Reduces Blood Glucose Independently of Insulin Sensitization in Obese Mice Short Title : T 2 and blood glucose

Aim: Thyroid hormones regulate metabolic response. While triiodothyronine (T3) is usually considered to be the active form of thyroid hormone, one form of diiodothyronine (3,5-T2) exerts T3-like effects on energy consumption and lipid metabolism. 3,5-T2 also improves glucose tolerance in rats and 3,5-T2 levels correlate with fasting glucose in humans. Presently, however, little is known about mechanisms of 3,5-T2 effects on glucose metabolism. Here, we set out to compare effects of T3, 3,5-T2 and another form of T2 (3,3-T2) in a mouse model of diet induced obesity and determined effects of T3 and 3,5-T2 on markers of classical insulin sensitization to understand how diiodothyronines influence blood glucose. Methods: Cell and protein based assays of thyroid hormone action. Assays of metabolic parameters in mice. Analysis of transcript and protein levels in different tissues by qRT-PCR and western blot. Results: T3 and 3,5-T2 both reduce body weight, adiposity and body temperature despite increased food intake. 3,3’-T2 lacks these effects. T3 and 3,5-T2 reduce blood glucose levels whereas 3,3’-T2 worsens glucose tolerance. Neither T3 or 3,5-T2 affects markers of insulin sensitization in skeletal muscle or white adipose tissue (WAT) but both reduce hepatic GLUT2 glucose transporter levels and glucose output. T3 and 3,5-T2 also induce expression of mitochondrial uncoupling proteins (UCPs) 3 and 1 in skeletal muscle and WAT, respectively. A cc ep te d A rt ic le This article is protected by copyright. All rights reserved. Conclusions: 3,5-T2 influences glucose metabolism in a manner that is distinct from insulin sensitization and involves reductions in hepatic glucose output and changes in energy utilization.