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The bile acid‐sequestering resin sevelamer eliminates the acute GLP ‐1 stimulatory effect of endogenously released bile acids in patients with type 2 diabetes
Author(s) -
Brønden Andreas,
Albér Anders,
Rohde Ulrich,
Gasbjerg Lærke S.,
Rehfeld Jens F.,
Holst Jens J.,
Vilsbøll Tina,
Knop Filip K.
Publication year - 2018
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/dom.13080
Subject(s) - medicine , endocrinology , farnesoid x receptor , type 2 diabetes , bile acid , glucagon like peptide 1 , sevelamer , gastric inhibitory polypeptide , cholecystokinin , insulin , diabetes mellitus , receptor , chemistry , glucagon , calcium , biochemistry , transcription factor , gene , hyperphosphatemia , nuclear receptor
Aims 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, double‐blinded cross‐over study including 15 metformin‐treated patients with type 2 diabetes. During 4 experimental study days, either sevelamer 3200 mg or placebo in combination with intravenous infusion of cholecystokinin (CCK) (0.4 pmol sulfated CCK‐8/kg/min) or saline was administered in randomized order. 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.