Hypothyroidism affects approximately 3% of pregnant women and has been linked to gestational diabetes mellitus (GDM). Few studies have investigated the mechanisms by which thyroid dysfunction in pregnancy may contribute to the development of GDM. This study used a model of hypothyroidism in pregnancy to explore disruption to key pathways that have previously been implicated in GDM.
Female Sprague-Dawley rats were exposed to either 0.02% (severe hypothyroidism, SEV) or 0.005% (moderate hypothyroidism, MOD) methimazole in their drinking water for seven days prior to mating and throughout pregnancy. On embryonic day (E) 16, pregnant dams were fasted prior to an intraperitoneal glucose tolerance test. Animals were culled on E20 for collection of maternal blood, tissues, and placentas for subsequent analysis.
This study is the first to provide novel evidence linking hypothyroidism to the pathogenesis of GDM. On E16, both MOD and SEV dams were glucose intolerant, and had a significant reduction in fasting plasma insulin and placental lactogen (rPL). Placental junctional zone expression of Prl3d1 and Prl3b1, two key placental peptides implicated in GDM, were not affected, however maternal plasma rPL remained decreased at E20. Pancreatic expression of Nkx6-1, a critical gene required for beta-cell expansion, was significantly reduced in MOD and SEV dams. This suggests that inefficient placental production of rPL may be failing to facilitate appropriate beta-cell expansion during pregnancy in hypothyroid dams, reducing insulin synthesis and secretion. Within maternal skeletal muscle, there was a significant reduction in Irs1 and GLUT4 in both MOD and SEV dams. In combination with changes in the pancreas, this suggests that hypothyroidism in pregnancy induces reduced insulin secretion and peripheral insulin resistance, culminating in a classic GDM-like phenotype. Further investigation into other pathways within the liver and pancreas that may contribute to dysregulated maternal glucose homeostasis in pregnancies affected by hypothyroidism are underway.