose dynamics through GLP-1 effects, DPP4 inhibitors are also associated with increased risk of hospitalization for heart failure (such as during saxagliptin), potentially related to negative effects of neuropeptides, CXCL12, and substance P. Long-term data on cardiovascular effects of DPP4 inhibition remain limited as the longest cardiovascular outcomes trial of DPP4 inhibitors was only three years. Our preliminary data in among individuals in the Penn Medicine Biobank show that on gene burden analysis for rare loss of function variants, DPP4 loss of function was significantly associated with heart failure. Phenotyping individuals with DPP4 loss of function will provide further insights as to the possible mechanism for this finding and long- term effects of decreased DPP4 activity and antigen in humans. We hypothesize that genetic DPP4 loss of function will be associated with improved metabolic parameters but also with heart failure and related biomarkers/ imaging. We will identify individuals in the Penn Medicine Biobank and Mayo Clinic Biobank with DPP4 loss of function variants and their matched controls and recruit them for a phenotyping study. We will also enroll participants in a pilot clinical trial to assess the response of individuals heterozygous for DPP4 loss of function to pharmacologic DPP4 inhibition. The candidate has a strong multi-disciplinary mentoring team with experts in patient oriented research, genetics, endocrinology, cardiology (advanced heart failure), mathematical modeling/ biostatistics, and metabolomics/ proteomics. The candidate will gain necessary skills and expertise during the award period in the areas of: genetics, a genetic-based approach to clinical trials recruitment, mathematical modeling of insulin sensitivity and insulin secretion, advanced biostatistics, and leadership skills. This will facilitate the candidate in achieving necessary milestones to become an independent academic physician-scientist specializing in the use of genetics and clinical trials approaches to answer questions in T2DM and metabolism, cardiovascular risk, and related therapies.