Elevated levels of IL-1Ra were associated with an increased risk of developing type 2 diabetes in this nested case-control study. We found a slight attenuation of this association when adjusting for waist circumference, which is consistent with IL-1Ra production in adipose tissue (13
). It is remarkable that the association was stable to adjustment for a range of further potential confounders, including fasting glucose and insulin. However, adjustment for 2-h glucose attenuated the association. This finding could be interpreted to indicate that increased IL-1Ra levels are a reaction to and not a cause of early postprandial hyperglycemia before the onset of diabetes. Studies with measurements of glycemic markers and IL-1Ra at multiple time points and analysis of their trajectories will be needed to clarify this point.
Our findings expand observations from cross-sectional studies that reported elevated levels of IL-1Ra in the circulation of individuals with obesity and insulin resistance (8
). Thus, individuals who will develop type 2 diabetes are characterized not only by an upregulation of proinflammatory immune mediators (1
) but also by the upregulation of at least one anti-inflammatory immune marker. Because animal studies and a recent clinical trial indicated that administration of IL-1Ra attenuates subclinical inflammation, supports β-cell function/insulin secretion, and may also improve insulin sensitivity (6
), it is tempting to speculate that elevated IL-1Ra levels in individuals at risk of type 2 diabetes may be an attempt to counteract the proinflammatory effects of interleukin-1β and to preserve insulin secretion and insulin sensitivity—an effort that eventually fails. However, our data cannot rule out the alternative interpretation that IL-1Ra has additional metabolic effects beyond the inhibition of interleukin-1β that could lead to insulin resistance and type 2 diabetes.
As a potential limitation of the study, it should be mentioned that point estimates and CIs are derived from nonweighted data from a nested case-control study and, therefore, their statistical inference may be restricted and may not represent the best available estimate within the context of the original cohort. Thus, further studies will be needed to support our hypothesis that individuals with high risk of type 2 diabetes are characterized by the presence of an early compensatory, anti-inflammatory response that precedes the development of the disease. This hypothesis could be tested by the analysis of further, mainly anti-inflammatory immune mediators, such as interleukin-10 or transforming growth factor-β in additional cohorts.