Effect of dipeptidyl peptidase 4 inhibition on growth hormone secretion

二肽基肽酶4抑制对生长激素分泌的影响

• 批准号: 9005877
• 负责人: Jessica K Devin
• 金额: $ 1.13万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2016-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9005877
• 关键词: Acute; Adult; Adverse effects; Affect; Alanine; Anti-Inflammatory Agents; Anti-inflammatory; Biochemical Markers; Biological Preservation; Biology; Blood Glucose; Blood Vessels; Blood flow; Body Composition; Body Weight decreased; Bradykinin; Brain natriuretic peptide; Cardiac; Cardiovascular Diseases; Cardiovascular system; Central obesity; Characteristics; Chronic; Complex; Country; Data; Dedications; Development; Development Plans; Diabetes Mellitus; Dipeptidyl Peptidases; Dyslipidemias; Endothelium; Event; Exhibits; Feedback; Fellowship; Female; Fibrinolysis; Forearm; Functional disorder; Growth Hormone Receptor; Half-Life; Health; Heart Diseases; Hyperglycemia; Hypertension; Hypothalamic structure; Impairment; Inflammation; Insulin Resistance; Knowledge; Life; Lipids; Lipolysis; Maintenance; Mentors; Metabolic; Metabolic Diseases; Metabolic syndrome; Morbidity - disease rate; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Oral; Ovarian; Patients; Pharmaceutical Preparations; Physicians; Physiological; Physiology; Pituitary Diseases; Pituitary Gland; Platelet aggregation; Play; Polycystic Ovary Syndrome; Population; Prevalence; Production; Proline; Prospective Studies; Receptor Activation; Research; Research Infrastructure; Research Personnel; Risk; Risk Factors; Role; Scientist; Secondary to; Somatotropin; Somatotropin-Releasing Hormone; Stem cells; Stimulus; Stroke; Substance P; Syndrome; Target Populations; Testing; Time; United States; Vasodilation; Visceral; Woman; blood glucose regulation; cardiometabolic risk; cardiovascular disorder risk; cardiovascular risk factor; career; career development; clinically relevant; cost effective; diabetic; experience; glucagon-like peptide; glucagon-like peptide 1; glucose tolerance; growth hormone deficiency; high risk; hormone therapy; improved; in vivo; incretin hormone; inhibitor/antagonist; interest; intimal medial thickening; intrahepatic; lean body mass; mortality; novel; patient oriented research; patient population; peptide hormone; pressure; prevent; programs; response; skills

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.]

描述（由申请人提供）：肥胖的成年人发生心血管事件的风险增加。虽然炎症和脂肪溶解增加、纤维蛋白溶解受损和胰岛素抵抗可能导致心血管风险增加，但生长激素（GH）轴的扰动也可能起作用。(7)腹部肥胖是内源性生长激素分泌的强烈负决定因素，相反，获得性生长激素缺乏的成年人会增加内脏脂肪（1;8-10）在研究期间，我证明未经治疗的生长激素缺乏的成年人有不利的纤维蛋白溶解特征和血管反应性受损，外源性生长激素增加了健康成年人的内皮祖细胞（11）。12)生长激素可以改善内皮和心脏功能、身体成分和心血管风险指标，但治疗受到包括高血糖在内的副作用的限制。（13-19）提高生长激素水平的另一种策略是通过防止二肽基肽酶4 （DPP4）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） DPP4抑制剂可降低肠促胰岛素激素的降解，从而改善2型糖尿病患者餐后高血糖。（23;24）普遍存在的DPP4的抑制作用通过倒数第二的丙氨酸或脯氨酸影响脱靶底物。在过去的两年中，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），（25）这一经历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来验证急性DPP4抑制将通过减少GHRH的降解来增加受刺激的GH分泌和GH依赖性的血管舒张。我进一步计划验证一个月的DPP4抑制剂治疗将增强生长激素分泌、血管功能和糖耐量的假设，这些患者的生长激素分泌受损，心脏代谢风险高。使用DPP4抑制剂治疗来恢复生长性GH分泌是一种潜在的高成本效益，高影响的方法，通过它我们可以改善特定目标人群的心脏代谢风险。我致力于临床医生的研究，并对GH轴及其对心血管的影响表现出一贯的兴趣。我很幸运地受益于范德比尔特大学受保护的时间和令人印象深刻的研究基础设施。我的导师是一位成功的内科科学家，她在血管生物学领域进行以假设为导向、以患者为导向的研究，她之前曾展示过她对引导内科科学家走向独立的奉献精神。[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了解，并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。]