Two independent studies indicated that PAX8 could play a role in glucose homeostasis and pancreatic islet physiology. Pax8 expression was reported in murine islets during gestation while a genome-wide study associated a polymorphism nearby PAX8 with type 2 diabetes. In addition, Pax8 is necessary for the synthesis of thyroid hormones, which are known to exert profound effects in whole body metabolism. Herein, we show that PAX8 protects pancreatic islets from apoptosis and have identified a detrimental polymorphism that may be associated with gestational diabetes as well as gestational thyroid dysfunction. However, Pax8 +/- female mice did not develop glucose intolerance during pregnancy and displayed normal circulating T4 levels at 6 months old. In contrast to females, Pax8 +/- male mice showed decreased T4 levels in blood. However, these mice were 8 months old; suggesting that the reduction in circulating T4 levels in Pax8 +/- animals may be developed with advancing age. Interestingly, untreated Pax8 +/- male mice showed glucose intolerance and insulin resistance, while T4 supplementation rescued the phenotype. Therefore, our results indicate that the alterations observed in glucose homeostasis are due to reduced T4 levels in circulation. Noteworthy, insulin signaling was preferentially impaired in the liver of Pax8 +/- male mice, where ROS production was found significantly increased. We next sought to investigate whether T4 supplementation could enhance glucose homeostasis in healthy wild type animals. Remarkably, T4 treatment was found to enhance glucose clearance and increase insulin expression in pancreatic islets. Basal circulating insulin concentration was also higher in T4-treated mice, which could be explained by an upregulation of glucokinase expression in pancreatic islets from these animals. Importantly, T4 supplementation also increased circulating insulin levels and insulin content in pancreatic islets in a model of experimental autoimmune diabetes. In addition, T4 supplementation improved the survival rate of mice treated with streptozotocin. Therefore, our results indicate that reduced circulating T4 levels are associated with impaired glucose homeostasis whereas T4 supplementation enhances glucose clearance and blunts the onset of experimental autoimmune diabetes.

Tesis llevada a cabo para conseguir el grado de Doctor por la Universidad de Pablo Olavide.--2018-07-09.--Sobresaliente

Peer reviewed