Effect of dipeptidyl peptidase 4 inhibition on growth hormone secretion

描述（由申请人提供）：患有肥胖症的成年人发生心血管事件的风险增加。虽然增加的炎症和脂解，受损的纤维蛋白溶解和胰岛素抵抗可能有助于增加心血管风险，生长激素（GH）轴的扰动也可能发挥作用。(7)腹部肥胖是内源性生长激素分泌的一个强有力的负决定因素，相反，获得性生长激素缺乏的成年人内脏肥胖增加。（1个; 8-10）在研究期间，我证明了未经治疗的GH缺乏症的成人具有不利的纤溶特征和受损的血管反应性，并且外源性GH增强了健康成人的内皮祖细胞。(11 GH给药可改善内皮和心脏功能、身体组成和心血管风险标志物，但治疗受到包括高血糖症在内的副作用的限制。（13-19）增加GH水平的另一种策略是通过防止二肽基肽酶4（DPP 4）降解其主要刺激物生长激素释放激素（GHRH）来增强其内源性分泌。（20-22）DPP 4抑制剂减少肠促胰岛素激素的降解，从而改善2型糖尿病患者的餐后高血糖症。(23 24）普遍存在的DPP 4的抑制影响具有倒数第二个丙氨酸或脯氨酸的脱靶底物。[Over在过去的两年里，我研究了急性DPP 4抑制对血管活性DPP 4底物降解的影响，包括肽激素胰高血糖素样肽-1（GLP-1）、脑钠肽（BNP）、缓激肽和P物质。(25)这一经历丰富了我对血管生物学和DPP 4生理学的理解，同时使我能够收集测试以下假设所需的技能和初步数据：急性DPP 4抑制将通过减少GHRH的降解来增加刺激的GH分泌和GH依赖性血管舒张。我计划进一步检验一个月的DPP 4抑制剂治疗将增强GH分泌受损和高心脏代谢风险患者人群的GH分泌、血管功能和葡萄糖耐量的假设。使用DPP 4抑制剂治疗恢复生理GH分泌是一种潜在的具有成本效益的高影响力的方法，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。[我致力于临床研究者的职业生涯，并对GH轴及其心血管效应表现出一贯的兴趣。]我很幸运能在范德比尔特享受到受保护的时间和令人印象深刻的研究基础设施。我由一位成功的医生科学家指导，她在血管生物学方面进行假设驱动，以患者为导向的研究，并且以前曾证明她致力于引导医生科学家独立。[The建议的职业发展计划和研究将提高我的生长激素生理学和血管生物学的知识，并将使我能够开发一个研究计划，有助于我们了解复杂的病理生理学基础肥胖和血管风险。

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.]