Association between the A-2518G polymorphism in the monocyte chemoattractant protein-1 gene and insulin resistance and Type 2 diabetes mellitus.

Abstract

AIMS/HYPOTHESIS:

The molecular mechanisms of obesity-related insulin resistance are incompletely understood. Macrophages accumulate in adipose tissue of obese individuals. In obesity, monocyte chemoattractant protein-1 (MCP-1), a key chemokine in the process of macrophage accumulation, is overexpressed in adipose tissue. MCP-1 is an insulin-responsive gene that continues to respond to exogenous insulin in insulin-resistant adipocytes and mice. MCP-1 decreases insulin-stimulated glucose uptake into adipocytes. The A-2518G polymorphism in the distal regulatory region of MCP-1 may regulate gene expression. The aim of this study was to investigate the impact of this gene polymorphism on insulin resistance.

METHODS:

We genotyped the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort ( n=3307). Insulin resistance, estimated by homeostasis model assessment, and Type 2 diabetes were diagnosed in 803 and 635 patients respectively.

RESULTS:

Univariate analysis revealed that plasma MCP-1 levels were significantly and positively correlated with WHR ( p=0.011), insulin resistance ( p=0.0097) and diabetes ( p<0.0001). Presence of the MCP-1 G-2518 allele was associated with decreased plasma MCP-1 ( p=0.017), a decreased prevalence of insulin resistance (odds ratio [OR]=0.82, 95% CI: 0.70-0.97, p=0.021) and a decreased prevalence of diabetes (OR=0.80, 95% CI: 0.67-0.96, p=0.014). In multivariate analysis, the G allele retained statistical significance as a negative predictor of insulin resistance (OR=0.78, 95% CI: 0.65-0.93, p=0.0060) and diabetes (OR=0.80, 95% CI: 0.66-0.96, p=0.018).

CONCLUSIONS/INTERPRETATION:

In a large cohort of Caucasians, the MCP-1 G-2518 gene variant was significantly and negatively correlated with plasma MCP-1 levels and the prevalence of insulin resistance and Type 2 diabetes. These results add to recent evidence supporting a role for MCP-1 in pathologies associated with hyperinsulinaemia.

• Authors: E Simeoni, M M Hoffmann, B R Winkelmann, J Ruiz, S Fleury, B O Boehm, W März, G Vassalli
• Journal: Diabetologia (Diabetologia) Vol. 47 Issue 9 Pg. 1574-80 (Sep 2004) ISSN: 0012-186X [Print] Germany
• PMID: 15349727 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCL2 protein, human
• Chemokine CCL2
• Guanine
• Glucose
• Adenine

Topics

• Adenine
• Aged
• Chemokine CCL2 (genetics)
• Cohort Studies
• Diabetes Mellitus, Type 2 (blood, genetics)
• Female
• Glucose (metabolism)
• Guanine
• Homeostasis
• Humans
• Hyperinsulinism (genetics)
• Insulin Resistance (physiology)
• Male
• Middle Aged
• Polymorphism, Single Nucleotide (genetics)