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

PLoS One. 2014 Jul 2;9(7):e100778. doi: 10.1371/journal.pone.0100778. eCollection 2014.

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.

Trial registration: www.ClinicalTrials.gov NCT01357876.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Bile Acids and Salts / metabolism
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Female
  • Glucagon-Like Peptide 1 / blood
  • Humans
  • Hypoglycemic Agents* / administration & dosage
  • Hypoglycemic Agents* / pharmacokinetics
  • Intestinal Mucosa* / metabolism
  • Intestines* / microbiology
  • Male
  • Metformin* / administration & dosage
  • Metformin* / pharmacokinetics
  • Microbiota / drug effects*
  • Middle Aged
  • Peptide YY / blood

Substances

  • Bile Acids and Salts
  • Blood Glucose
  • Hypoglycemic Agents
  • Peptide YY
  • Glucagon-Like Peptide 1
  • Metformin

Associated data

  • ClinicalTrials.gov/NCT01357876

Grant support

The study has been fully funded by GlaxoSmithKline. The funder provided support in the form of salaries for authors [AN, SM, AWN, DB, SVH, ET, DR, AS, JRB and DJN], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.