Liraglutide is a glucagon-like peptide-1 (GLP-1) analog developed for type 2 diabetes. Long-term liraglutide exposure in rodents was associated with thyroid C-cell hyperplasia and tumors. Here, we report data supporting a GLP-1 receptor-mediated mechanism for these changes in rodents. The GLP-1 receptor was localized to rodent C-cells. GLP-1 receptor agonists stimulated calcitonin release, up-regulation of calcitonin gene expression, and subsequently C-cell hyperplasia in rats and, to a lesser extent, in mice. In contrast, humans and/or cynomolgus monkeys had low GLP-1 receptor expression in thyroid C-cells, and GLP-1 receptor agonists did not activate adenylate cyclase or generate calcitonin release in primates. Moreover, 20 months of liraglutide treatment (at >60 times human exposure levels) did not lead to C-cell hyperplasia in monkeys. Mean calcitonin levels in patients exposed to liraglutide for 2 yr remained at the lower end of the normal range, and there was no difference in the proportion of patients with calcitonin levels increasing above the clinically relevant cutoff level of 20 pg/ml. Our findings delineate important species-specific differences in GLP-1 receptor expression and action in the thyroid. Nevertheless, the long-term consequences of sustained GLP-1 receptor activation in the human thyroid remain unknown and merit further investigation.
Prochloraz is a commonly used fungicide that has shown multiple mechanisms of action in vitro. It antagonizes the androgen and the estrogen receptors, agonizes the Ah receptor, and inhibits aromatase activity. In vivo prochloraz acts antiandrogenically in the Hershberger assay by reducing weights of reproductive organs, affecting androgen-regulated gene expressions, and increasing luteinizing hormone (LH) levels. The purpose of this study was to investigate reproductive toxic effects after exposure during gestation and lactation to prochloraz alone and a mixture of five pesticides (deltamethrin, methiocarb, prochloraz, simazine, and tribenuron-methyl). Prochloraz (30 mg/kg/day) or the mixture (20 mg/kg/day) was dosed to pregnant Wistar dams from gestational day (GD) 7 until postnatal day (PND) 16. Some dams were taken for cesarean section at GD 21, and others were allowed to give birth. Results showed that prochloraz and the mixture significantly reduced plasma and testicular testosterone levels in GD 21 male fetuses, whereas testicular progesterone was increased. Gestational length was increased by prochloraz. Chemical analysis of the rat breast milk showed that prochloraz was transferred to the milk. In males a significant increase of nipple retention was found, and the bulbourethral gland weight was decreased, whereas other reproductive organs were unaffected. In addition cytochrome P450 (CYP)1A activities in livers were induced by prochloraz, possibly as a result of Ah receptor activation. Behavioral studies showed that the activity level and sweet preference of adult males were significantly increased. Overall these results strongly indicate that prochloraz feminizes the male offspring after perinatal exposure, and that these effects are due, at least in part, to diminished fetal steroidogenesis.
Liraglutide is a glucagon-like peptide-1 (GLP-1) analog developed for type 2 diabetes. Long-term liraglutide exposure in rodents was associated with thyroid C-cell hyperplasia and tumors. Here, we report data supporting a GLP-1 receptor-mediated mechanism for these changes in rodents. The GLP-1 receptor was localized to rodent C-cells. GLP-1 receptor agonists stimulated calcitonin release, up-regulation of calcitonin gene expression, and subsequently C-cell hyperplasia in rats and, to a lesser extent, in mice. In contrast, humans and/or cynomolgus monkeys had low GLP-1 receptor expression in thyroid C-cells, and GLP-1 receptor agonists did not activate adenylate cyclase or generate calcitonin release in primates. Moreover, 20 months of liraglutide treatment (at Ͼ60 times human exposure levels) did not lead to C-cell hyperplasia in monkeys. Mean calcitonin levels in patients exposed to liraglutide for 2 yr remained at the lower end of the normal range, and there was no difference in the proportion of patients with calcitonin levels increasing above the clinically relevant cutoff level of 20 pg/ml. Our findings delineate important species-specific differences in GLP-1 receptor expression and action in the thyroid. Nevertheless, the long-term consequences of sustained GLP-1 receptor activation in the human thyroid remain unknown and merit further investigation.
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