OBJECTIVE -The C-174G promoter polymorphism of the interleukin (IL)-6 gene was found to influence transcriptional activity and plasma IL-6 levels in humans. We addressed the question of whether the C-174G IL-6 polymorphism contributes to variation of insulin sensitivity.RESEARCH DESIGN AND METHODS -Two cohorts of subjects were genotyped. Cohort 1 includes 275 nondiabetic subjects who underwent a euglycemic-hyperinsulinemic clamp. Cohort 2 includes 77 patients with morbid obesity who underwent laparoscopic adjustable gastric banding (LAGB).RESULTS -The genotypes were consistent with Hardy-Weinberg equilibrium proportions. In cohort 1, insulin sensitivity was reduced in carriers of the Ϫ174G/G genotype as compared with subjects carrying the C allele (P ϭ 0.004). Carriers of Ϫ174G/G displayed significantly higher plasma IL-6 levels in comparison with carriers of the C allele. In a stepwise linear regression analysis, the C-174G polymorphism was independently associated with insulin sensitivity; however, after inclusion of plasma IL-6 concentrations, the polymorphism was excluded from the model explaining insulin sensitivity variability, thus suggesting that the polymorphism was affecting insulin sensitivity by regulating IL-6 plasma levels. IL-6 mRNA levels were measured by real-time RT-PCR in subcutaneous fat obtained from obese patients of cohort 2 during LAGB. Carriers of Ϫ174G/G showed increased IL-6 expression compared with subjects carrying the C allele (P ϭ 0.04). There was a significant correlation between adipose IL-6 mRNA expression and insulin resistance assessed by homeostasis model assessment ( ϭ 0.28, P ϭ 0.014).CONCLUSIONS -These results indicate that the Ϫ174G/G genotype of the IL-6 gene may contribute to variations in insulin sensitivity.
Diabetes Care 28:2007-2012, 2005T here is increasing evidence suggesting the concept that chronic lowgrade activation of the immune system may play a role in the pathogenesis of insulin resistance and type 2 diabetes (1-3). Cross-sectional and prospective studies have shown that increased levels of systemic inflammatory markers such as interleukin (IL)-6, a major proinflammatory cytokine expressed in several tissues including leukocytes, adipocytes, and endothelial cells, are associated with type 2 diabetes and glucose disorders (1-3). Both circulating levels of IL-6 and adipose tissue IL-6 content have been correlated with insulin resistance (4,5). Moreover, high circulating IL-6 concentrations have been found to predict the development of type 2 diabetes (6).It has been reported that the common C-174G polymorphism in the promoter of the human IL-6 gene regulates its transcription in vitro with the G allele, showing increased transcriptional activity both under basal condition and in response to inflammatory stimuli such as lipopolysaccharides or IL-1 (7). However, data on the effects of this polymorphism on IL-6 levels in vivo have led to conflicting results. Some studies have shown that individuals with the G/G genotype have higher circulating IL-6 levels, as w...