Natural Antibiotics and Insulin Sensitivity: The Role of Bactericidal/Permeability-Increasing Protein

Abstract

The innate immune system can immediately respond to microorganism intrusion by helping to prevent further invasion. Bactericidal/permeability-increasing protein (BPI) is a major constituent of neutrophils that possesses anti-inflammatory properties. Inflammation is increasingly recognized as a component of the metabolic syndrome. We hypothesized that the production of BPI could be linked to insulin sensitivity and glucose tolerance. We studied circulating BPI across categories of glucose tolerance. We also studied whether these cross-sectional associations were of functional importance. For this reason, we investigated circulating bioactive lipopolysaccharide and the effects of changing insulin action-after treatment with an insulin sensitizer (metformin)-on circulating BPI in subjects with glucose intolerance. Finally, we tested whether a 3'-untranslated region (UTR) BPI polymorphism led to differences in BPI and insulin action among nondiabetic subjects. Age- and BMI-adjusted circulating BPI was significantly lower among patients with type 2 diabetes. Circulating BPI correlated negatively with fasting and postload glucose and insulin concentrations. In subjects with glucose intolerance, BPI was also linked to BMI, waist-to-hip ratio, and age- and BMI-adjusted insulin sensitivity. Bioactive lipopolysaccharide was negatively correlated with circulating BPI (r = -0.57, P < 0.0001) and positively with plasma lipopolysaccharide-binding protein (r = 0.54, P = 0.002). In parallel to improved insulin sensitivity, plasma BPI significantly increased in the metformin group but not in the placebo group. A 3'-UTR BPI polymorphism was simultaneously associated with plasma BPI concentration, waist-to-hip ratio, fasting and postload insulin concentration, fasting plasma triglycerides, and insulin sensitivity. These findings suggest that this component of the innate immune system is associated with metabolic pathways.

Circulating lipopolysaccharide-binding protein (LBP) as a marker of obesity-related insulin resistance

“…Serum concentrations of soluble TNFR2 are believed to reflect the degree of activation of the TNF system. 26 In addition, circulating LBP concentration was in concordance with other possible candidate markers of obesity-related insulin resistance and closely associated with innate immune system response such as C-reactive protein, 27 bactericidal/permeability-increasing 14 and complement factor B. 18 Otherwise, the strong circulating LBP reduction after fat mass loss opens new perspectives.…”

“…(1) The strong relationship between circulating LBP and obesity, previously reported, 14,16 mainly in subjects with GIT and T2DM. In a previous cross-sectional study, we have reported that plasma LBP was positively associated with several components of the metabolic syndrome and negatively associated with insulin sensitivity 14 in non-diabetic subjects.…”

“…At 20 min, regular insulin (Actrapid, Novo, Denmark; 0.03 U kg À1 ) was injected as a bolus. Additional samples were obtained from a contralateral antecubital vein at times 1,2,3,4,5,6,7,8,10,12,14,16,19,20,22,23,24,25,27,30,40,50,60,70,80,90, 100, 120, 140, 160 and 180 min. Samples were rapidly collected through a three-way stopcock connected to the butterfly needle.…”

“…LBP co-purifies with high-density lipoprotein (HDL) particles and additional studies have shown that LBP can transfer LPS to lipoproteins, neutralizing LPS effects. 13 Serum LBP concentration was described as a marker of coronary artery disease 14,15 and has been recently found to be associated with obesity and related disorders in apparently healthy Chinese subjects. 16 We here confirm the previously reported association of circulating LBP with insulin resistance and obesity in a Caucasian population.…”

“…16 We here confirm the previously reported association of circulating LBP with insulin resistance and obesity in a Caucasian population. 14 To gain insights into these associations, we investigated the effects of diet weight loss in humans and the effects of high-fat diet (HFD), metformin and genetic insulin sensitization (glucagon-like peptide 1 receptor knockout (GLPIR KO) model) in mice.…”