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
Highlights
Metformin, a biguanide derivate, is the first line of treatment in patients with type 2 diabetes mellitus (T2DM), in conjunction with lifestyle modification, as indicated in the guidelines issued by the American Diabetes Association and European Association for the Study of Diabetes [1]
We have demonstrated that metformin has effects on bile acid metabolism, entero-endocrine hormone secretion and gut microbiome changes in patients with T2DM, challenging the concept that the glucose lowering effects of metformin are attributable solely to activation of AMP kinase (AMPK) [38], and antagonism of glucagonmediated elevation of cAMP in the hepatocytes [39]
We investigated the entero-hepatic flux of bile acids by analyzing three matrices which had been collected in patients who had been sampled at baseline (On-Metformin Visit 1), after a 7 days withdrawal (Visit 2), after a variable period determined by the partial loss of fasting glycaemic control (a 25% increase of the mean capillary blood glucose (CBG) obtained at baseline; Visit 3), and after reinstatement of the usual daily dose of metformin and restitution of baseline fasting CBG values (Visit 4)
Summary
A biguanide derivate, is the first line of treatment in patients with type 2 diabetes mellitus (T2DM), in conjunction with lifestyle modification, as indicated in the guidelines issued by the American Diabetes Association and European Association for the Study of Diabetes [1]. Mitochondrial function and AMPK activity in liver and skeletal muscle have received much attention as potential mechanisms by which metformin has its beneficial effects. In T2DM, fasting and post-prandial circulating levels of GIP are normal or increased, but the b-cell response to this peptide is diminished. B-cells remain responsive to the insulinotropic action of GLP-1, but meal-stimulated GLP-1 increases are diminished [11]. Some have reported that metformin increases circulating active GLP-17–36 [14,15,16] or total GLP-1 [17,18], while others describe a lack of effect on DPP-IV [19] or variable inhibition. There is evidence that metformin may reduce bile acid reabsorption in the distal ileum [21], and this may result in greater availability of bile acids in the colon for interaction with the farnesoid-X receptor (FXR) [22] and TGR5 receptors [23]
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