Thyroid hormone potentiates insulin signaling and attenuates hyperglycemia and insulin resistance in a mouse model of type 2 diabetes.
OBJECTIVE
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.


METHODS
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).


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
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.
Lin
Yi
Y
Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Sun
Zhongjie
Z
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D001795:Blood Pressure Determination; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D006339:Heart Rate / Q000187:drug effects; D006943:Hyperglycemia / Q000188:drug therapy* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014284:Triiodothyronine / Q000378:metabolism / Q000494:pharmacology*
D051792:Basic Helix-Loop-Helix Proteins; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D014284:Triiodothyronine; C093564:Neurogenic differentiation factor 1