Microbially produced glucagon-like peptide 1 improves glucose tolerance in mice

Arora T., Wegmann U., Bobhate A., Lee Y. S., Greiner T. U., Drucker D. J., Narbad A., Backhed F.. (2016)

Molecular metabolism, (2016) 1 6, 1-6

Objective: The enteroendocrine hormone glucagon-like peptide 1 (GLP-1) is an attractive anti-diabetic therapy. Here, we generated a recombinant Lactococcus lactis strain genetically modified to produce GLP-1 and investigated its ability to improve glucose tolerance in mice on chow or high-fat diet (HFD). Methods: We transformed L. lactis FI5876 with either empty vector or murine GLP1 expression vector to generate uk200 and glp1 L. lactis, respectively, and determined their potential to secrete insulin by incubating primary islets from wild-type (WT) and GLP-1 receptor knockout (GLP1R-KO) mice with culture supernatant of these strains. In addition, we administered these strains to mice on chow or HFD. At the end of the study period, we measured plasma GLP-1 levels, performed intraperitoneal glucose tolerance tests and insulin tolerance tests, and determined hepatic expression of the gluconeogenic genes g6pase and pepck. Results: Insulin release from primary islets of WT but not GLP1R-KO mice was higher following incubation with culture supernatant from glp1 L. lactis compared with uk200 L. lactis. In mice on chow, supplementation with glp1 versus uk200 L. lactis promoted increased vena porta levels of GLP-1 in both WT and GLP1R-KO mice; however, glp1 L. lactis promoted improved glucose tolerance in WT but not GLP1R-KO mice, indicating a requirement for GLP-1 receptor. In mice on HFD and thus with impaired glucose tolerance, supplementation with glp1 versus uk200 L. lactis promoted a pronounced improvement in glucose tolerance together with increased insulin levels. Supplementation with glp1 versus uk200 L. lactis did not affect insulin tolerance but resulted in reduced expression of g6pase in both chow and HFD-fed mice. Conclusion: The L. lactis strain genetically modified to produce GLP-1 is capable of stimulating insulin secretion from islets and improving glucose tolerance in mice. Keywords Lactococcus lactis, glucose tolerance, recombinant bacteria, GLP-1

Molecular metabolism, (2016) 1 6, 1-6

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