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

Abstract

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.

• Authors: Yi Lin, Zhongjie Sun
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 162 Issue 3 Pg. 597-610 (Feb 2011) ISSN: 1476-5381 [Electronic] England
• PMID: 20883475 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Blood Glucose
• Hypoglycemic Agents
• Insulin
• Nerve Tissue Proteins
• Triiodothyronine
• Neurogenic differentiation factor 1

Topics

• 3T3-L1 Cells
• Adipocytes (drug effects, metabolism)
• Animals
• Basic Helix-Loop-Helix Transcription Factors (genetics, metabolism)
• Blood Glucose (metabolism)
• Blood Pressure Determination
• Body Temperature (drug effects)
• Body Weight (drug effects)
• Diabetes Mellitus, Type 2 (drug therapy, metabolism)
• Disease Models, Animal
• Heart Rate (drug effects)
• Hyperglycemia (drug therapy, metabolism)
• Hypoglycemic Agents (pharmacology)
• Insulin (blood, metabolism, pharmacology)
• Insulin Resistance
• Islets of Langerhans (drug effects, metabolism)
• Male
• Mice
• Mice, Mutant Strains
• Nerve Tissue Proteins (genetics, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Signal Transduction (drug effects)
• Triiodothyronine (metabolism, pharmacology)