Elucidating the Central Determinant of Gestational Diabetes

Gestational diabetes mellitus (GDM) is now the most common medical disorder of pregnancy. It is associated with adverse outcomes during gestation, and can lead to long-term health complications including Type 2 Diabetes in mothers and glucose intolerance, obesity, and metabolic syndrome in offspring. Targeted interventions to prevent the onset of GDM may mitigate adverse metabolic consequences. Elucidating the central drivers of glucose metabolism in pregnancy will facilitate the identification of effective biomarkers for predicting GDM and may give rise to mechanism based interventions. The central melanocortin system is a key regulator of appetite and metabolism. It is comprised of POMC and AgRP neurons and their receptors. We have recently established CSF measurements of POMC and AgRP as reliable markers of brain melanocortin activity in humans. Using these markers, we have demonstrated that a state of gestational leptin resistance characterized by a decrease in leptin transport into the brain and resistance to the suppressive effects of leptin on AgRP. Our preliminary data also show that plasma AgRP – a peripheral biomarker of the hypothalamic neuropeptide AgRP, is markedly elevated in pregnant women. The goal of this project is to define pregnancy-specific adaptations in leptin, glucocorticoid, and melanocortin physiology in women with gestational diabetes and to determine whether peripheral concentrations of AgRP can be used to predict GDM early in gestation.