Roy E. Weiss, MD

Our laboratory is concerned with identifying the causes and risk factors associate with gestational diabetes mellitus (GDM). Cortisol is an important regulator of glucose and lipid metabolism, antagonizing insulin action in liver, adipose tissue, and muscle. Normal pregnancy is characterized by 2-4 fold elevations in serum cortisol. The hypercortisolism of pregnancy may play a role in some of the metabolic perturbations commonly seen in pregnancy. Elevations in serum cortisol may contribute to insulin resistance during gestation, and in combination with inadequate compensatory insulin secretion, may result in GDM. The overall goal of this study is to investigate the role of pregnancy related hypercortisolism in the development of GDM. We have 3 related hypotheses: (1) That women with GDM have higher levels of circulating cortisol and a reduction in the sensitivity to feedback by cortisol than normal glucose tolerant (NGT) pregnant woman; (2) Women with GDM have increased conversion of cortisone to the active hormone cortisol and (3) Women with GDM will more likely have a polymorphism in the glucocorticoid receptor that is associated with increased sensitivity to cortisol. To test these hypotheses directly we will assess the hypothalamic–pituitary–adrenal (HPA) axis in women with GDM by several methods; (2) We will measure 11b-hydroxysteroid dehydrogenase activity in the adipose tissue of women with NGT and GDM obtained at c-section; and (3) Determination of the polymorphisms of the glucocorticoid receptor in women with GDM. The results of the proposed studies are expected to make an important contribution to the understanding of the physiology GDM with diagnostic and clinical implications for its management.

Mechanisms of hypercortisolism in pregnancy. Increase serum cortisol is a response to ACTH stimulation of the pituitary from either increased CRF stimulation from placenta, decreased corticotroph sensitivity to feedback of cortisol. Increased CBG (cortisol binding globulin) from the liver secondary to estrogen effect also increases cortisol. The contribution of increased renal clearance is uncertain.