Kisspeptin: A Novel Regulator of Insulin in Pregnancy

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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.