Research Article Details
| Article ID: | A52937 |
| PMID: | 19277603 |
| Source: | Diabetologia |
| 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. |
| 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-alpha [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. |
| DOI: | 10.1007/s00125-009-1309-8 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| S05 | Anti-inflammatory | inflammatory | Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor | Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T08 | Tumor necrosis factor | TNF | inhibitor | Cytokine | P01375 | TNFA_HUMAN | Details |
| T10 | Caspase-1 | CASP1 | inhibitor | Enzyme | P29466 | CASP1_HUMAN | Details |
| T18 | Acetyl-CoA carboxylase 1 | ACACA | inhibitor | Enzyme | Q13085 | ACACA_HUMAN | Details |
| T20 | Fatty acid synthase | FASN | inhibitor | Enzyme | P49327 | FAS_HUMAN | Details |
| T24 | C-C chemokine receptor type 2 | CCR2 | antagonist | GPCR | P41597 | CCR2_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |