BACKGROUND

Evidence from animal models and observational epidemiology points to a role for chronic inflammation, in which interleukin 6 (IL-6) is a key player, in the pathophysiology of type 2 diabetes (T2D). However, it is unknown whether IL-6 mediated inflammation is implicated in the pathophysiology of T2D.

METHODS

We performed a meta-analysis of 15 prospective studies to investigate associations between IL-6 levels and incident T2D including 5,421 cases and 31,562 non-cases. We also estimated the association of a loss-of-function missense variant (Asp358Ala) in the IL-6 receptor gene (IL6R), previously shown to mimic the effects of IL-6R inhibition, in a large trans-ethnic meta-analysis of six T2D case-control studies including 260,614 cases and 1,350,640 controls.

FINDINGS

In a meta-analysis of 15 prospective studies, higher levels of IL-6 (per log pg/mL) were significantly associated with a higher risk of incident T2D (1·24 95% CI, 1·17, 1·32; P = 1 × 10). In a trans-ethnic meta-analysis of 260,614 cases and 1,350,640 controls, the IL6R Asp358Ala missense variant was associated with lower odds of T2D (OR, 0·98; 95% CI, 0·97, 0·99; P = 2 × 10). This association was not due to diagnostic misclassification and was consistent across ethnic groups. IL-6 levels mediated up to 5% of the association between higher body mass index and T2D.

INTERPRETATION

Large-scale human prospective and genetic data provide evidence that IL-6 mediated inflammation is implicated in the etiology of T2D but suggest that the impact of this pathway on disease risk in the general population is likely to be small.

FUNDING

The EPICNorfolk study has received funding from the Medical Research Council (MRC) (MR/N003284/1, MC-UU_12015/1 and MC_PC_13048) and Cancer Research UK (C864/A14136). The Fenland Study is funded by the MRC (MC_UU_12015/1 and MC_PC_13046).