Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus.

<h4>Unlabelled</h4>Metformin, a biguanide derivate, has pleiotropic effects beyond glucose reduction, including improvement of lipid profiles and lowering microvascular and macrovascular complications associated with type 2 diabetes mellitus (T2DM). These effects have been ascribed to ad...

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Autores principales:	Antonella Napolitano, Sam Miller, Andrew W Nicholls, David Baker, Stephanie Van Horn, Elizabeth Thomas, Deepak Rajpal, Aaron Spivak, James R Brown, Derek J Nunez
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0210c4a3a2ff4b068af2ccf58d9a2e0f
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spelling	oai:doaj.org-article:0210c4a3a2ff4b068af2ccf58d9a2e0f2021-11-25T06:09:50ZNovel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus.1932-620310.1371/journal.pone.0100778https://doaj.org/article/0210c4a3a2ff4b068af2ccf58d9a2e0f2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24988476/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Unlabelled</h4>Metformin, a biguanide derivate, has pleiotropic effects beyond glucose reduction, including improvement of lipid profiles and lowering microvascular and macrovascular complications associated with type 2 diabetes mellitus (T2DM). These effects have been ascribed to adenosine monophosphate-activated protein kinase (AMPK) activation in the liver and skeletal muscle. However, metformin effects are not attenuated when AMPK is knocked out and intravenous metformin is less effective than oral medication, raising the possibility of important gut pharmacology. We hypothesized that the pharmacology of metformin includes alteration of bile acid recirculation and gut microbiota resulting in enhanced enteroendocrine hormone secretion. In this study we evaluated T2DM subjects on and off metformin monotherapy to characterize the gut-based mechanisms of metformin. Subjects were studied at 4 time points: (i) at baseline on metformin, (ii) 7 days after stopping metformin, (iii) when fasting blood glucose (FBG) had risen by 25% after stopping metformin, and (iv) when FBG returned to baseline levels after restarting the metformin. At these timepoints we profiled glucose, insulin, gut hormones (glucagon-like peptide-1 (GLP-1), peptide tyrosine-tyrosine (PYY) and glucose-dependent insulinotropic peptide (GIP) and bile acids in blood, as well as duodenal and faecal bile acids and gut microbiota. We found that metformin withdrawal was associated with a reduction of active and total GLP-1 and elevation of serum bile acids, especially cholic acid and its conjugates. These effects reversed when metformin was restarted. Effects on circulating PYY were more modest, while GIP changes were negligible. Microbiota abundance of the phylum Firmicutes was positively correlated with changes in cholic acid and conjugates, while Bacteroidetes abundance was negatively correlated. Firmicutes and Bacteroidetes representation were also correlated with levels of serum PYY. Our study suggests that metformin has complex effects due to gut-based pharmacology which might provide insights into novel therapeutic approaches to treat T2DM and associated metabolic diseases.<h4>Trial registration</h4>www.ClinicalTrials.gov NCT01357876.Antonella NapolitanoSam MillerAndrew W NichollsDavid BakerStephanie Van HornElizabeth ThomasDeepak RajpalAaron SpivakJames R BrownDerek J NunezPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 7, p e100778 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Antonella Napolitano Sam Miller Andrew W Nicholls David Baker Stephanie Van Horn Elizabeth Thomas Deepak Rajpal Aaron Spivak James R Brown Derek J Nunez Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus.
description	<h4>Unlabelled</h4>Metformin, a biguanide derivate, has pleiotropic effects beyond glucose reduction, including improvement of lipid profiles and lowering microvascular and macrovascular complications associated with type 2 diabetes mellitus (T2DM). These effects have been ascribed to adenosine monophosphate-activated protein kinase (AMPK) activation in the liver and skeletal muscle. However, metformin effects are not attenuated when AMPK is knocked out and intravenous metformin is less effective than oral medication, raising the possibility of important gut pharmacology. We hypothesized that the pharmacology of metformin includes alteration of bile acid recirculation and gut microbiota resulting in enhanced enteroendocrine hormone secretion. In this study we evaluated T2DM subjects on and off metformin monotherapy to characterize the gut-based mechanisms of metformin. Subjects were studied at 4 time points: (i) at baseline on metformin, (ii) 7 days after stopping metformin, (iii) when fasting blood glucose (FBG) had risen by 25% after stopping metformin, and (iv) when FBG returned to baseline levels after restarting the metformin. At these timepoints we profiled glucose, insulin, gut hormones (glucagon-like peptide-1 (GLP-1), peptide tyrosine-tyrosine (PYY) and glucose-dependent insulinotropic peptide (GIP) and bile acids in blood, as well as duodenal and faecal bile acids and gut microbiota. We found that metformin withdrawal was associated with a reduction of active and total GLP-1 and elevation of serum bile acids, especially cholic acid and its conjugates. These effects reversed when metformin was restarted. Effects on circulating PYY were more modest, while GIP changes were negligible. Microbiota abundance of the phylum Firmicutes was positively correlated with changes in cholic acid and conjugates, while Bacteroidetes abundance was negatively correlated. Firmicutes and Bacteroidetes representation were also correlated with levels of serum PYY. Our study suggests that metformin has complex effects due to gut-based pharmacology which might provide insights into novel therapeutic approaches to treat T2DM and associated metabolic diseases.<h4>Trial registration</h4>www.ClinicalTrials.gov NCT01357876.
format	article
author	Antonella Napolitano Sam Miller Andrew W Nicholls David Baker Stephanie Van Horn Elizabeth Thomas Deepak Rajpal Aaron Spivak James R Brown Derek J Nunez
author_facet	Antonella Napolitano Sam Miller Andrew W Nicholls David Baker Stephanie Van Horn Elizabeth Thomas Deepak Rajpal Aaron Spivak James R Brown Derek J Nunez
author_sort	Antonella Napolitano
title	Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus.
title_short	Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus.
title_full	Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus.
title_fullStr	Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus.
title_full_unstemmed	Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus.
title_sort	novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/0210c4a3a2ff4b068af2ccf58d9a2e0f
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Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus.

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