Microbially produced glucagon-like peptide 1 improves glucose tolerance in mice
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 (...
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doaj-b048ec4f1b7d4a9d9cb7601cb75249e32020-11-24T23:06:13ZengElsevierMolecular Metabolism2212-87782016-08-0158725730Microbially produced glucagon-like peptide 1 improves glucose tolerance in miceTulika Arora0Udo Wegmann1Anup Bobhate2Ying Shiuan Lee3Thomas U. Greiner4Daniel J. Drucker5Arjan Narbad6Fredrik Bäckhed7Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, SwedenGut Health and Food Safety Programme, Institute of Food Research, Norwich NR4 7UA, UKGut Health and Food Safety Programme, Institute of Food Research, Norwich NR4 7UA, UKWallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, SwedenWallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, SwedenDepartment of Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, CanadaGut Health and Food Safety Programme, Institute of Food Research, Norwich NR4 7UA, UKWallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Corresponding author. Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden. Tel.: +46 31 342 7833; fax: +46 31 82 37 62.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 (pUK200) or murine GLP-1 expression vector to generate LL-UK200 and LL-GLP1, respectively, and determined their potential to induce insulin secretion 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 and insulin tolerance tests, and determined hepatic expression of the gluconeogenic genes G6pc and Pepck. Results: Insulin release from primary islets of WT but not GLP1R-KO mice was higher following incubation with culture supernatant from LL-GLP1 compared with LL-UK200. In mice on chow, supplementation with LL-GLP1 versus LL-UK200 promoted increased vena porta levels of GLP-1 in both WT and GLP1R-KO mice; however, LL-GLP1 promoted improved glucose tolerance in WT but not in GLP1R-KO mice, indicating a requirement for the GLP-1 receptor. In mice on HFD and thus with impaired glucose tolerance, supplementation with LL-GLP1 versus LL-UK200 promoted a pronounced improvement in glucose tolerance together with increased insulin levels. Supplementation with LL-GLP1 versus LL-UK200 did not affect insulin tolerance but resulted in reduced expression of G6pc in both chow and HFD-fed mice. Conclusions: 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-1http://www.sciencedirect.com/science/article/pii/S2212877816300692 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Tulika Arora Udo Wegmann Anup Bobhate Ying Shiuan Lee Thomas U. Greiner Daniel J. Drucker Arjan Narbad Fredrik Bäckhed |
spellingShingle |
Tulika Arora Udo Wegmann Anup Bobhate Ying Shiuan Lee Thomas U. Greiner Daniel J. Drucker Arjan Narbad Fredrik Bäckhed Microbially produced glucagon-like peptide 1 improves glucose tolerance in mice Molecular Metabolism |
author_facet |
Tulika Arora Udo Wegmann Anup Bobhate Ying Shiuan Lee Thomas U. Greiner Daniel J. Drucker Arjan Narbad Fredrik Bäckhed |
author_sort |
Tulika Arora |
title |
Microbially produced glucagon-like peptide 1 improves glucose tolerance in mice |
title_short |
Microbially produced glucagon-like peptide 1 improves glucose tolerance in mice |
title_full |
Microbially produced glucagon-like peptide 1 improves glucose tolerance in mice |
title_fullStr |
Microbially produced glucagon-like peptide 1 improves glucose tolerance in mice |
title_full_unstemmed |
Microbially produced glucagon-like peptide 1 improves glucose tolerance in mice |
title_sort |
microbially produced glucagon-like peptide 1 improves glucose tolerance in mice |
publisher |
Elsevier |
series |
Molecular Metabolism |
issn |
2212-8778 |
publishDate |
2016-08-01 |
description |
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 (pUK200) or murine GLP-1 expression vector to generate LL-UK200 and LL-GLP1, respectively, and determined their potential to induce insulin secretion 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 and insulin tolerance tests, and determined hepatic expression of the gluconeogenic genes G6pc and Pepck. Results: Insulin release from primary islets of WT but not GLP1R-KO mice was higher following incubation with culture supernatant from LL-GLP1 compared with LL-UK200. In mice on chow, supplementation with LL-GLP1 versus LL-UK200 promoted increased vena porta levels of GLP-1 in both WT and GLP1R-KO mice; however, LL-GLP1 promoted improved glucose tolerance in WT but not in GLP1R-KO mice, indicating a requirement for the GLP-1 receptor. In mice on HFD and thus with impaired glucose tolerance, supplementation with LL-GLP1 versus LL-UK200 promoted a pronounced improvement in glucose tolerance together with increased insulin levels. Supplementation with LL-GLP1 versus LL-UK200 did not affect insulin tolerance but resulted in reduced expression of G6pc in both chow and HFD-fed mice. Conclusions: 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 |
url |
http://www.sciencedirect.com/science/article/pii/S2212877816300692 |
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