BACKGROUND AND PURPOSE: The thyroid hormone, triiodothyronine (T3) has many 
metabolic functions. Unexpectedly, exogenous T3 lowered blood glucose in db/db 
mice, a model of type 2 diabetes. Here, we have explored this finding and its 
possible mechanisms further.
EXPERIMENTAL APPROACH: db/db and lean mice were treated with T3, the 
phosphoinositide 3- kinase (PI3-kinase) inhibitor, LY294002, plus T3, or 
vehicles. Blood glucose, insulin sensitivity, levels and synthesis were 
measured. Effects of T3 on intracellular insulin signaling were analyzed in 
3T3-L1 pre-adipocytes with Western blotting. Knock-down of the thyroid hormone 
receptor α1 (TRα1) in 3T3-L1 cells was achieved with an appropriate silencing 
RNA (siRNA).
KEY RESULTS: Single injections of T3 (7 ng·g⁻¹ i.p.) rapidly and markedly 
attenuated hyperglycemia. Treatment with T3 (14 ng·g⁻¹·day⁻¹, 18 days) 
dose-dependently attenuated blood glucose and increased insulin sensitivity in 
db/db mice. Higher doses of T3 (28 ng·g⁻¹·day⁻¹) reversed insulin resistance in 
db/db mice. T3 also increased insulin levels in plasma and the neurogenic 
differentiation factor (an insulin synthesis transcription factor) and insulin 
storage in pancreatic islets in db/db mice. These anti-diabetic effects of T3 
were abolished by the PI3-kinase inhibitor (LY294002). In 3T3-L1 preadipocytes, 
T3 enhanced insulin-induced tyrosine phosphorylation of insulin receptor 
substrate (IRS)-1 and activation of PI3-kinase, effects blocked by siRNA for 
TRα1.
CONCLUSIONS AND IMPLICATIONS: T3 potentiated insulin signaling, improved insulin 
sensitivity, and increased insulin synthesis, which may contribute to its 
anti-diabetic effects. These findings may provide new approaches to the 
treatment of type 2 diabetes.