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 drinking water from seven days prior to mating and throughout pregnancy. On embryonic day (E) 16, pregnant dams were subjected to an intraperitoneal glucose tolerance test. Animals were culled on E20 for collection of maternal blood, tissues, and placentas for analysis.
On E16, both MOD and SEV dams were glucose intolerant, and had a significant reduction in fasting plasma insulin and placental lactogen (rPL). Maternal plasma rPL remained decreased at E20. Maternal pancreatic beta-cell mass was not affected by hypothyroidism, however SEV dams had a greater proportion of small beta-cell clusters (<5000µm2) and a lesser proportion of large beta-cell clusters (>1000 µm2) relative to control dams. Reduced expression of several genes involved in the insulin signalling pathway within maternal adipose tissue and skeletal muscle of hypothyroid dams may also be contributing to glucose intolerance. Taken together, these findings suggest that hypothyroidism is inducing some placental dysfunction and reducing rPL production which culminates in reduced pancreatic beta-cell expansion and insulin secretion. Furthermore, reduced insulin signalling within peripheral tissue may also be contributing to the glucose intolerance present on E16, culminating in a classic GDM-like phenotype. Further investigation into the placental contributions to GDM within the context of maternal hypothyroidism are underway to further characterise the mechanistic link between these two highly prevalent endocrine conditions.