TY - JOUR

T1 - Glucose-lowering effects and mechanisms of the bile acid-sequestering resin sevelamer

AU - Brønden, Andreas

AU - Mikkelsen, Kristian

AU - Sonne, David P

AU - Hansen, Morten

AU - Våben, Christoffer

AU - Gabe, Maria N

AU - Rosenkilde, Mette

AU - Tremaroli, Valentina

AU - Wu, Hao

AU - Bäckhed, Fredrik

AU - Rehfeld, Jens F

AU - Holst, Jens J

AU - Vilsbøll, Tina

AU - Knop, Filip K

N1 - This article is protected by copyright. All rights reserved.

PY - 2018/7

Y1 - 2018/7

N2 - AIMS: Sevelamer, a non-absorbable amine-based resin used for treatment of hyperphosphatemia, has been demonstrated to hold a marked bile acid-binding potential alongside beneficial effects on lipid and glucose metabolism. The aim of this study was to investigate the glucose-lowering effect and mechanism(s) of sevelamer in patients with type 2 diabetes.MATERIALS AND METHODS: In this double-blinded randomized controlled trial, we randomized 30 patients with type 2 diabetes to sevelamer (n=20) or placebo (n=10). Participants were subjected to standardized 4-hour liquid meal tests at baseline and following seven days of treatment. The main outcome measure was plasma glucagon-like peptide-1 excursions as measured by area under the curve. In addition, blood was sampled for measurements of glucose, lipids, glucose-dependent insulinotropic polypeptide, C-peptide, glucagon, fibroblast growth factor-19, cholecystokinin and bile acids. Assessments of gastric emptying, resting energy expenditure and gut microbiota composition were performed.RESULTS: Sevelamer elicited a significant placebo-corrected reduction in plasma glucose with concomitant reduced fibroblast growth factor-19 concentrations, increased de novo synthesis of bile acids, a shift towards a more hydrophilic bile acid pool and increased lipogenesis. No glucagon-like peptide-1-mediated effects on insulin, glucagon or gastric emptying were evident, which point to limited contribution of this incretin hormone to the glucose-lowering effect of sevelamer. Furthermore, no sevelamer-mediated effects on gut microbiota composition or resting energy expenditure were observed.CONCLUSIONS: Sevelamer reduced plasma glucose concentrations in patients with type 2 diabetes by mechanisms that seemed to involve decreased intestinal and hepatic bile acid-mediated farnesoid X receptor activation.

AB - AIMS: Sevelamer, a non-absorbable amine-based resin used for treatment of hyperphosphatemia, has been demonstrated to hold a marked bile acid-binding potential alongside beneficial effects on lipid and glucose metabolism. The aim of this study was to investigate the glucose-lowering effect and mechanism(s) of sevelamer in patients with type 2 diabetes.MATERIALS AND METHODS: In this double-blinded randomized controlled trial, we randomized 30 patients with type 2 diabetes to sevelamer (n=20) or placebo (n=10). Participants were subjected to standardized 4-hour liquid meal tests at baseline and following seven days of treatment. The main outcome measure was plasma glucagon-like peptide-1 excursions as measured by area under the curve. In addition, blood was sampled for measurements of glucose, lipids, glucose-dependent insulinotropic polypeptide, C-peptide, glucagon, fibroblast growth factor-19, cholecystokinin and bile acids. Assessments of gastric emptying, resting energy expenditure and gut microbiota composition were performed.RESULTS: Sevelamer elicited a significant placebo-corrected reduction in plasma glucose with concomitant reduced fibroblast growth factor-19 concentrations, increased de novo synthesis of bile acids, a shift towards a more hydrophilic bile acid pool and increased lipogenesis. No glucagon-like peptide-1-mediated effects on insulin, glucagon or gastric emptying were evident, which point to limited contribution of this incretin hormone to the glucose-lowering effect of sevelamer. Furthermore, no sevelamer-mediated effects on gut microbiota composition or resting energy expenditure were observed.CONCLUSIONS: Sevelamer reduced plasma glucose concentrations in patients with type 2 diabetes by mechanisms that seemed to involve decreased intestinal and hepatic bile acid-mediated farnesoid X receptor activation.

KW - Journal Article

U2 - 10.1111/dom.13272

DO - 10.1111/dom.13272

M3 - Journal article

VL - 20

SP - 1623

EP - 1631

JO - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1462-8902

IS - 7

ER -