The bile acid TUDCA increases glucose-induced insulin secretion via the cAMP/PKA pathway in pancreatic beta cells

Vettorazzi, Jean Franciesco; Ribeiro, Rosane Aparecida; Borck, Patrícia Cristine; Branco, Renato Chaves Souto; Soriano, Sergi; Merino, Beatriz; Boschero, Antônio Carlos; Nadal, Ángel; Quesada, Iván; Carneiro, Everardo M.

doi:10.1016/j.metabol.2015.10.021

Cited by 80 publications

(63 citation statements)

References 37 publications

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“…29,31 Also, activation of TGR5 was shown to stimulate GLP-1 production from pancreatic alpha cells under hyperglycaemic conditions and GLP-1-mediated beta cell proliferation. 33 In their human studies, Hansen et al and Rohde et al found an increase in GLP-1, when subjects were exposed to exogenous chenodeoxycholic acid and CCK-induced gallbladder emptying, respectively, 28,34 suggesting that both exogenously delivered and endogenous bile acids in the small intestine increase GLP-1 secretion (for details, see below). 32 The nuclear farnesoid X receptor (FXR) is also found in pancreatic beta cells, and has been shown to be involved in insulin release.…”

Section: Bile Acidsmentioning

confidence: 99%

“…31 Another study demonstrated the bile acid tauroursodeoxycholic acid to cause increased insulin release in pancreatic islets from mice. 33 In their human studies, Hansen et al and Rohde et al found an increase in GLP-1, when subjects were exposed to exogenous chenodeoxycholic acid and CCK-induced gallbladder emptying, respectively, 28,34 suggesting that both exogenously delivered and endogenous bile acids in the small intestine increase GLP-1 secretion (for details, see below).…”

Section: Bile Acidsmentioning

confidence: 99%

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Evidence connecting old, new and neglected glucose‐lowering drugs to bile acid‐induced GLP‐1 secretion: A review

Kårhus

Brønden

Sonne

et al. 2017

Diabetes Obesity Metabolism

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Bile acids are amphipathic water-soluble steroid-based molecules best known for their important lipid-solubilizing role in the assimilation of fat. Recently, bile acids have emerged as metabolic integrators with glucose-lowering potential. Among a variety of gluco-metabolic effects, bile acids have been demonstrated to modulate the secretion of the gut-derived incretin hormone glucagon-like peptide-1 (GLP-1), possibly via the transmembrane receptor Takeda G-protein-coupled receptor 5 and the nuclear farnesoid X receptor, in intestinal L cells. The present article critically reviews current evidence connecting established glucose-lowering drugs to bile acid-induced GLP-1 secretion, and discusses whether bile acid-induced GLP-1 secretion may constitute a new basis for understanding how metformin, inhibitors of the apical sodium-dependent bile acids transporter, and bile acid sequestrants - old, new and neglected glucose-lowering drugs - improve glucose metabolism.

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Section: Bile Acidsmentioning

confidence: 99%

Section: Bile Acidsmentioning

confidence: 99%

Evidence connecting old, new and neglected glucose‐lowering drugs to bile acid‐induced GLP‐1 secretion: A review

Kårhus

Brønden

Sonne

et al. 2017

Diabetes Obesity Metabolism

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“…Li et al, 2011), modulates energy expenditure (Watanabe et al, 2006), stimulates GLP-1 release from intestinal L cells (Habib et al, 2013; Katsuma et al, 2005; Thomas et al, 2009), suppresses hepatic glycogenolysis (Potthoff et al, 2013) reduces inflammation (Frikke Schmidt et al, 2016) and inflammatory macrophage activation (Kawamata et al, 2003; Keitel et al, 2008; Lou et al, 2014; Maruyama et al, 2002; Y. D. Wang et al, 2008), improves pancreatic function (Kumar et al, 2016; Vettorazzi et al, 2016) and improves non-alcoholic fatty liver disease (Ding et al, 2016). TGR5 knockout mice have mildly reduced BA pools (Maruyama et al, 2006; Vassileva et al, 2006), impaired glucose tolerance (Thomas et al, 2009) and exacerbated inflammatory responses (Péan et al, 2013).…”

Section: Bile Acidsmentioning

confidence: 99%

Bile acids and bariatric surgery

Albaugh

Banan

Ajouz

et al. 2017

Molecular Aspects of Medicine

104

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Bariatric surgery, specifically Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), are the most effective and durable treatments for morbid obesity and potentially a viable treatment for type 2 diabetes (T2D). The resolution rate of T2D following these procedures is between 40-80% and far surpasses that achieved by medical management alone. The molecular basis for this improvement is not entirely understood, but has been attributed in part to the altered enterohepatic circulation of bile acids. In this review we highlight how bile acids potentially contribute to improved lipid and glucose homeostasis, insulin sensitivity and energy expenditure after these procedures. The impact of altered bile acid levels in enterohepatic circulation is also associated with changes in gut microflora, which may further contribute to some of these beneficial effects. We highlight the beneficial effects of experimental surgical procedures in rodents that alter bile secretory flow without gastric restriction or altering nutrient flow. This information suggests a role for bile acids beyond dietary fat emulsification in altering whole body glucose and lipid metabolism strongly, and also suggests emerging roles for the activation of the bile acid receptors farnesoid x receptor (FXR) and G-protein coupled bile acid receptor (TGR5) in these improvements. The limitations of rodent studies and the current state of our understanding is reviewed and the potential effects of bile acids mediating the short-and long-term metabolic improvements after bariatric surgery is critically examined.

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“…While OLA is proposed to be a TGR5 agonist in pancreatic islets by one study (4), another group excludes an increase in cAMP concentration by OLA normally observed downstream of TGR5 activation (14). In addition, direct effects of OLA on b-cells through increased acetylcholine levels and the muscarinic M 3 receptor were reported (15).Since it was discovered that TGR5 is present in pancreatic b-cells, several in vitro studies described a direct effect of TGR5 on islet cell function (4,(16)(17)(18). First, Kumar et al (4) showed the stimulating effect of TGR5 agonists on insulin secretion in b-cells by an increase of intracellular Ca 2+ concentration ([Ca 2+ ] c ) due to Ca 2+…”

mentioning

confidence: 99%

TGR5 Activation Promotes Stimulus-Secretion Coupling of Pancreatic β-Cells via a PKA-Dependent Pathway

et al. 2018

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The Takeda-G-protein-receptor-5 (TGR5) mediates physiological actions of bile acids. Since it was shown that TGR5 is expressed in pancreatic tissue, a direct TGR5 activation in b-cells is currently postulated and discussed. The current study reveals that oleanolic acid (OLA) affects murine b-cell function by TGR5 activation. Both a G as inhibitor and an inhibitor of adenylyl cyclase (AC) prevented stimulating effects of OLA. Accordingly, OLA augmented the intracellular cAMP concentration. OLA and two well-established TGR5 agonists, RG239 and tauroursodeoxycholic acid (TUDCA), acutely promoted stimulus-secretion coupling (SSC). OLA reduced K ATP current and elevated current through Ca 2+ channels. Accordingly, in mouse and human b-cells, TGR5 ligands increased the cytosolic Ca 2+ concentration by stimulating Ca 2+ influx. Higher OLA concentrations evoked a dual reaction, probably due to activation of a counterregulating pathway. Protein kinase A (PKA) was identified as a downstream target of TGR5 activation. In contrast, inhibition of phospholipase C and phosphoinositide 3-kinase did not prevent stimulating effects of OLA. Involvement of exchange protein directly activated by cAMP 2 (Epac2) or farnesoid X receptor (FXR2) was ruled out by experiments with knockout mice. The proposed pathway was not influenced by local glucagon-like peptide 1 (GLP-1) secretion from a-cells, shown by experiments with MIN6 cells, and a GLP-1 receptor antagonist. In summary, these data clearly demonstrate that activation of TGR5 in b-cells stimulates insulin secretion via an AC/cAMP/PKA-dependent pathway, which is supposed to interfere with SSC by affecting K ATP and Ca 2+ currents and thus membrane potential.In recent years, it became evident that the membrane protein Takeda-G-protein-receptor-5 (TGR5), also known as GPBA, MBAR, or Gpbar1, plays an important role in energy and glucose metabolism (1,2). TGR5 is present in several tissues and cell types including heart, spleen, intestine, macrophages, and pancreas (3,4). The receptor is involved in physiological processes such as inflammation, gallbladder filling, gastrointestinal motility, and thermogenesis (1,5-7). TGR5 stimulates secretion of glucagon-like peptide 1 (GLP-1) from intestinal L cells and thus regulates glucose metabolism (8-10). TGR5 activation leads to energy expenditure, which in turn improves glucose homeostasis (9). Noteworthy, after vertical sleeve gastrectomy, TGR5 contributes to the beneficial effects of the surgery (11).The endogenous ligands of the receptor are bile acids that potently regulate glucose homeostasis (3). For oleanolic acid (OLA), a triterpene isolated from Olea europaea that improves metabolic disorders and has antidiabetes effects (12,13), the situation is less clear. While OLA is proposed to be a TGR5 agonist in pancreatic islets by one study (4), another group excludes an increase in cAMP concentration by OLA normally observed downstream of TGR5 activation (14). In addition, direct effects of OLA on b-cells through increased acetylcholine leve...

show abstract

The bile acid TUDCA increases glucose-induced insulin secretion via the cAMP/PKA pathway in pancreatic beta cells

Cited by 80 publications

References 37 publications

Evidence connecting old, new and neglected glucose‐lowering drugs to bile acid‐induced GLP‐1 secretion: A review

Evidence connecting old, new and neglected glucose‐lowering drugs to bile acid‐induced GLP‐1 secretion: A review

Bile acids and bariatric surgery

TGR5 Activation Promotes Stimulus-Secretion Coupling of Pancreatic β-Cells via a PKA-Dependent Pathway

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