Effects of hypothyroidism on pancreatic islet development and tissue insulin signalling pathways in the ovine fetus

Thyroid hormones are important regulators of fetal growth and maturation, although their mechanism of action and interactions with other hormones are unclear. The overall aim of the project was to elucidate the effects of hypothyroidism on the growth and development of the sheep fetus in late gestation. Specifically, the project investigated the extent to which the changes in fetal growth induced by thyroid hormone deficiency were mediated by changes in pancreatic islet development and insulin signalling in fetal tissues. In nineteen twin-bearing pregnant ewes at 105-110 days of gestation (dGA; term~145dGA) and under general anaesthesia, one fetus was thyroidectomised, while the other was sham-operated. At either 129 or 143dGA, umbilical blood samples and a variety of fetal tissues were collected after euthanasia. Hypothyroidism in utero did not affect fetal bodyweight but impaired skeletal growth and led to disproportionate patterns of organ growth. A 30-40% increase in pancreatic β-cell mass was observed in the thyroid deficient fetuses, compared to sham controls, and this was associated with increased plasma insulin and leptin concentrations. In studies using isolated fetal ovine pancreatic islets, β-cell proliferation in vitro was inhibited by T3 in a dose-dependent manner but was stimulated by the highest dose of insulin. Pancreatic β-cell proliferation was inhibited at low, and stimulated at high, leptin concentrations. Perirenal adipose tissue was enlarged in the hypothyroid fetuses due to an increase in the proportion of unilocular adipocytes, characteristic of white adipose tissue. The greater relative unilocular adipocyte mass was caused by hyperplasia in association with upregulation of the insulin signalling pathway. Kidneys of hypothyroid fetuses had no apparent changes in glomerular or tubular structure, but a greater water content may have accounted for the increased kidney mass seen in the thyroid deficient fetuses, compared to sham controls. No changes in insulin signalling or sodium transporter expression were seen in the kidneys of the hypothyroid fetuses. This research demonstrates that the thyroid hormones are required in the ovine fetus during late gestation for the normal development of the endocrine pancreas, adipose tissue and kidney. Alterations in organ development in response to hypothyroidism may have short and long term consequences for carbohydrate metabolism, obesity and renal function