Context: Lactoferrin is an innate immune system protein with multiple benefitial health activities. To gain insight in the interaction between innate immune system and metabolic disturbances (obesity and insulin resistance).

Objective: We investigated the relationship between circulating lactoferrin and chronic inflammation-associated insulin resistance according glucose tolerance status in Caucasic population.

Design, setting, participants and main outcome measures: Circulating non-stressed lactoferrin (ELISA), metabolic variables and inflammatory markers were measured in 229 men, 94 with normal (NGT) and 135 with altered glucose tolerance (AGT). Lactoferrin secretion by neutrophil was investigated in whole blood culture (4 young NGT subjects, 4 older NGT subjects and 4 patients with type 2 diabetes) under microbial lipopolysaccharide (LPS) with IL-6, and rosiglitazone treatment. We also tested the lactoferrin action in THP-1 cells under LPS stimulus.

Results: Circulating lactoferrin was significantly decreased in patients with AGT (431.5 ± 187.5 vs. 493.5 ± 238.9 ng/ml, p=0.02). In addition, circulating lactoferrin was negatively associated with hyperglycemia and obesity measures and positively with insulin sensitivity. Lactoferrin was negatively related to inflammatory markers, especially in AGT subjects.

In ex vivo experiments, we have found a significant decrease in LPS-induced lactoferrin release from neutrophils in subjects with type 2 diabetes. IL-6 co-incubation decreased LPS-induced lactoferrin release in NGT subjects (p<0.001). Finally, rosiglitazone treatment led to increased lactoferrin secretion (398 ± 193 vs. 280.1 ± 104.9 ng/ml, p<0.0001). Lactoferrin decreased NF- activation and IL-6, IL-8 and MCP-1 expression under LPS challenge.

Conclusions: Decreased circulating lactoferrin levels may play a role in chronic low level inflammation-associated insulin resistance.