Kisspeptin: A Novel Regulator of Insulin in Pregnancy

项目总结 这一提议的主要假设是Kispeptin可能解释了血糖的许多变化 妊娠期间的代谢：正常妊娠期间高水平的Kispeptin促进胰岛素释放以维持 正常血糖和相对低血症可能是妊娠期病理生理缺陷的基础。 糖尿病(GDM)。检验这一总体假设的最初步骤是：1)定义 Kispeptin(妊娠期)对非妊娠妇女胰岛素生理的影响 水平预测妊娠期糖尿病的发展。考虑到怀孕期间调节新陈代谢的因素的复杂性 和胰岛素生理学，这些初步研究旨在分离一个因素的影响：Kispeptin。这 建议使用黄金标准(高血糖和高胰岛素正常血糖钳夹)和生理学(混合 餐耐量试验)随机、安慰剂对照和盲法临床试验中评估Kispeptin的方法 对非妊娠妇女胰岛素分泌和胰岛素敏感性的影响。更进一步，这笔赠款利用 具有纵向妊娠样本和患者结局数据的综合样本库以进行测量 并确定妊娠早期的Kispeptin水平是否可以预测 GDM的发展。这笔赠款将加深我们对妊娠高粘蛋白血症影响的理解。 胰岛素和胰岛素的生理与妊娠期糖尿病的发生发展。 这份申请详细说明了一项为期五年的全面培训计划，旨在指导患者的职业发展- 以研究为导向。申请人提出研究，包括专门设计的独立临床试验。 提供孕期生理学和胰岛素生理学机制方面的重点培训。要做到这一点 为了实现目标，她选择了具有互补专业知识的导师：斯蒂芬妮·塞米娜拉博士是接吻方面的专家 生理学，在人类生理学研究方面有很强的背景，她是生殖科主任 马萨诸塞州综合医院(MGH)内分泌科；帕特里克·卡塔拉诺医生是妊娠专家 生理学和妊娠期糖尿病，他是塔夫茨大学的妇产科教授 医学院和母婴研究所首席研究员；何塞·弗洛雷斯博士是一位专家 他是麻省理工学院糖尿病部门的主任。这 指导团队将很好地定位申请者，使其能够在 新陈代谢，重点是妊娠和生殖激素的影响，NICHD的一项关键研究 优先领域。申请人的职业发展计划需要严格的课程和研讨会，亲身实践 实践经验，以及具有不同科学专业知识的科学顾问的密切指导。总而言之， 在此奖项期间获得的经验将作为申请者独立的、学术的 作为一名内科科学家，在人类代谢性疾病的翻译研究方面拥有专业知识。

PROJECT SUMMARY The overarching hypothesis of this proposal is that kisspeptin may explain many of the changes in glucose metabolism in pregnancy: high levels of kisspeptin during normal pregnancy amplify insulin release to maintain normoglycemia, and relative hypokisspeptinemia may underlie the pathophysiologic defects in gestational diabetes mellitus (GDM). The initial steps to examining this overarching hypothesis are to 1) define the effect of kisspeptin (at pregnancy levels) on insulin physiology in non-pregnant women and 2) to determine if kisspeptin levels predict the development of GDM. Given the complexity of factors in pregnancy that regulate metabolism and insulin physiology, these initial studies are designed to isolate the effect of one factor: kisspeptin. This proposal utilizes gold standard (hyperglycemic and hyperinsulinemic euglycemic clamps) and physiologic (mixed meal tolerance test) methods in randomized, placebo-controlled and blinded clinical trials to assess kisspeptin’s impact on insulin secretion and insulin sensitivity in non-pregnant women. Going further, the grant utilizes comprehensive specimen banks with longitudinal pregnancy samples and patient outcome data to measure kisspeptin levels across pregnancy and to determine if kisspeptin levels early in pregnancy can predict the development of GDM. This grant will refine our understanding of the impact of hyperkisspeptinemia of pregnancy on insulin and incretin physiology and development of GDM. This application details a comprehensive five-year training program for mentored career development in patient- oriented research. The Applicant proposes research, including independent clinical trials, specifically constructed to provide focused training pregnancy physiology and in the mechanisms of insulin physiology. To achieve this goal, she has chosen mentors with complementary expertise: Dr. Stephanie Seminara is an expert in kisspeptin physiology with a strong background in human physiology research, and she is Chief of the Reproductive Endocrine Unit at Massachusetts General Hospital (MGH); Dr. Patrick Catalano is an expert in pregnancy physiology and gestational diabetes, and he is a Professor of Obstetrics and Gynecology at Tufts University School of Medicine and Principal Investigator in the Mother Infant Research Institute; Dr. Jose Florez is an expert in physiological mechanisms in the development of diabetes, and he is Chief of the Diabetes Unit at MGH. This mentoring team will position the Applicant well to launch a successful independent investigative career in metabolism, with a focus on pregnancy and the influence of reproductive hormones, a key NICHD research priority area. The Applicant's career development plan entails rigorous coursework and seminars, hands-on practical experience, and close guidance from scientific advisors with diverse scientific expertise. Collectively, the experience gained during this award will serve as the foundation for the Applicant's independent, academic career as a physician-scientist with expertise in translational research in human metabolic disease.