Effect of dipeptidyl peptidase 4 inhibition on growth hormone secretion

描述(由申请人提供)：肥胖的成年人心血管事件的风险增加。虽然炎症和脂解增加、纤溶受损和胰岛素抵抗可能会增加心血管风险，但生长激素(GH)轴的扰动也可能起到作用。(7)腹部肥胖是内源性GH分泌的强烈负面决定因素，相反，获得性GH缺陷的成年人会发展为内脏脂肪增加。(1；8-10)在团契期间，我证明了未经治疗的GH缺陷成年人具有不利的纤溶特征和血管反应性受损，外源性GH增加了健康成年人的内皮祖细胞。12)尽管治疗受到包括高血糖在内的副作用的限制，但给予生长激素可改善血管内皮和心脏功能、身体成分和心血管风险标志物。(13-19)提高生长激素水平的另一种策略是通过阻止其主要刺激物--生长激素释放激素(GHRH)通过二肽基肽酶4(DPP4)的降解来增强其内源性分泌。(20-22)DPP4抑制剂可减少胰岛素激素的降解，从而改善2型糖尿病患者的餐后高血糖。(23；24)抑制普遍存在的DPP4会通过倒数第二个丙氨酸或脯氨酸影响非靶标底物。[在过去的两年里，我研究了急性DPP4抑制对血管活性DPP4底物降解的影响，包括肽激素胰高血糖素样肽-1(GLP-1)、脑利钠肽(BNP)、缓激肽和P物质。(25)这次经验丰富了我对血管生物学和DPP4生理学的理解，同时使我能够收集所需的技能和初步数据]测试这一假设，即急性DPP4抑制将通过减少GHRH的降解来增加刺激的GH分泌和GH依赖的血管扩张。我还计划进一步验证这样的假设，即一个月的DPP4抑制剂治疗将增强生长激素分泌、血管功能和葡萄糖耐量，这些患者患有生长激素分泌受损和心脏代谢风险高的患者。使用DPP4抑制剂疗法恢复生理性生长激素分泌是一种潜在的成本效益高的方法，通过这种方法，我们可以改善特定目标人群的心脏代谢风险。[我致力于临床医生兼研究人员的职业生涯，并对生长激素轴及其心血管效应表现出一贯的兴趣。]我很幸运地受益于范德比尔特的受保护时间和令人印象深刻的研究基础设施。我得到了一位成功的内科科学家的指导，她在血管生物学方面进行了假设驱动的、以患者为导向的研究，并且之前已经证明了她致力于引导内科科学家走向独立。[拟议的职业发展计划和研究将增强我对生长激素生理学和血管生物学的知识，并将使我能够制定一个研究计划，有助于我们了解肥胖和血管风险背后的复杂病理生理学。]

DESCRIPTION (provided by applicant): Adults with obesity are at increased risk for cardiovascular events. While increased inflammation and lipolysis, impaired fibrinolysis, and insulin resistance may contribute to increased cardiovascular risk, perturbation of the growth hormone (GH) axis may also play a role.(7) Abdominal obesity is a strong negative determinant of endogenous GH secretion and, conversely, adults with acquired GH deficiency develop increased visceral adiposity.(1;8-10) During fellowship, I demonstrated that adults with untreated GH deficiency have an unfavorable fibrinolytic profile and impaired vascular reactivity, and that exogenous GH augments endothelial progenitor cells in healthy adults.(11;12) GH administration improves endothelial and cardiac function, body composition, and markers of cardiovascular risk, though therapy is limited by side effects including hyperglycemia.(13-19) An alternative strategy to increase GH levels is to enhance its endogenous secretion by preventing the degradation of its primary stimulus, growth hormone releasing hormone (GHRH), by dipeptidyl peptidase 4 (DPP4). (20-22) DPP4 inhibitors decrease the degradation of the incretin hormones and thereby improve post-prandial hyperglycemia in patients with type 2 diabetes mellitus. (23;24) Inhibition of the ubiquitous DPP4 affects off-target substrates with a penultimate alanine or proline. [Over the last two years, I have investigated the effect of acute DPP4 inhibition on the degradation of vasoactive DPP4 substrates, including the peptide hormones glucagon like peptide -1 (GLP-1), brain natriuretic peptide (BNP), bradykinin and substance P.(25) This experience has enriched my understanding of vascular biology and DPP4 physiology while allowing me to gather the skills and preliminary data needed to] test the hypothesis that acute DPP4 inhibition will increase stimulated GH secretion and GH-dependent vasodilation by decreasing the degradation of GHRH. I further plan to test the hypothesis that one month of DPP4 inhibitor therapy will enhance GH secretion, vascular function and glucose tolerance in a patient population with impaired GH secretion and high cardio-metabolic risk. The use of DPP4 inhibitor therapies to restore physiologic GH secretion is a potentially cost-effective, high impact approach by which we can improve cardio-metabolic risk in specific target populations. [I am committed to a career as a clinician- investigator and have demonstrated a consistent interest in the GH axis and its cardiovascular effects.] I am fortunate to benefit from protected time and an impressive research infrastructure at Vanderbilt. I am mentored by a successful physician-scientist who conducts hypothesis-driven, patient-oriented, research in vascular biology and who has previously demonstrated her dedication to shepherding physician-scientists to independence. [The proposed career development plan and studies will enhance my knowledge of GH physiology and vascular biology, and will allow me to develop a research program which contributes to our understanding of the complex pathophysiology underlying obesity and vascular risk.]