The human gut and its microbial content (microbiome) may contribute to the pathogenesis of obesity, insulin resistance and type 2 diabetes. Possible mechanisms include altered bacterial profile, increased intestinal permeability, and elevated bacterial lipopolysaccharide (LPS) leading to low-grade systemic inflammation termed metabolic endotoxemia. We hypothesized that two interventions with putative LPS-lowering effects, sevelamer and a synbiotic (combination pre- and probiotic), would improve peripheral insulin sensitivity in obese subjects. Based upon pre-clinical studies, sevelamer is reported to sequester LPS in the GI tract, whereas a synbiotic of Bifidobacterium longum plus oligofructose can improve intestinal barrier integrity. We randomized 22, normal glucose tolerant (NGT), lean (15F/7M, BMI=23.0, age=45.4yr, A1c=5.3%) and 28 NGT, obese subjects (20F/8M, BMI=32.7, age=51.9yr, A1c=5.5%) to receive oral sevelamer, synbiotic or placebo daily for 28 days. Insulin sensitivity (euglycemic clamp), cholesterol, endotoxemia (LPS, LBP, CD14), and intestinal permeability (lactulose/mannitol ratio, zonulin) were assessed before and after intervention. Obese subjects had reduced baseline insulin sensitivity compared to lean subjects (M value, -28.6%, p=0.0001 based on 2-sample t-test). Generalized estimating equation analysis showed that sevelamer increased insulin sensitivity (M value, +25.6%, p=0.022) and lowered plasma LDL (-16.4%, p=0.016) in obese subjects compared to placebo-treated obese subjects. Synbiotic did not significantly alter insulin sensitivity or lipids compared to placebo in obese subjects. Lean subjects saw no change in insulin sensitivity with either treatment. Neither treatment significantly altered plasma LPS or intestinal permeability in lean or obese subjects.
In conclusion, sevelamer improves insulin sensitivity and LDL in obese subjects, and this effect is mostly independent of parameters of endotoxemia and intestinal permeability.
E. Baeuerle: None. H. Liang: None. V. Ganapathy: None. R. Fernandez: None. N. Sathavarodom: None. C. Wang: None. S.E. Espinoza: None. N. Musi: None.
American Diabetes Association (7-13-GSK-01 to N.M.); National Institutes of Health (T32GM113896)