TY - JOUR

T1 - The bile acid-sequestering resin sevelamer eliminates the acute GLP-1 stimulatory effect of endogenously released bile acids in patients with type 2 diabetes

AU - Brønden, Andreas

AU - Albér, Anders

AU - Rohde, Ulrich

AU - Gasbjerg, Laerke S

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 - 2018/2/1

Y1 - 2018/2/1

N2 - AIMS: The discovery of the specific bile acid receptors farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) in enteroendocrine L cells has prompted research focusing on the impact of bile acids on glucagon-like peptide-1 (GLP-1) secretion and glucose metabolism. The aim of the present study was to assess the GLP-1 secretory and gluco-metabolic effects of endogenously released bile, with and without concomitant administration of the bile acid-sequestering resin, sevelamer, in patients with type 2 diabetes.MATERIALS AND METHODS: We performed a randomized, placebo-controlled, and double-blinded cross-over study including 15 metformin-treated patients with type 2 diabetes. Four experimental study days in randomized order with administration of either sevelamer 3,200 mg or placebo in combination with intravenous infusion of cholecystokinin (CCK) (0.4 pmol sulfated CCK-8/kg/min). The primary endpoint was plasma GLP-1 excursions as measured by incremental area under the curve. Secondary endpoints included plasma responses of glucose, triglycerides, insulin, CCK, fibroblast growth factor-19 and 7α-hydroxy-4-cholesten-3-one (C4). In addition, gallbladder dynamics, gastric emptying, resting energy expenditure, appetite and ad libitum food intake were assessed.RESULTS: CCK-mediated gallbladder emptying was demonstrated to elicit a significant induction of GLP-1 secretion compared to saline, whereas concomitant single-dose administration of the bile acid sequestrant sevelamer was shown to eliminate the acute bile acid-induced increase in plasma GLP-1 excursions.CONCLUSIONS: Single-dose administration of sevelamer eliminated bile acid-mediated GLP-1 secretion in patients with type 2 diabetes, which could be explained by reduced bile acid stimulation of the basolaterally localized TGR5 on enteroendocrine L cells.

AB - AIMS: The discovery of the specific bile acid receptors farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) in enteroendocrine L cells has prompted research focusing on the impact of bile acids on glucagon-like peptide-1 (GLP-1) secretion and glucose metabolism. The aim of the present study was to assess the GLP-1 secretory and gluco-metabolic effects of endogenously released bile, with and without concomitant administration of the bile acid-sequestering resin, sevelamer, in patients with type 2 diabetes.MATERIALS AND METHODS: We performed a randomized, placebo-controlled, and double-blinded cross-over study including 15 metformin-treated patients with type 2 diabetes. Four experimental study days in randomized order with administration of either sevelamer 3,200 mg or placebo in combination with intravenous infusion of cholecystokinin (CCK) (0.4 pmol sulfated CCK-8/kg/min). The primary endpoint was plasma GLP-1 excursions as measured by incremental area under the curve. Secondary endpoints included plasma responses of glucose, triglycerides, insulin, CCK, fibroblast growth factor-19 and 7α-hydroxy-4-cholesten-3-one (C4). In addition, gallbladder dynamics, gastric emptying, resting energy expenditure, appetite and ad libitum food intake were assessed.RESULTS: CCK-mediated gallbladder emptying was demonstrated to elicit a significant induction of GLP-1 secretion compared to saline, whereas concomitant single-dose administration of the bile acid sequestrant sevelamer was shown to eliminate the acute bile acid-induced increase in plasma GLP-1 excursions.CONCLUSIONS: Single-dose administration of sevelamer eliminated bile acid-mediated GLP-1 secretion in patients with type 2 diabetes, which could be explained by reduced bile acid stimulation of the basolaterally localized TGR5 on enteroendocrine L cells.

KW - Journal Article

U2 - 10.1111/dom.13080

DO - 10.1111/dom.13080

M3 - Journal article

C2 - 28786523

VL - 20

SP - 362

EP - 369

JO - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1462-8902

IS - 2

ER -