Mentored Patient-Oriented Research Career Development Award

作为一名候选人，我在医学和妇产科部门之间有着长期的跨部门合作，长期目标是成为妊娠糖尿病（GDM）和胎盘激素生理学的独立研究人员。K-23奖将使我能够结合我通过获得MSPH学位获得的临床研究技能和我通过内分泌学奖学金获得的基本研究技能，以成为一名富有成效的临床研究者。我建议以患者为导向的研究集中在GDM异常胰岛素信号传导的机制和胎盘激素在导致妊娠胰岛素抵抗中的作用。这个奖项将使我获得专业知识，在执行成人GCRC患者为导向的研究。这项纵向研究的目的是确定妊娠期糖尿病妇女胰岛素信号传导的潜在异常，确定这些异常是否持续存在于产后葡萄糖耐量正常化的妇女与那些没有正常化的妇女，并确定导致妊娠胰岛素抵抗的胎盘激素。妊娠期糖尿病（GDM）占妊娠期糖尿病的3-10%，发病率呈上升趋势，但对胰岛素抵抗的分子机制知之甚少。它导致母亲和胎儿的显著发病率，包括母亲发生2型DM的风险为50%，以及后代儿童肥胖和成人DM的高患病率。本研究将通过纵向前瞻性研究骨骼肌中胰岛素信号的异常来研究GDM患者与妊娠对照组相比的胰岛素抵抗机制。 这将通过在这两组妇女怀孕24-32周口服葡萄糖负荷前后进行肌肉活检来实现。为了检查这些异常在产后是否持续存在，将在产后8-12周在相同的葡萄糖负荷之前和之后重复进行肌肉活检。将有GDM病史且糖耐量恢复正常的女性与产后糖耐量持续受损的女性进行比较。最后，将通过将非妊娠女性在择期腹部手术中采集的肌纤维暴露于胎盘激素（包括人胎盘生长激素和人胎盘催乳素）来检查妊娠期胰岛素抵抗的原因。这将决定体内胰岛素信号传导异常是否可以在体外用胎盘激素单独或组合重建。确定这一高风险人群中胰岛素信号传导的异常以及胎盘激素在介导妊娠胰岛素抵抗中的作用至关重要，以便最终在预防母亲2型糖尿病以及后代肥胖和葡萄糖耐量方面取得进展。

As a candidate, I have a longstanding interdepartmental collaboration between the departments of Medicine and Obstetrics and Gynecology with a long-term goal to become an independent researcher in gestational diabetes (GDM) and placental hormone physiology. The K-23 Award would allow me to combined clinical research skills I have gained by attaining my MSPH degree and basic research skills I am obtaining through my endocrinology fellowship in order to become a productive clinical investigator. My proposed patient oriented research focuses on the mechanisms of abnormal insulin signaling in GDM and the role of placental hormones in causing the insulin resistance of pregnancy. This award would allow me to gain expertise in executing patient oriented research on the Adult GCRC. The goal of this proposed longitudinal research project is to define the underlying abnormalities in insulin signaling in women with gestational diabetes, determine whether these abnormalities persist in women with normalize their glucose tolerance postpartum versus those who do not, and determine the placental hormones responsible for causing the insulin resistance of pregnancy. Gestational diabetes (GDM) complicates 3-10% of all pregnancies and is increasing in incidence, yet little is known about the molecular mechanisms of the insulin resistance. It results in significant morbidity to both the mother and the fetus, including a 50% risk of developing Type 2 DM in the mother, and a high prevalence of childhood obesity and adult DM in the offspring. This research would examine mechanisms of insulin resistance in others with GDM compared to pregnant controls by studying abnormalities in insulin signaling in skeletal muscle in a longitudinal prospective manner. This would be achieved by obtaining muscle biopsies before and after an oral glucose load in these two groups of women at 24-32 weeks of pregnancy. In order to examine whether or not these abnormalities persist postpartum, repeat muscle biopsies will be taken at 8-12 weeks postpartum before and after the same glucose load. Women with history of GDM who normalize their glucose tolerance will be compared to those who continue to have impaired glucose tolerance postpartum. Lastly, the cause of the insulin resistance in pregnancy will be examined by exposing muscle fibers taken at elective abdominal surgeries in non- pregnant women to placental hormones, including human placental growth hormone and human placental lactogen. This will determine whether the in-vivo insulin signaling abnormalities can be recreated in vitro with placental hormones individuals or in combination. Identifying the abnormalities in insulin signaling in this high risk population as well as the role of placental hormones in mediating the insulin resistance of pregnancy is critical so that progress can ultimately be made towards the prevention of Type 2 diabetes in the mother as well obesity and glucose tolerance in her offspring.