Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas

Kuhre, Rune Ehrenreich; Albrechtsen, Nicolai J. Wewer; Larsen, Olav; Jepsen, Sara L.; Balk-Møller, Emilie; Andersen, David W.; Deacon, Carolyn F.; Schoonjans, Kristina; Reimann, Frank; Gribble, Fiona M.; Albrechtsen, Reidar; Hartmann, Bolette; Rosenkilde, Mette M.; Holst, Jens J.

doi:10.1016/j.molmet.2018.03.007

Cited by 156 publications

(161 citation statements)

References 53 publications

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“…Thus, the aim of this study was to test whether the effects of SGLT2 on glucagon secretion demonstrated in vitro could be reproduced in a more physiological setting. As glucagon secretion is tightly regulated by blood glucose, which is lowered by SGLT2 inhibitors, we chose the isolated perfused rat pancreas as experimental model [6,7], where perfusate glucose is kept constant. We studied the effects of the SLGT2 inhibitor dapagliflozin, the SGLT1/2 inhibitor phloridzin and the metabolically inert SGLT-specific substrate methyl-α-D-glucopyranoside (α-MGP) on glucagon secretion in this model.…”

Section: Introductionmentioning

confidence: 99%

No direct effect of SGLT2 activity on glucagon secretion

et al. 2019

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Aims/hypothesis Sodium-glucose cotransporter (SGLT) 2 inhibitors constitute a new class of glucose-lowering drugs, but they increase glucagon secretion, which may counteract their glucose-lowering effect. Previous studies using static incubation of isolated human islets or the glucagon-secreting cell line α-TC1 suggested that this results from direct inhibition of alpha cell SGLT1/2-activity. The aim of this study was to test whether the effects of SGLT2 on glucagon secretion demonstrated in vitro could be reproduced in a more physiological setting. Methods We explored the effect of SGLT2 activity on glucagon secretion using isolated perfused rat pancreas, a physiological model for glucagon secretion. Furthermore, we investigated Slc5a2 (the gene encoding SGLT2) expression in rat islets as well as in mouse and human islets and in mouse and human alpha, beta and delta cells to test for potential inter-species variations. SGLT2 protein content was also investigated in mouse, rat and human islets. Results Glucagon output decreased three-to fivefold within minutes of shifting from low (3.5 mmol/l) to high (10 mmol/l) glucose (4.0 ± 0.5 pmol/15 min vs 1.3 ± 0.3 pmol/15 min, p < 0.05). The output was unaffected by inhibition of SGLT1/2 with dapagliflozin or phloridzin or by addition of the SGLT1/2 substrate α-methylglucopyranoside, whether at low or high glucose concentrations (p = 0.29-0.99). Insulin and somatostatin secretion (potential paracrine regulators) was also unaffected. Slc5a2 expression and SGLT2 protein were marginal or below detection limit in rat, mouse and human islets and in mouse and human alpha, beta and delta cells. Conclusions/interpretation Our combined data show that increased plasma glucagon during SGLT2 inhibitor treatment is unlikely to result from direct inhibition of SGLT2 in alpha cells, but instead may occur downstream of their blood glucoselowering effects.

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Section: Introductionmentioning

confidence: 99%

No direct effect of SGLT2 activity on glucagon secretion

et al. 2019

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“…Application of 100 μmol/L TDCA, via the vasculature, in perfused rat small intestine, robustly increased GLP-1 release, whereas luminal application of TDCA at the same concentration was significantly less effective, 29 presumably because TDCA stimulates GLP-1 secretion by postabsorptive activation of basolateral located Taconic-G-proteincoupled receptors (TGR5). 30 Our results indicate that ABA is more LANCL2 has been identified as the mammalian receptor mediating the functional effects of ABA in mammals. 21,31,32 ABA, via LANCL2 binding, stimulates insulin release and insulin-independent glucose uptake in myocytes and adipocytes and induces brown fat activity.…”

Section: Aba Stimulates Glp-1 Secretion From the Proximal Small Intmentioning

confidence: 66%

“…Nevertheless, it should also be noted that ABA administration in the intestinal perfusion system gave similar results to taurodeoxycholate (TDCA). Application of 100 μmol/L TDCA, via the vasculature, in perfused rat small intestine, robustly increased GLP‐1 release, whereas luminal application of TDCA at the same concentration was significantly less effective, presumably because TDCA stimulates GLP‐1 secretion by post‐absorptive activation of basolateral located Taconic‐G‐protein‐coupled receptors (TGR5) . Our results indicate that ABA is more effective, at least in this experimental setting, when acting from the vascular side compared with the luminal side: however, a direct effect of luminal ABA, in vivo, on GLP‐1 release cannot be excluded.…”

Section: Discussionmentioning

confidence: 79%

Abscisic acid stimulates the release of insulin and of GLP‐1 in the rat perfused pancreas and intestine

Booz

Kuhre

Saltiel

et al. 2018

Diabetes Metabolism Res

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Aims Previous results indicate that nanomolar concentrations of abscisic acid (ABA) stimulate insulin release from β‐pancreatic cells in vitro and that oral ABA at 50 mg/kg increases plasma GLP‐1 in the fasted rat. The aim of this study was to test the effect of ABA on the perfused rat pancreas and intestine, to verify the insulin‐ and incretin‐releasing actions of ABA in controlled physiological models. Materials and methods Rat pancreas and small intestine were perfused with solutions containing ABA at high‐micromolar concentrations, or control secretagogues. Insulin and GLP‐1 concentrations in the venous effluent were analysed by radioimmunoassay, and ABA levels were determined by ELISA. Results High micromolar concentrations of ABA induced GLP‐1 secretion from the proximal half of the small intestine and insulin secretion from pancreas. GLP‐1 stimulated ABA secretion from pancreas in a biphasic manner. Notably, a positive correlation was found between the ABA area under the curve (AUC) and the insulin AUC upon GLP‐1 administration. Conclusion Our results indicate the existence of a cross talk between GLP‐1 and ABA, whereby ABA stimulates GLP‐1 secretion, and vice versa. Release of ABA could be considered as a new promising molecule in the strategy of type 2 diabetes treatment and as a new endogenous hormone in the regulation of glycaemia.

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“…Bile acids are ligands of the G‐protein‐coupled receptor Takeda G‐protein‐coupled receptor 5 (TGR5), and the nuclear receptor farnesoid X receptor (FXR), both of which are expressed in L‐cells. In preclinical models, activation of TGR5 by bile acids increases GLP‐1 secretion, whereas activation of FXR has been reported to result in both suppression and stimulation of GLP‐1 secretion. For example, FXR null mice have been observed to have better glucose control and enhanced GLP‐1 secretion in some studies, but impaired glucose tolerance in others .…”

Section: Gastrointestinal Effects Of Metformin: Role Of Gut Peptidesmentioning

confidence: 99%

Mechanism of glucose‐lowering by metformin in type 2 diabetes: Role of bile acids

Sansome

Xie

Veedfald

et al. 2019

Diabetes Obesity Metabolism

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Type 2 diabetes mellitus (T2DM) is an increasingly prevalent chronic condition, characterized by abnormally elevated blood glucose concentrations and, as a consequence, increased risk of micro‐ and macrovascular complications. Metformin is usually the first‐line glucose‐lowering medication in T2DM; however, despite being used for more than 60 years, the mechanism underlying the glucose‐lowering action of metformin remains incompletely understood. Although metformin reduces hepatic glucose production, there is persuasive evidence that the gastrointestinal tract is crucial in mediating this effect, particularly via secretion of the incretin hormone glucagon‐like peptide 1 (GLP‐1). It is now well recognized that bile acids, in addition to their established function in fat digestion and absorption, are important regulators of glucose metabolism. Exposure of the small and large intestine to bile acids induces GLP‐1 secretion, modulates the composition of the gut microbiota, and reduces postprandial blood glucose excursions in humans with and without T2DM. Metformin reduces intestinal bile acid resorption substantially, such that intraluminal bile acids may, at least in part, account for its glucose‐lowering effect. The present review focuses on the conceptual shift in our understanding as to how metformin lowers blood glucose in T2DM, with a particular emphasis on the role of intestinal bile acids.

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Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas

Cited by 156 publications

References 53 publications

No direct effect of SGLT2 activity on glucagon secretion

No direct effect of SGLT2 activity on glucagon secretion

Abscisic acid stimulates the release of insulin and of GLP‐1 in the rat perfused pancreas and intestine

Mechanism of glucose‐lowering by metformin in type 2 diabetes: Role of bile acids

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