Inflammatory Markers and Risk of Type 2 Diabetes: A systematic review and meta-analysis

OBJECTIVE

There has been growing evidence that inflammatory markers play a role in the development of type 2 diabetes. We aimed to systematically review prospective studies on the associations of elevated levels of interleukin-6 (IL-6) and C-reactive protein (CRP) with increased risk of type 2 diabetes by conducting a meta-analysis.

RESEARCH DESIGN AND METHODS

A systematic search of the PubMed, EMBASE, ISI Web of Knowledge, and Cochrane Library databases up until 10 February 2012 was conducted to retrieve prospective studies matched to search terms. We used generalized least-squares trend estimation to assess dose-response relationships. The summary risk estimates were pooled using either fixed-effects or random-effects models to incorporate between-study variation.

RESULTS

The meta-analysis, including 10 prospective studies, with a total of 19,709 participants and 4,480 cases, detected a significant dose-response association of IL-6 levels with type 2 diabetes risk (relative risk [RR] 1.31 [95% CI 1.17–1.46]). For CRP, the meta-analysis involving 22 cohorts, with a total of 40,735 participants and 5,753 cases, showed that elevated CRP levels were significantly associated with increased risk of type 2 diabetes (1.26 [1.16–1.37]), with the absence of publication bias. Sensitivity and subgroup analyses further supported the associations.

CONCLUSIONS

This meta-analysis provides further evidence that elevated levels of IL-6 and CRP are significantly associated with increased risk of type 2 diabetes.The rapid worldwide increase in the prevalence of type 2 diabetes has become a serious public health problem (1). Type 2 diabetes may be accompanied by long-term microvascular and macrovascular complications, which lead to both morbidity and mortality (2). In addition, as many as one-third of individuals with type 2 diabetes are undiagnosed. However, accumulating evidence shows that inflammation may play a crucial intermediary role in the pathogenesis of type 2 diabetes, thus relating diabetes to a number of commonly coexisting conditions thought to originate via inflammatory mechanisms (3). In this regard, more recent data suggest that interleukin-6 (IL-6) and C-reactive protein (CRP) are associated with type 2 diabetes (4–10). IL-6, a pleiotropic proinflammatory cytokine, is produced by a variety of cells, including activated leukocytes, endothelial cells, and adipocytes (11). CRP is an acute-phase plasma protein synthesized by the liver and has been shown to be a sensitive, systemic biomarker of inflammation (3). The stability of this protein during long-term frozen blood storage and the availability of inexpensive, precise, and standardized assays have assisted studies of CRP (12).One potential implication of the many studies suggesting a relation between inflammation and diabetes is that inflammatory markers may be used to refine diabetes risk prediction and thus better target individuals for lifestyle interventions. However, the results reported on the association between IL-6 and diabetes risk have varied across studies (13–16). To date, no systematic review has been performed to evaluate the available evidence on the association of IL-6 levels with the risk of type 2 diabetes. Two previous meta-analyses evaluating the association of CRP and diabetes risk have yielded contradictory results. One previous meta-analysis (17) suggested that a positive association exists between CRP and diabetes risk. In contrast, another meta-analysis (18) concluded that CRP may not be an independent risk factor for the development of diabetes.The objective of the current study was to estimate the magnitude of the relationships between IL-6 and CRP levels and the risk of type 2 diabetes in prospective studies and to quantify these relationships in a meta-analysis.