Plasma bile acids are not associated with energy metabolism in humans

Brufau, Gemma; Bahr, Matthias J.; Staels, Bart; Claudel, Thierry; Ockenga, J.; Böker, K. H. W.; Murphy, Elizabeth J.; Prado, Kris; Stellaard, Frans; Manns, Michael P.; Kuipers, Folkert; Tietge, Uwe J. F.

doi:10.1186/1743-7075-7-73

Cited by 68 publications

(47 citation statements)

References 19 publications

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“…Presumably, the ability of bile acids to increase energy expenditure is linked to a TGR5-mediated rise in cAMP, which results in augmented activation of D2 and thereby increased conversion of T 4 into T 3 in BAT (rodents) and muscle (humans) (11). However, human studies have yielded conflicting results (111,112,113 …”

Section: Bile Acids Activate Gpcrsmentioning

confidence: 99%

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

Sonne

Hansen

Knop

2014

European Journal of Endocrinology

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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.

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Section: Bile Acids Activate Gpcrsmentioning

confidence: 99%

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

Sonne

Hansen

Knop

2014

European Journal of Endocrinology

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“…In mice, this leads to increased energy expenditure, but the picture is less clear for humans. 9,10 For these reasons, TGR5 agonists may be useful agents to not only treat diabetes with concurrent management of glucose levels and body weight but also potentially address other aspects of metabolic syndrome.…”

mentioning

confidence: 99%

Identification of Tetrahydropyrido[4,3-d]pyrimidine Amides as a New Class of Orally Bioavailable TGR5 Agonists

Piotrowski

Futatsugi

Warmus

et al. 2012

ACS Med. Chem. Lett.

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Takeda G-protein-coupled receptor 5 (TGR5) represents an exciting biological target for the potential treatment of diabetes and metabolic syndrome. A new class of high-throughput screening (HTS)-derived tetrahydropyrido- [4,3-d]pyrimidine amide TGR5 agonists is disclosed. We describe our effort to identify an orally available agonist suitable for assessment of systemic TGR5 agonism. This effort resulted in identification of 16, which had acceptable potency and pharmacokinetic properties to allow for in vivo assessment in dog. A key aspect of this work was the calibration of human and dog in vitro assay systems that could be linked with data from a human ex vivo peripheral blood monocyte assay that expresses receptor at endogenous levels. Potency from the human in vitro assay was also found to correlate with data from an ex vivo human whole blood assay. This calibration exercise provided confidence that 16 could be used to drive plasma exposures sufficient to test the effects of systemic activation of TGR5. KEYWORDS: GPCR, TGR5, agonist, diabetes, GLP-1 T GR5 (Takeda G-protein-coupled receptor 5) is a class A G-protein-coupled receptor (GPCR) expressed in liver, skeletal muscle, intestine, brown adipose tissues, and monocytes. 1−4 Activation of the TGR5 receptor upon ligand binding results in Gα s -coupled activation of adenylate cyclase. The subsequent downstream signaling cascade is believed to drive multiple effects that are cell type-dependent including (1) enhanced glucagon-like peptide-1 (GLP-1) release from intestinal cells potentially offering improved glycemic control through potentiation of glucose-dependent insulin secretion; 5 (2) nuclear effects, such as endothelial nitric oxide synthase activation and increased nitric oxide production in liver cells; 6 and (3) reduction of macrophage inflammation and lipid loading leading to inhibition of atherosclerosis. 7,8 Activation of TGR5 can also induce type 2 iodothyronine deiodinase in brown adipose tissue. In mice, this leads to increased energy expenditure, but the picture is less clear for humans. 9,10 For these reasons, TGR5 agonists may be useful agents to not only treat diabetes with concurrent management of glucose levels and body weight but also potentially address other aspects of metabolic syndrome.Bile acids are the purported endogenous agonists for TGR5. Of the several bile acids that act as ligands, taurine-conjugated lithocholic acid, lithocholic acid, deoxycholic acid, chenodeoxycholic acid, and cholic acid have all been shown to dose dependently induce accumulation of cyclic adenosine 5′-monophosphate (cAMP) in TGR5-transfected Chinese hamster ovary (CHO) cells. 11 Significant effort has been devoted to synthetic bile acids, such as INT-777 (1). 12,13 In addition, several other nonbile acid agonists have been reported in the literature (2−4), 14−16 which offer the potential for higher selectivity over other bile acid-mediated pathways (Figure 1). Previous work with 1 demonstrated in vivo modulation of

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“…Alternatively, BAS might promote secretion of glucagonlike peptide 1 (GLP-1) [9] and increase energy expenditure [10] via TGR5 activation. There are no data supporting these hypotheses in humans and despite a consistent glucose lowering effect, existing data suggest no change in insulin sensitivity [11] with BAS, no association between glycaemic control and bile acid metabolism [12] and no association between bile acids and energy expenditure in humans [13]. Accordingly, the primary objective of this study was to elucidate the mechanisms of glucose lowering by colesevelam through in-depth examination of glucose metabolic pathways in people with type 2 diabetes.…”

Section: Introductionmentioning

confidence: 99%

Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study

et al. 2011

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Aims/hypothesis The primary aim of this completed multicentre randomised, parallel, double-blind placebo-controlled study was to elucidate the mechanisms of glucose-lowering with colesevelam and secondarily to investigate its effects on lipid metabolism (hepatic de novo lipogenesis, cholesterol and bile acid synthesis). Methods Participants with type 2 diabetes (HbA 1c 6.7-10.0% [50-86 mmol/mol], fasting glucose <16.7 mmol/l, fasting triacylglycerols <3.9 mmol/l and LDL-cholesterol >1.55 mmol/l) treated with diet and exercise, sulfonylurea, metformin or a combination thereof, were randomised by a central coordinator to either 3.75 g/day colesevelam (n=30) or placebo (n=30) for 12 weeks at three clinical sites in the USA. The primary measure was the change from baseline in glucose kinetics with colesevelam compared to placebo treatment. Fasting and postprandial glucose, lipid and bile acid pathways were measured at baseline and post-treatment using stable isotope techniques. Plasma glucose, insulin, total glucagon-like peptide-1 (GLP-1), total glucose-dependent insulinotropic polypeptide (GIP), glucagon and fibroblast growth factor-19 (FGF-19) concentrations were measured during the fasting state and following a meal tolerance test. Data was collected by people blinded to treatment. Colesevelam increased cholesterol and bile acid synthesis and decreased FGF-19 concentrations. However, no effect was seen on fractional hepatic de novo lipogenesis. Conclusions/interpretation Colesevelam, a non-absorbed bile acid sequestrant, increased circulating incretins and improved tissue glucose metabolism in both the fasting and postprandial states in a manner different from other approved oral agents.Trial registration: ClinicalTrials.gov NCT00596427 Funding: The study was funded by Daiichi Sankyo.

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Plasma bile acids are not associated with energy metabolism in humans

Cited by 68 publications

References 19 publications

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

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

Identification of Tetrahydropyrido[4,3-d]pyrimidine Amides as a New Class of Orally Bioavailable TGR5 Agonists

Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study

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