The bile acid-sequestering resin sevelamer eliminates the acute GLP-1 stimulatory effect of endogenously released bile acids in patients with type 2 diabetes
- Authors:
-
- Brønden, Andreas ;
- Albér, Anders ;
- Rohde, Ulrich ;
-
Gasbjerg, Laerke S
;
Close
0000-0002-7880-8515
Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, Københavns Universitet - Rehfeld, Jens F ;
-
Holst, Jens J
;
Close0000-0001-6853-3805
Translational Metabolic Physiology, NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, Københavns Universitet - Vilsbøll, Tina ;
- Knop, Filip K
- DOI:
- 10.1111/dom.13080
- Abstract:
- 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.
- Type:
- Journal article
- Language:
- English
- Published in:
- Diabetes, Obesity and Metabolism, 2018, Vol 20, Issue 2, p. 362-369
- Keywords:
- Journal Article; Research Support, Non-U.S. Gov't
- Main Research Area:
- Medical science
- Publication Status:
- Published
- Review type:
- Peer Review
- Submission year:
- 2018
- Scientific Level:
- Scientific
- ID:
- 2372797183
