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Diabetes 54:2305-2313, 2005
© 2005 by the American Diabetes Association, Inc.

Expression of CD68 and Macrophage Chemoattractant Protein-1 Genes in Human Adipose and Muscle Tissues

Association With Cytokine Expression, Insulin Resistance, and Reduction by Pioglitazone

Gina B. Di Gregorio1,2, Aiwei Yao-Borengasser1,2, Neda Rasouli1,2, Vijayalakshmi Varma1,2, Tong Lu1,2, Leslie M. Miles1,2, Gouri Ranganathan1,2, Charlotte A. Peterson1,3, Robert E. McGehee4, and Philip A. Kern1,2

1 Central Arkansas Veterans Healthcare System, Little Rock, Arkansas
2 Department of Medicine, Division of Endocrinology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
3 Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas
4 Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas

To examine the role of adipose-resident macrophages in insulin resistance, we examined the gene expression of CD68, a macrophage marker, along with macrophage chemoattractant protein-1 (MCP-1) in human subcutaneous adipose tissue using real-time RT-PCR. Both CD68 and MCP-1 mRNAs were expressed in human adipose tissue, primarily in the stromal vascular fraction. When measured in the adipose tissue from subjects with normal glucose tolerance, covering a wide range of BMI (21–51 kg/m2) and insulin sensitivity (SI) (0.6–8.0 x 10–4min–1 · µU–1 · ml–1), CD68 mRNA abundance, which correlated with the number of CD68-positive cells by immunohistochemistry, tended to increase with BMI but was not statistically significant. However, there was a significant inverse relation between CD68 mRNA and SI (r = –0.55, P = 0.02). In addition, there was a strong positive relationship among adipose tissue CD68 mRNA, tumor necrosis factor-{alpha} (TNF-{alpha}) secretion in vitro (r = 0.79, P < 0.005), and plasma interleukin-6 (r = 0.67, P < 0.005). To determine whether improving SI in subjects with impaired glucose tolerance (IGT) was associated with decreased CD68 expression, IGT subjects were treated for 10 weeks with pioglitazone or metformin. Pioglitazone increased SI by 60% and in the same subjects reduced both CD68 and MCP-1 mRNAs by >50%. Furthermore, pioglitazone resulted in a reduction in the number of CD68-positive cells in adipose tissue and reduced plasma TNF-{alpha}. Metformin had no effect on any of these measures. Thus, treatment with pioglitazone reduces expression of CD68 and MCP-1 in adipose tissue, apparently by reducing macrophage numbers, resulting in reduced inflammatory cytokine production and improvement in SI.

Address correspondence and reprint requests to Philip A. Kern MD, Associate Chief of Staff, Research, Central Arkansas Veterans Healthcare System, 598/151 LR, 4300 West 7th St., Little Rock, AR 72205. E-mail: kernphilipa{at}uams.edu

Abbreviations: FSIGTT, frequently sampled intravenous glucose tolerance test; IGT, impaired glucose tolerance; IL, interleukin; MCP-1, macrophage chemoattractant protein-1; NGT, normal glucose tolerance; PPAR-{gamma}, peroxisome proliferator–activated receptor-{gamma}; TNF-{alpha}, tumor necrosis factor-{alpha}


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