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AIMS/HYPOTHESIS: During pregnancy, maternal metabolic disease 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 offspring remains poorly understood. METHODS: We investigated this using a mouse model of hypothyroidism, induced by administration of an iodine-deficient diet supplemented with propylthiouracil during gestation. RESULTS: Here, we show that, when fed normal chow, adult mice born to hypothyroid mothers were more glucose-tolerant due to beta cell hyperproliferation (two- to threefold increase in Ki67-positive beta cells) and increased insulin sensitivity. However, following 8 weeks of high-fat feeding, these offspring gained 20% more body weight, became profoundly hyperinsulinaemic (with a 50% increase in fasting insulin concentration), insulin-resistant and glucose-intolerant compared with controls from euthyroid mothers. Furthermore, altered glucose metabolism was maintained in a second generation of animals. CONCLUSIONS/INTERPRETATION: Therefore, gestational hypothyroidism induces long-term alterations in endocrine pancreas function, which may have implications for type 2 diabetes prevention in affected individuals.

Original publication

DOI

10.1007/s00125-020-05172-x

Type

Journal article

Journal

Diabetologia

Publication Date

2020

Volume

63

Pages

1822 - 1835

Keywords

Animals Antithyroid Agents/toxicity Blood Glucose/*metabolism Cell Proliferation Diet, High-Fat Disease Models, Animal Female Glucose Intolerance/*metabolism Hyperinsulinism/metabolism Hypothyroidism/*metabolism Insulin Resistance Insulin-Secreting Cells/*metabolism Iodine/deficiency Islets of Langerhans/*embryology/metabolism Mice Pregnancy Pregnancy Complications/*metabolism Prenatal Exposure Delayed Effects/*metabolism Propylthiouracil/toxicity Stress, Physiological *Beta cell function *Calcium imaging *Diabetes *Hypothyroidism *Pancreas