title: Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus.
abstract: 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.
  
  
  BACKGROUND
  www.ClinicalTrials.gov NCT01357876.
authors.affiliation: Immuno-Inflammation Unit, GSK R&D, Stevenage, Herts, United Kingdom.
authors.forename: Antonella
authors.initials: A
authors.lastname: Napolitano
authors.affiliation: Quantitative Sciences, GSK R&D, Stevenage, Herts, United Kingdom.
authors.forename: Sam
authors.initials: S
authors.lastname: Miller
authors.affiliation: Safety Assessment, GSK R&D, Ware, Herts, United Kingdom.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Nicholls
authors.affiliation: Safety Assessment, GSK R&D, Ware, Herts, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Baker
authors.affiliation: Target and Pathways Validation, GSK R&D, Upper Providence, Pennsylvania, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Van Horn
authors.affiliation: Target and Pathways Validation, GSK R&D, Upper Providence, Pennsylvania, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Thomas
authors.affiliation: Computational Biology, GSK R&D, Upper Providence, Pennsylvania, United States of America.
authors.forename: Deepak
authors.initials: D
authors.lastname: Rajpal
authors.affiliation: Computational Biology, GSK R&D, Upper Providence, Pennsylvania, United States of America.
authors.forename: Aaron
authors.initials: A
authors.lastname: Spivak
authors.affiliation: Computational Biology, GSK R&D, Upper Providence, Pennsylvania, United States of America.
authors.forename: James R
authors.initials: JR
authors.lastname: Brown
authors.affiliation: Enteroendocrine Discovery Unit, GlaxoSmithKline R&D, GSK R&D, Research Triangle Park, North Carolina, United States of America.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Nunez
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001647:Bile Acids and Salts / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000382:microbiology; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000493:pharmacokinetics; D064307:Microbiota / Q000187:drug effects*; D008875:Middle Aged; D019894:Peptide YY / Q000097:blood
chemical_list: D001647:Bile Acids and Salts; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D019894:Peptide YY; D052216:Glucagon-Like Peptide 1; D008687:Metformin