Probiotics as a novel approach to modulate incretins, insulin secretion and risk factors of type 2 diabetes and complications

Abstract

<u>Background and Aim</u>: Ingestion of probiotics can modify gut microbiota and alter insulin resistance and diabetes development in rodents. We hypothesized that daily intake of <em>Lactobacillus (L.)</em> reuteri increases insulin sensitivity by changing cytokine release and insulin secretion via modulation of glucagon-like peptide (GLP-1, GLP-2) release.<br /><u>Material and Methods</u>: A prospective, double-blind, randomized trial was performed in 21 glucose tolerant humans (10 obese; age 51±2 years, BMI 36.0±4.8 kg/m²; 11 lean; 49±4 years, BMI 23.6±1.9 kg/m²). Participants ingested 10¹⁰ L. reuteri or placebo b.i.d. over 4 weeks. Oral glucose tolerance and isoglycemic glucose infusion tests were used to assess GLP-1, GLP-2 and C-peptide secretion, hyperinsulinemic-euglycemic clamps with [6,6-²H₂]glucose to measure peripheral insulin sensitivity (M-value) and endogenous glucose production (EGP). Muscle and hepatic lipid contents were measured by ¹H magnetic resonance spectroscopy. Immune status was assessed by measuring systemic cytokines, high-sensitive C-reactive protein (hsCRP) and lipopolysaccharide (LPS) concentrations. <br /><u>Results</u>: Intervention did not affect body mass, ectopic fat content and circulating cytokines. M was 37% lower (p<0.01) in obese than in lean volunteers, but both M-value and EGP did not change upon <em>L. reuteri</em> treatment. However, administration of <em>L. reuteri</em> increased glucose-stimulated insulin and C-peptide secretion by 49% (p<0.05) and 55% (p<0.05), respectively. Moreover, administration of L. reuteri improved the glucose-stimulated GLP-1 and GLP-2 release by 76% and 43%, respectively, compared to placebo (p<0.05). <br /><u>Conclusions</u>: Enrichment of gut microbiota with L. reuteri increased incretin-mediated insulin and C-peptide release, without effects on insulin sensitivity in glucose tolerant human subjects. These results suggest that modifying the microbiome could increase insulin secretion and thereby serve as a novel therapeutic tool for the treatment of type 2 diabetes. However, further studies are needed to address this issue in this emerging research field.