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

ABSTRACT: UNLABELLED: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.

SUBMITTER: Napolitano A

PROVIDER: S-EPMC4079657 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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

Napolitano Antonella A Miller Sam S Nicholls Andrew W AW Baker David D Van Horn Stephanie S Thomas Elizabeth E Rajpal Deepak D Spivak Aaron A Brown James R JR Nunez Derek J DJ

PloS one 20140702 7

<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 effectiv ...[more]

PMID: 24988476

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Project description:UnlabelledGPR119 receptor agonists improve glucose metabolism and alter gut hormone profiles in animal models and healthy subjects. We therefore investigated the pharmacology of GSK1292263 (GSK263), a selective GPR119 agonist, in two randomized, placebo-controlled studies that enrolled subjects with type 2 diabetes. Study 1 had drug-naive subjects or subjects who had stopped their diabetic medications, and Study 2 had subjects taking metformin. GSK263 was administered as single (25-800 mg; n = 45) or multiple doses (100-600 mg/day for 14 days; n = 96). Placebo and sitagliptin 100 mg/day were administered as comparators. In Study 1, sitagliptin was co-administered with GSK263 or placebo on Day 14 of dosing. Oral glucose and meal challenges were used to assess the effects on plasma glucose, insulin, C-peptide, glucagon, peptide tyrosine-tyrosine (PYY), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). After 13 days of dosing, GSK263 significantly increased plasma total PYY levels by ∼ five-fold compared with placebo, reaching peak concentrations of ∼ 50 pM after each of the three standardized meals with the 300 mg BID dose. Co-dosing of GSK263 and metformin augmented peak concentrations to ∼ 100 pM at lunchtime. GSK263 had no effect on active or total GLP-1 or GIP, but co-dosing with metformin increased post-prandial total GLP-1, with little effect on active GLP-1. Sitagliptin increased active GLP-1, but caused a profound suppression of total PYY, GLP-1, and GIP when dosed alone or with GSK263. This suppression of peptides was reduced when sitagliptin was co-dosed with metformin. GSK263 had no significant effect on circulating glucose, insulin, C-peptide or glucagon levels. We conclude that GSK263 did not improve glucose control in type 2 diabetics, but it had profound effects on circulating PYY. The gut hormone effects of this GPR119 agonist were modulated when co-dosed with metformin and sitagliptin. Metformin may modulate negative feedback loops controlling the secretion of enteroendocrine peptides.Trial registrationClinicaltrials.gov NCT01119846 Clinicaltrials.gov NCT01128621.

Project description:BackgroundSmall cross-sectional studies have suggested that metformin, a first-line oral hypoglycemic agent, may lower thyroid-stimulating hormone (TSH) levels. Our objective was to determine whether the use of metformin monotherapy, when compared with sulfonylurea monotherapy, is associated with an increased risk of low TSH levels (<0.4 mIU/L) in patients with type 2 diabetes mellitus.MethodsUsing the Clinical Practice Research Datalink, we identified patients who began receiving metformin or sulfonylurea monotherapy between Jan. 1, 1988, and Dec. 31, 2012. We assembled 2 subcohorts of patients with treated hypothyroidism or euthyroidism, and followed them until Mar. 31, 2013. We used Cox proportional hazards models to evaluate the association of low TSH levels with metformin monotherapy, compared with sulfonylurea monotherapy, in each subcohort.ResultsA total of 5689 patients with treated hypothyroidism and 59,937 euthyroid patients were included in the subcohorts. Among patients with treated hypothyroidism, 495 events of low TSH levels were observed during follow-up (incidence rate 119.7/1000 person-years). In the euthyroid group, 322 events of low TSH levels were observed (incidence rate 4.5/1000 person-years). Compared with sulfonylurea monotherapy, metformin monotherapy was associated with a 55% increased risk of low TSH levels in patients with treated hypothyroidism (incidence rate 79.5/1000 person-years v. 125.2/1000 person-years, adjusted hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.09-2.20), with the highest risk in the 90-180 days after initiation (adjusted HR 2.30, 95% CI 1.00-5.29). No association was observed in euthyroid patients (adjusted HR 0.97, 95% CI 0.69-1.36).InterpretationIn this longitudinal population-based study, metformin use was associated with an increased incidence of low TSH levels in patients with treated hypothyroidism, but not in euthyroid patients. The clinical consequences of this need further investigation.

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

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

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