The bile acid‐sequestering resin sevelamer eliminates the acuteGLP‐1 stimulatory effect of endogenously released bile acids in patients with type 2 diabetes

2017 ◽  
Vol 20 (2) ◽  
pp. 362-369 ◽  
Author(s):  
Andreas Brønden ◽  
Anders Albér ◽  
Ulrich Rohde ◽  
Lærke S. Gasbjerg ◽  
Jens F. Rehfeld ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Bile Acid ◽  
Bile Acids

scholarly journals MECHANISMS IN ENDOCRINOLOGY: Bile acid sequestrants in type 2 diabetes: potential effects on GLP1 secretion

2014 ◽  
Vol 171 (2) ◽  
pp. R47-R65 ◽  
Author(s):  
David P Sonne ◽  
Morten Hansen ◽  
Filip K Knop
Keyword(s):  
Type 2 Diabetes ◽  
Bile Acid ◽  
Bile Acids ◽  
G Protein ◽  
Farnesoid X Receptor ◽  
Bile Acid Metabolism ◽  
Bile Acid Sequestrants ◽  
G Protein Coupled

Bile acid sequestrants have been used for decades for the treatment of hypercholesterolaemia. Sequestering of bile acids in the intestinal lumen interrupts enterohepatic recirculation of bile acids, which initiate feedback mechanisms on the conversion of cholesterol into bile acids in the liver, thereby lowering cholesterol concentrations in the circulation. In the early 1990s, it was observed that bile acid sequestrants improved glycaemic control in patients with type 2 diabetes. Subsequently, several studies confirmed the finding and recently – despite elusive mechanisms of action – bile acid sequestrants have been approved in the USA for the treatment of type 2 diabetes. Nowadays, bile acids are no longer labelled as simple detergents necessary for lipid digestion and absorption, but are increasingly recognised as metabolic regulators. They are potent hormones, work as signalling molecules on nuclear receptors and G protein-coupled receptors and trigger a myriad of signalling pathways in many target organs. The most described and well-known receptors activated by bile acids are the farnesoid X receptor (nuclear receptor) and the G protein-coupled cell membrane receptor TGR5. Besides controlling bile acid metabolism, these receptors are implicated in lipid, glucose and energy metabolism. Interestingly, activation of TGR5 on enteroendocrine L cells has been suggested to affect secretion of incretin hormones, particularly glucagon-like peptide 1 (GLP1 (GCG)). This review discusses the role of bile acid sequestrants in the treatment of type 2 diabetes, the possible mechanism of action and the role of bile acid-induced secretion of GLP1 via activation of TGR5.

scholarly journals Duodenal mucosal resurfacing with GLP-1 receptor agonism increases postprandial unconjugated bile acid in patients with insulin-dependent type 2 diabetes

2021 ◽  
Author(s):  
Suzanne Meiring ◽  
Emma CE Meessen ◽  
Annieke C.G. van Baar ◽  
Frits Holleman ◽  
Max Nieuwdorp ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Bile Acid ◽  
Bile Acids ◽  
Combination Treatment ◽  
Metabolic Health ◽  
Acid Uptake ◽  
Secondary Bile Acid ◽  
Endoscopic Ablation ◽  
Insulin Dependent

Introduction: Duodenal Mucosal Resurfacing (DMR) is a new endoscopic ablation technique aimed at improving glycemia and metabolic control in patients with type 2 diabetes mellitus (T2DM). DMR appears to improve insulin resistance, which is the root cause of T2DM, but its mechanism of action is largely unknown. Bile acids function as intestinal signalling molecules in glucose and energy metabolism via the activation of farnesoid X receptor and secondary signalling (e.g. via fibroblast growth factor 19[FGF19]), and are linked to metabolic health. Methods: We investigated the effect of DMR and GLP-1 on postprandial bile acid responses in 16 patients with insulin-dependent T2DM, using mixed meal tests performed at baseline and six months after the DMR procedure. Results: The combination treatment allowed discontinuation of insulin treatment in 11/16 (69%) of patients while improving glycaemic and metabolic health. We found increased postprandial unconjugated bile acid responses (all p<0.05), an overall increased secondary bile acid response (p=0.036) and a higher 12α-hydroxylated:non12α-hydroxylated ratio (p<0.001). Total bile acid concentrations were unaffected by the intervention. Postprandial FGF19 and 7-alpha-hydroxy-4-cholesten-3-one (C4) concentrations decreased post-intervention (both p<0.01). Conclusion and discussion: Our study demonstrates that DMR with GLP-1 modulates the postprandial bile acid response. The alterations in postprandial bile acid responses may be the result of changes in the microbiome, ileal bile acid uptake and improved insulin sensitivity. Controlled studies are needed to elucidate the mechanism linking the combination treatment to metabolic health and bile acids.

Abstract 401: Altered Bile Acid Profiles With Colesevelam Treatment Are Associated With Improved Glycemic Control in Type 2 Diabetes

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Carine Beysen ◽  
Miram Chan ◽  
Ellen Tsang ◽  
Chancy Fessler ◽  
Gregg Czerwieniec ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Bile Acid ◽  
Glycemic Control ◽  
Bile Acids ◽  
Ldl Cholesterol ◽  
Whole Body ◽  
Oral Glucose ◽  
Fasting Plasma ◽  
Lipid Parameters

Bile acid sequestrants (BAS) such as colesevelam are effective therapies for lowering LDL-cholesterol and improving glycemic control in individuals with type 2 diabetes. It is however not clear if changes in glucose metabolism with BAS treatment are regulated via changes in whole body BA metabolism. We performed a post-hoc analysis of circulating bile acid levels to investigate whether changes in glucose and lipid parameters are associated with alterations in plasma bile acids (BA) concentrations with colesevelam treatment. Subjects with type 2 diabetes (n=49) treated with diet and exercise, sulfonylurea, metformin or a combination thereof, were treated with 3.75 g/day colesevelam for 12 weeks. Fasting bile acid concentrations were measured by LC/MS and glucose and lipid kinetics were measured using stable isotope techniques at baseline and post-treatment. Colesevelam treatment reduced fasting LDL-cholesterol and increased HDL-cholesterol and triglyceride concentrations. No changes were seen in fasting total cholesterol concentrations and de novo lipogenesis (DNL). Beta-cell function (HOMA-B), glycolytic disposal of oral glucose and fasting plasma glucose clearance improved significantly. Colesevelam treatment resulted in a smaller (-40% from baseline) and more hydrophilic fasting plasma BA pool. All BA’s measured except for cholic acid, glycocholic acid and taurocholic acid decreased with treatment. Changes in total BA concentrations were inversely correlated with changes in A1C and a positive correlation was seen with fasting insulin concentrations. Changes in BA concentrations did not correlated with changes in lipid parameters. These data suggest that altered bile acids levels may contribute to improved glycemic control with colesevelam treatment in subjects with type 2 diabetes.

Pharmacological effects of secondary bile acid microparticles in diabetic murine model

2020 ◽  
Vol 16 ◽  
Author(s):  
Armin Mooranian ◽  
Nassim Zamani ◽  
Bozica Kovacevic ◽  
Corina Mihaela Ionescu ◽  
Giuseppe Luna ◽  
...  
Keyword(s):  
Bile Acid ◽  
Blood Glucose ◽  
Bile Acids ◽  
Lithocholic Acid ◽  
Diabetes Treatment ◽  
Secondary Bile Acid ◽  
Glucose Levels ◽  
Anti Inflammatory ◽  
Antidiabetic Effects

Aim: Examine bile acids effects in Type 2 diabetes. Background: In recent studies, the bile acid ursodeoxycholic acid (UDCA) has shown potent anti-inflammatory effects in obese patients while in type 2 diabetics (T2D) levels of the pro-inflammatory bile acid lithocholic acid were increased, and levels of the anti-inflammatory bile acid chenodeoxycholic acid were decreased, in plasma. Objective: Hence, this study aimed to examine applications of novel UDCA nanoparticles in diabetes. Methods: Diabetic balb/c adult mice were divided into three equal groups and gavaged daily with either empty microcapsules, free UDCA, or microencapsulated UDCA over two weeks. Their blood, tissues, urine, and faeces were collected for blood glucose, inflammation, and bile acid analyses. UDCA resulted in modulatory effects on bile acids profile without antidiabetic effects suggesting that bile acid modulation was not directly linked to diabetes treatment. Results: UDCA resulted in modulatory effects on bile acids profile without antidiabetic effects suggesting that bile acid modulation was not directly linked to diabetes treatment. Conclusion: Bile acids modulated the bile profile without affecting blood glucose levels.

scholarly journals Farnesoid X Receptor an Emerging Target to Combat Obesity

2017 ◽  
Vol 35 (3) ◽  
pp. 185-190 ◽  
Author(s):  
C. Daniel De Magalhaes Filho ◽  
Michael Downes ◽  
Ronald M. Evans
Keyword(s):  
Type 2 Diabetes ◽  
Bile Acid ◽  
Treatment Options ◽  
Farnesoid X Receptor ◽  
Whole Body ◽  
Body Lipid ◽  
Associated Diseases ◽  
Attractive Candidate ◽  
Potential Use

Obesity and its associated diseases, including type 2 diabetes, have reached epidemic levels worldwide. However, available treatment options are limited and ineffective in managing the disease. There is therefore an urgent need for the development of new pharmacological solutions. The bile acid (BA) Farnesoid X receptor (FXR) has recently emerged as an attractive candidate. Initially described for their role in lipid and vitamin absorption from diet, BAs are hormones with powerful effects on whole body lipid and glucose metabolism. In this review, we focus on FXR and how 2 decades of work on this receptor, both in rodents and humans, have led to the development of drug agonists with potential use in humans for treatment of conditions ranging from obesity-associated diseases to BA dysregulation.

scholarly journals Single-Dose Metformin Enhances Bile Acid–Induced Glucagon-Like Peptide-1 Secretion in Patients With Type 2 Diabetes

2017 ◽  
Vol 102 (11) ◽  
pp. 4153-4162 ◽  
Author(s):  
Andreas Brønden ◽  
Anders Albér ◽  
Ulrich Rohde ◽  
Jens F Rehfeld ◽  
Jens J Holst ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Single Dose ◽  
Bile Acid ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals MECHANISMS IN ENDOCRINOLOGY: FXR signalling: a novel target in metabolic diseases

2021 ◽  
Vol 184 (5) ◽  
pp. R193-R205
Author(s):  
David P Sonne
Keyword(s):  
Type 2 Diabetes ◽  
Bile Acid ◽  
Gastrointestinal Tract ◽  
Glucose Metabolism ◽  
Metabolic Diseases ◽  
Farnesoid X Receptor ◽  
Optimal Size ◽  
Lipid Digestion ◽  
Alcoholic Fatty Liver

During the last decades, it has become clear that the gastrointestinal tract plays a pivotal role in the regulation of glucose homeostasis. More than 40 hormones originate from the gastrointestinal tract and several of these impact glucose metabolism and appetite regulation. An astonishing example of the gut’s integrative role in glucose metabolism originates from investigations into bile acid biology. From primary animal studies, it has become clear that bile acids should no longer be labelled as simple detergents necessary for lipid digestion and absorption but should also be recognised as metabolic regulators implicated in lipid, glucose and energy metabolism. The nuclear farnesoid X receptor (FXR) is a part of an exquisite bile acid-sensing system that among other things ensures the optimal size of the bile acid pool. In addition, intestinal and hepatic FXR also impact the regulation of several metabolic processes such as glucose and lipid metabolism. Accordingly, natural and synthetic FXR agonists and certain FXR-regulated factors (i.e. fibroblast growth factor 19 (FGF19)) are increasingly being evaluated as treatments for metabolic diseases such as type 2 diabetes and non-alcoholic fatty liver disease (and its inflammatory version, non-alcoholic steatohepatitis). Interestingly, decreased FXR activation also benefits glucose metabolism. This can be obtained by reducing bile acid absorption using bile acid sequestering agents (approved for the treatment of type 2 diabetes) or inhibitors of intestinal bile acid transporters,that is the apical sodium-dependent bile acid transporter (ASBT). This article discusses recent clinical trials that provide insights about the role of FXR-FGF19-targetted therapy for the treatment of metabolic diseases.

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