Ileo-colonic delivery of conjugated bile acids improves glucose homeostasis via colonic GLP-1-producing enteroendocrine cells in human obesity and diabetes.
Administration, Oral
Bile Acids and Salts
/ administration & dosage
Biological Transport
Blood Glucose
/ metabolism
Capsules
Cell Line
Cholestenones
/ blood
Colon
/ drug effects
Diabetes Mellitus, Type 2
/ genetics
Diffusion Chambers, Culture
Enteroendocrine Cells
/ cytology
Fasting
/ physiology
Fibroblast Growth Factors
/ blood
Fructosamine
/ blood
Gene Expression
Glucagon-Like Peptide 1
/ blood
Homeostasis
/ drug effects
Humans
Ileum
/ drug effects
Insulin
/ blood
Obesity
/ genetics
Postprandial Period
Primary Cell Culture
Receptors, G-Protein-Coupled
/ blood
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
May 2020
May 2020
Historique:
received:
15
01
2020
revised:
26
03
2020
accepted:
03
04
2020
pubmed:
29
4
2020
medline:
2
4
2021
entrez:
29
4
2020
Statut:
ppublish
Résumé
The bile acid (BA) pathway plays a role in regulation of food intake and glucose metabolism, based mainly on findings in animal models. Our aim was to determine whether the BA pathway is altered and correctable in human obesity and diabetes. We conducted 3 investigations: 1) BA receptor pathways were studied in NCI-H716 enteroendocrine cell (EEC) line, whole human colonic mucosal tissue and in human colonic EEC isolated by Fluorescence-activated Cell Sorting (ex vivo) from endoscopically-obtained biopsies colon mucosa; 2) We characterized the BA pathway in 307 participants by measuring during fasting and postprandial levels of FGF19, 7αC4 and serum BA; 3) In a placebo-controlled, double-blind, randomised, 28-day trial, we studied the effect of ileo-colonic delivery of conjugated BAs (IC-CBAS) on glucose metabolism, incretins, and lipids, in participants with obesity and diabetes. Human colonic GLP-1-producing EECs express TGR5, and upon treatment with bile acids in vitro, human EEC differentially expressed GLP-1 at the protein and mRNA level. In Ussing Chamber, GLP-1 release was stimulated by Taurocholic acid in either the apical or basolateral compartment. FGF19 was decreased in obesity and diabetes compared to controls. When compared to placebo, IC-CBAS significantly decreased postprandial glucose, fructosamine, fasting insulin, fasting LDL, and postprandial FGF19 and increased postprandial GLP-1 and C-peptide. Increase in faecal BA was associated with weight loss and with decreased fructosamine. In humans, BA signalling machinery is expressed in colonic EECs, deficient in obesity and diabetes, and when stimulated with IC-CBAS, improved glucose homeostasis. ClinicalTrials.gov number, NCT02871882, NCT02033876. Research support and drug was provided by Satiogen Pharmaceuticals (San Diego, CA). AA, MC, and NFL report grants (AA- C-Sig P30DK84567, K23 DK114460; MC- NIH R01 DK67071; NFL- R01 DK057993) from the NIH. JR was supported by an Early Career Grant from Society for Endocrinology.
Sections du résumé
BACKGROUND
BACKGROUND
The bile acid (BA) pathway plays a role in regulation of food intake and glucose metabolism, based mainly on findings in animal models. Our aim was to determine whether the BA pathway is altered and correctable in human obesity and diabetes.
METHODS
METHODS
We conducted 3 investigations: 1) BA receptor pathways were studied in NCI-H716 enteroendocrine cell (EEC) line, whole human colonic mucosal tissue and in human colonic EEC isolated by Fluorescence-activated Cell Sorting (ex vivo) from endoscopically-obtained biopsies colon mucosa; 2) We characterized the BA pathway in 307 participants by measuring during fasting and postprandial levels of FGF19, 7αC4 and serum BA; 3) In a placebo-controlled, double-blind, randomised, 28-day trial, we studied the effect of ileo-colonic delivery of conjugated BAs (IC-CBAS) on glucose metabolism, incretins, and lipids, in participants with obesity and diabetes.
FINDINGS
RESULTS
Human colonic GLP-1-producing EECs express TGR5, and upon treatment with bile acids in vitro, human EEC differentially expressed GLP-1 at the protein and mRNA level. In Ussing Chamber, GLP-1 release was stimulated by Taurocholic acid in either the apical or basolateral compartment. FGF19 was decreased in obesity and diabetes compared to controls. When compared to placebo, IC-CBAS significantly decreased postprandial glucose, fructosamine, fasting insulin, fasting LDL, and postprandial FGF19 and increased postprandial GLP-1 and C-peptide. Increase in faecal BA was associated with weight loss and with decreased fructosamine.
INTERPRETATIONS
CONCLUSIONS
In humans, BA signalling machinery is expressed in colonic EECs, deficient in obesity and diabetes, and when stimulated with IC-CBAS, improved glucose homeostasis. ClinicalTrials.gov number, NCT02871882, NCT02033876.
FUNDING
BACKGROUND
Research support and drug was provided by Satiogen Pharmaceuticals (San Diego, CA). AA, MC, and NFL report grants (AA- C-Sig P30DK84567, K23 DK114460; MC- NIH R01 DK67071; NFL- R01 DK057993) from the NIH. JR was supported by an Early Career Grant from Society for Endocrinology.
Identifiants
pubmed: 32344198
pii: S2352-3964(20)30134-1
doi: 10.1016/j.ebiom.2020.102759
pmc: PMC7186521
pii:
doi:
Substances chimiques
Bile Acids and Salts
0
Blood Glucose
0
Capsules
0
Cholestenones
0
FGF19 protein, human
0
GPBAR1 protein, human
0
Insulin
0
Receptors, G-Protein-Coupled
0
Fructosamine
4429-04-3
Fibroblast Growth Factors
62031-54-3
Glucagon-Like Peptide 1
89750-14-1
Banques de données
ClinicalTrials.gov
['NCT02033876', 'NCT02871882']
Types de publication
Journal Article
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
102759Subventions
Organisme : Medical Research Council
ID : MC_UU_12012/3
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK057993
Pays : United States
Organisme : NIDDK NIH HHS
ID : K23 DK114460
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000135
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK084567
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_00014/3
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK067071
Pays : United States
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
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