The possible mechanisms by which maternal hypothyroidism impairs insulin secretion in adult male offspring in rats

New Findings What is the central question of this study? Thyroid hormones play key roles in somatic growth and metabolism. Previous studies have recently shown that maternal hypothyroidism leads to impaired glucose metabolism and reduced insulin secretion in adult offspring in rats, but the mechanistic basis of the secretory defect in maternal hypothyroid islets is unknown. What is the main finding and its importance? Our findings demonstrate that reduction in the availability of thyroid hormones during fetal life leads to impaired insulin secretion that is probably related to alterations in different steps of the insulin secretion pathway, including abnormalities in glycolytic pathways and altered behaviour of ATP‐sensitive K+ channels and Ca2+ L‐type channels of β‐cells. Previous studies have recently shown that maternal hypothyroidism leads to impaired glucose metabolism and reduced insulin secretion in adult offspring in rats. The aim of this study was to locate the defect in the insulin secretion pathway induced by maternal hypothyroidism. Pregnant Wistar rats were divided into two groups; the control group consumed water, while the hypothyroid (FH) group received water containing 0.025% 6‐propyl‐2‐thiouracil during gestation. An intravenous glucose tolerance test was carried out on 5‐month‐old male offspring. In in vitro studies, the effects of various secretagogues and inhibitors acting at different levels of the insulin secretion cascade were investigated, and insulin content, insulin secretion and glucokinase activity of the islets were compared. Although insulin content of the FH islets did not differ from that of control islets, insulin secretion from FH islets was reduced when it was challenged by glucose or arginine. Compared with control islets, activities of both hexokinase and glucokinase were also significantly decreased in the FH islets. Although, in both groups, increasing glibenclamide and nifedipine concentrations in the presence of 16.7 mmol l−1 glucose increased and decreased insulin secretion, respectively, the percentage of changes in secretion of FH islets was significantly lower compared with control islets. The response of FH islets to high extracellular potassium concentration and diazoxide was also significantly lower than that of the control islets. These findings demonstrate that impaired insulin secretion in the FH group is probably related to alterations in different steps of the insulin secretion pathway and not in the insulin pool of β‐cells.