Gq and Gs signaling acting in synergy to control GLP-1 secretion

Hauge, M.; Ekberg, Jeppe H.; Engelstoft, Maja S.; Timshel, Pascal; Madsen, Andreas Nygaard; Schwartz, Thue W.

doi:10.1016/j.mce.2016.11.024

Cited by 48 publications

(47 citation statements)

References 53 publications

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“…In a similar way, we demonstrated that delphinidin increases cAMP production in Caco-2 cells via FFA1. There is recent evidence that certain FFA1 ligands can cause the receptor to couple selectively to the Gq or Gs protein [38], with those agonists that can simultaneously activate both pathways being more effective [39]. Previously, this has been described in enteroendocrine cells; however, absorptive intestinal cells and enteroendocrine cells share many common signaling elements, including GPCRs, SGLT1, Ca 2+ , and cAMP [40], and thus could show similar responses upon FFA1 activation.…”

Section: Discussionmentioning

confidence: 99%

Delphinidin Reduces Glucose Uptake in Mice Jejunal Tissue and Human Intestinal Cells Lines through FFA1/GPR40

Hidalgo

Teuber

Morera

et al. 2017

IJMS

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Anthocyanins are pigments with antihyperglycemic properties, and they are potential candidates for developing functional foods for the therapy or prevention of Diabetes mellitus type 2 (DM2). The mechanism of these beneficial effects of anthocyanins are, however, hard to explain, given their very low bioavailability due to poor intestinal absorption. We propose that free fatty acid receptor 1 (FFA1, also named GPR40), is involved in an inhibitory effect of the anthocyanidin delphinidin over intestinal glucose absorption. We show the direct effects of delphinidin on the intestine using jejunum samples from RF/J mice, and the human intestinal cell lines HT-29, Caco-2, and NCM460. By the use of specific pharmacological antagonists, we determined that delphinidin inhibits glucose absorption in both mouse jejunum and a human enterocytic cell line in a FFA1-dependent manner. Delphinidin also affects the function of sodium-glucose cotransporter 1 (SGLT1). Intracellular signaling after FFA1 activation involved cAMP increase and cytosolic Ca2+ oscillations originated from intracellular Ca2+ stores and were followed by store-operated Ca2+ entry. Taken together, our results suggest a new GPR-40 mediated local mechanism of action for delphinidin over intestinal cells that may in part explain its antidiabetic effect. These findings are promising for the search for new prevention and pharmacological treatment strategies for DM2 management.

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Section: Discussionmentioning

confidence: 99%

Delphinidin Reduces Glucose Uptake in Mice Jejunal Tissue and Human Intestinal Cells Lines through FFA1/GPR40

Hidalgo

Teuber

Morera

et al. 2017

IJMS

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“…There has also been recent evidence for functional cross-talk between Gs and Gq-coupled receptors in the regulation of long chain fatty acid mediated incretin secretion. Recent findings have shown that GPR40-mediated GLP-1 release by colonic enteroendocrine cells requires high cAMP levels, achieved via the bile acid receptor TGR5 or GPR119-dependent Gs activity (28,29). Although these studies suggest functional cross talk at the level of G-protein dependent signaling between Gq-and Gs-coupled GPCRs, whether this is mediated via heteromerization remains to be demonstrated.…”

Section: Metabolism and Nutritionmentioning

confidence: 99%

Impact of G protein-coupled receptor heteromers in endocrine systems

Jonas

Hanyaloglu

2017

Molecular and Cellular Endocrinology

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Abbreviations:1B adrenergic receptors (1BR) Evidence over the last 20 years has highlighted homo and heteromerization as a key mode of mediating GPCR functional diversity. This review will discuss the concept of GPCR heteromerization and its relevance to endocrine function, detailing in vitro and in vivo evidence, and exploring current and potential pharmacological strategies for specific targeting of GPCR heteromers in endocrine heath and disease.;3

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“…TAK‐875) were found to selectively act on islet beta cells and increase insulin secretion with little effect on GLP‐1 secretion possibly through selective coupling to Gα q signal transduction pathways (Hauge et al ., ). However, newer classes of FFA1 receptor agonists molecules increase GLP‐1 secretion by apparently coupling to both G s and G q pathways (Hauge et al ., ), making these molecules significantly more attractive as candidate therapeutic agents. The potential for FFA1 receptor agonists to stimulate sufficient GLP‐1 secretion for reducing body weight may enhance the attraction of this type of molecule.…”

Section: Exploring Gpcr‐based Mechanisms To Increase Circulating Glp‐1mentioning

confidence: 97%