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Diabetologia
Published in: Diabetologia 5/2009

01-05-2009 | Article

Inhibition of the chemokine (C–C motif) ligand 2/chemokine (C–C motif) receptor 2 pathway attenuates hyperglycaemia and inflammation in a mouse model of hepatic steatosis and lipoatrophy

Authors: S. J. Yang, H. B. IglayReger, H. C. Kadouh, P. F. Bodary

Published in: Diabetologia | Issue 5/2009

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Abstract

Aims/hypothesis

Using a mouse model of lipoatrophic diabetes, we hypothesised that the chemokine (C–C motif) ligand 2 (CCL2)/chemokine (C–C motif) receptor 2 (CCR2) pathway contributes to hepatic macrophage accumulation and insulin resistance through induction of a chronic inflammatory state.

Methods

Metabolic variables of insulin resistance and inflammation were characterised in wild-type and lipoatrophic A-ZIP/F-1 transgenic (AZIP-Tg) mice. The AZIP-Tg mice were then treated with a CCR2 antagonist (RS504393, 2 mg kg−1 day−1) or vehicle for 28 days via a subcutaneous mini-osmotic pump to examine the role of the CCL2/CCR2 pathway in lipoatrophic diabetes.

Results

The lipoatrophic AZIP-Tg mice were diabetic with high fasting glucose and serum insulin concentrations compared with littermate controls. The livers of AZIP-Tg mice were more than threefold enlarged and exhibited increased triacylglycerol content. CCL2 levels were highly elevated in both liver and serum of the AZIP-Tg mice compared with controls. In addition, the circulating CCL2 concentration was associated with increased macrophage accumulation and inflammation as documented by upregulation of Cd68 gene and Tnf-α [also known as Tnf] gene in livers from the AZIP-Tg mice. Treatment of the lipoatrophic AZIP-Tg mice with the CCR2 antagonist ameliorated the hyperglycaemia, hyperinsulinaemia and hepatomegaly in conjunction with a reduction in liver inflammation.

Conclusions/interpretation

These findings demonstrate a significant role of the CCL2/CCR2 pathway in lipoatrophy-induced diabetes and provide clear evidence that metabolic improvements resulting from the inhibition of this inflammatory pathway are not adipose tissue-dependent.
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Metadata
Title
Inhibition of the chemokine (C–C motif) ligand 2/chemokine (C–C motif) receptor 2 pathway attenuates hyperglycaemia and inflammation in a mouse model of hepatic steatosis and lipoatrophy
Authors
S. J. Yang
H. B. IglayReger
H. C. Kadouh
P. F. Bodary
Publication date
01-05-2009
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 5/2009
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-009-1309-8

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