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

Yi Lin, Zhongjie Sun

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50 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)597-610
Number of pages14
JournalBritish Journal of Pharmacology
Volume162
Issue number3
DOIs
StatePublished - Feb 1 2011
Externally publishedYes

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Thyroid Hormones
Hyperglycemia
Type 2 Diabetes Mellitus
Insulin Resistance
Insulin
1-Phosphatidylinositol 4-Kinase
Blood Glucose
Thyroid Hormone Receptors
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Triiodothyronine
RNA Interference
3T3-L1 Cells
Insulin Receptor Substrate Proteins
Islets of Langerhans
Adipocytes
Tyrosine
Transcription Factors
Western Blotting
Phosphorylation
Injections

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

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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.",
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