-Exploiting-the-physiological-responses-to-nutrient-ingestion-might-reveal-at-least-in-the-first-stages-of-the-diabetic-disease-a-potent-tool-to-improve-TRIAL-REGISTRATION-ClinicalTrials-w

gov NCT02342834 FUNDING: This work was supported by grants from the University of Pisa (Fondi di Ateneo) and by FCT Novel gut-based pharmacology of metformin in patients with type 2 diabetes Triangle Park, North Carolina, United States of America.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. Endocrine function drugs 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.Conflict of interest statement: Competing Interests: The study was sponsored by GlaxoSmithKline R&D. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. Employees of GlaxoSmithKline R&D were involved in the design of the study, data collection and analysis, decision to publish, and preparation of the manuscript.

Early improvement in glycemic control after bariatric surgery and its relationships with insulin, GLP-1, and glucagon secretion in type 2 diabetic São Paulo, Rua Leandro Dupret 365, CEP 04025011, Vila Clementino, São Paulo, BACKGROUND: The surgical treatment of obesity ameliorates metabolic abnormalities in patients with type 2 diabetes. The objective of this study was to evaluate the early effects of Roux-en-Y gastric bypass (RYGB) on metabolic and hormonal parameters in patients with type 2 diabetes (T2DM).METHODS: Ten patients with T2DM (BMI, 39 ± 1) were evaluated before and 7, 30, and 90 days after RYGB. A meal test was performed, and plasma insulin, glucose, glucagon, and glucagon-like-peptide 1 (GLP-1) levels were measured at RESULTS: Seven days after RYGB, a significant reduction was observed in HOMA-IR index from 7 ± 5 to 2 ± 1; p < 05 was associated with a nonsignificant reduction in body weight. The insulin and GLP-1 curves began to show a peak at 30 min after food ingestion, while there was a progressive decrease in glucagon and blood glucose levels throughout the meal test. Thirty and 90 days after RYGB, along with progressive weight loss, blood glucose and hormonal changes remained in the same direction and became more expressive with the post-meal insulin curve suggesting recovery of the first phase of insulin secretion and with the increase in insulinogenic index, denoting improvement in β-cell function. Furthermore, Pancreatic hormones and other blood sugar regulating drugs was found between changes in GLP-1 and insulin levels measured at 30 min after meal (r = 0; p = 000).

CONCLUSION: Our data suggest that the RYGB surgery, beyond weight loss, induces early beneficial hormonal changes which favor glycemic control in type 2 Therapeutic potential of targeting intestinal bitter taste receptors in diabetes Taiwan; Herbal Sciences Program, Bastyr University, Seattle, WA, USA. Electronic Intestinal release of incretin hormones after food intake promotes glucose-dependent insulin secretion and regulates glucose homeostasis.