Protection from inflammatory disease in insulin resistance: the role of mannan-binding lectin

Aims/hypothesis: Decreased sensing of the innate immune system may lead to chronic activation of the inflammatory cascade. We hypothesised that mannan-binding lectin (MBL) deficiency may confer risk of obesity and insulin resistance. Materials and methods We performed a cross-sectional study of MBL protein concentration (n = 434) and MBL2 gene mutations (exon 1) (n = 759) in association with obesity, markers of inflammation and insulin action (euglycaemic clamp, n = 113), and a longitudinal study of MBL protein before and after weight loss in obese patients (n = 10). We also studied the effects of MBL in vitro in muscle cells and circulating MBL-A (mouse equivalent of human MBL) in a mouse model. Results: Among 434 consecutive non-diabetic men, the age-adjusted serum MBL concentration was lower in obese subjects than in lean subjects (median: 959 mu g/ml [interquartile range: 116.8-2,044 mu g/ml] vs 1,365 [467-2,513] mu g/ml; p = 0.01) and was accompanied by increased serum inflammatory markers. Insulin action correlated significantly with serum MBL (r = 0.49, p < 0.0001). Serum MBL concentration increased by a median of 110.2% after weight loss. The change in serum concentration of MBL was positively associated with the increase in insulin sensitivity (r = 0.713, p = 0.021). At least one MBL2 gene mutation was present in 48.2% of obese vs 39.3% of non-obese subjects (p = 0.037). The plasma concentration of MBL-A was lower in insulin-resistant obese ob/ob mice, as was the glucose/insulin ratio. Incubation of rat soleus muscle with human MBL markedly increased fatty acid oxidation. Conclusions/interpretation: These findings suggest that MBL, previously thought only to be involved in inflammation and immune system function, affects metabolic pathways.