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

Abstract

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.

• Authors: Andreas Brønden, Anders Albér, Ulrich Rohde, Laerke S Gasbjerg, Jens F Rehfeld, Jens J Holst, Tina Vilsbøll, Filip K Knop
• Journal: Diabetes, obesity & metabolism (Diabetes Obes Metab) Vol. 20 Issue 2 Pg. 362-369 (02 2018) ISSN: 1463-1326 [Electronic] England
• PMID: 28786523 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 John Wiley & Sons Ltd.

Chemical References

• Bile Acids and Salts
• Chelating Agents
• Cholagogues and Choleretics
• Gastrointestinal Agents
• Hypoglycemic Agents
• Glucagon-Like Peptide 1
• Metformin
• Sevelamer
• Sincalide

Topics

• Aged
• Bile Acids and Salts (antagonists & inhibitors, metabolism)
• Chelating Agents (therapeutic use)
• Cholagogues and Choleretics (administration & dosage, pharmacology)
• Cross-Over Studies
• Diabetes Mellitus, Type 2 (blood, drug therapy, metabolism)
• Double-Blind Method
• Drug Therapy, Combination
• Enteroendocrine Cells (drug effects, metabolism)
• Female
• Gallbladder Emptying (drug effects)
• Gastric Emptying (drug effects)
• Gastrointestinal Agents (therapeutic use)
• Glucagon-Like Peptide 1 (antagonists & inhibitors, blood, metabolism)
• Humans
• Hypoglycemic Agents (therapeutic use)
• Infusions, Intravenous
• Male
• Metformin (therapeutic use)
• Middle Aged
• Sevelamer (therapeutic use)
• Sincalide (administration & dosage, pharmacology)