Maternal hypothyroidism in mice influences glucose metabolism in adult offspring

Abstract

Running title: transgenerational effect of gestational hypothyroidism on beta cell function SIGNIFICANCE Diabetes and hypothyroidism are two major public health issues, affecting ~ 9 and 2 % of the population worldwide, respectively. As master metabolic gatekeepers, the thyroid hormones play an essential role in metabolism and fetal development. However, gestation increases demand on the thyroid axis in the mother, leading to hypothyroidism in 0.5 % of pregnancies.Maternal hypothyroidism is associated with deficits in fetal growth that may lead to long-term alterations in metabolism in the offspring. We therefore sought to investigate the effects of gestational hypothyroidism on glucose metabolism in adult offspring and their descendants, and how this may predispose to diabetes development. ABSTRACTDuring pregnancy, maternal metabolic diseases and hormonal imbalance may alter fetal beta cell development and/or proliferation, thus leading to an increased risk for developing type 2 diabetes in adulthood. Although thyroid hormones play an important role in fetal endocrine pancreas development, the impact of maternal hypothyroidism on glucose homeostasis in adult offsprings remains poorly understood. Here, we show that when fed normal chow, adult mice born to hypothyroid mothers were more glucose-tolerant due to beta cell hyperproliferation and increased insulin sensitivity. However, following high fat feeding, these offsprings became profoundly hyperinsulinemic, insulin-resistant and glucose-intolerant compared to controls from euthyroid mothers. Suggesting presence of epigenetic changes, altered glucose metabolism was maintained in a second generation of animals. As such, gestational hypothyroidism induces long-term and persistent alterations in endocrine pancreas function, which may have important implications for type 2 diabetes prevention in affected individuals.

Maternal thyroid disease and adiposity in mother and child

“…The hypothesis of foetal programming by maternal thyroid disease has also been proposed in relation to metabolic and cardiovascular outcomes in the offspring. Considering the diverse role of thyroid hormones in humans and during development, it can be hypothesized that peripheral metabolic effects as well as alterations of central hormonal regulation may play a role 30,31 . Thus, experimental data have proposed an association and observational studies within birth cohorts from Denmark, the Netherlands and the United Kingdom have investigated the hypothesis in humans 4,5,7 .…”

Free thyroxine in early pregnancy is an independent negative predictor of 3rd trimester HbA1c. Odense child cohort

“…In a sheep model, hypothyroidism during pregnancy was obtained by removing the foetal thyroid gland in late pregnancy 23 and hypothyroidism was linked to higher pancreatic β-cell mass and more circulating insulin was measured in umbilical cord blood. 23 Furthermore, hypothyroidism in utero in mice 24 and rats 25,26 predisposed to T2D in adult offspring, especially if the offspring was challenged by metabolic stress, for example high fat diet. 24 These findings suggest that low thyroid function could be a mechanism for transgenerational transfer of metabolic risk.…”

“…23 Furthermore, hypothyroidism in utero in mice 24 and rats 25,26 predisposed to T2D in adult offspring, especially if the offspring was challenged by metabolic stress, for example high fat diet. 24 These findings suggest that low thyroid function could be a mechanism for transgenerational transfer of metabolic risk. In OCC, the hypothesis of transgenerational transfer of early pregnancy FT4 levels and future health will be tested by measuring fat mass and HbA1c in children at the age of 7-9 years.…”