Glucose‐induced cAMP elevation in β‐cells involves amplification of constitutive and glucagon‐activated GLP‐1 receptor signalling

Shuai, Hongyan; Xu, Yunjian; Ahooghalandari, Parvin; Tengholm, Anders

doi:10.1111/apha.13611

Cited by 17 publications

(14 citation statements)

References 60 publications

(145 reference statements)

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“…Forskolin at increasing concentrations induced cAMP raise in the concentration range spanning at least two orders of magnitude to promote electrical activity, and raise [Ca 2+ ] c , from both intracellular and extracellular sources ( 33 ). GLP1R signaling in β-cells has been reported to contribute to basal and glucose-induced cAMP production and insulin secretion ( 34 ). In addition, clinical work has shown that α 2 A-adrenoceptor antagonists, in clinical use as antipsychotics and antidepressants, potentiate the insulinotropic effect of drugs used in diabetes therapy, leading to severe adverse effects ( 4 ), supporting the modulatory role of cAMP on Ca 2+ -dependent insulin release in beta cells.…”

Section: Introductionmentioning

confidence: 99%

Physiological levels of adrenaline fail to stop pancreatic beta cell activity at unphysiologically high glucose levels

et al. 2022

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Adrenaline inhibits insulin secretion from pancreatic beta cells to allow an organism to cover immediate energy needs by unlocking internal nutrient reserves. The stimulation of α2-adrenergic receptors on the plasma membrane of beta cells reduces their excitability and insulin secretion mostly through diminished cAMP production and downstream desensitization of late step(s) of exocytotic machinery to cytosolic Ca2+ concentration ([Ca2+]c). In most studies unphysiologically high adrenaline concentrations have been used to evaluate the role of adrenergic stimulation in pancreatic endocrine cells. Here we report the effect of physiological adrenaline levels on [Ca2+]c dynamics in beta cell collectives in mice pancreatic tissue slice preparation. We used confocal microscopy with a high spatial and temporal resolution to evaluate glucose-stimulated [Ca2+]c events and their sensitivity to adrenaline. We investigated glucose concentrations from 8-20 mM to assess the concentration of adrenaline that completely abolishes [Ca2+]c events. We show that 8 mM glucose stimulation of beta cell collectives is readily inhibited by the concentration of adrenaline available under physiological conditions, and that sequent stimulation with 12 mM glucose or forskolin in high nM range overrides this inhibition. Accordingly, 12 mM glucose stimulation required at least an order of magnitude higher adrenaline concentration above the physiological level to inhibit the activity. To conclude, higher glucose concentrations stimulate beta cell activity in a non-linear manner and beyond levels that could be inhibited with physiologically available plasma adrenaline concentration.

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Section: Introductionmentioning

confidence: 99%

Physiological levels of adrenaline fail to stop pancreatic beta cell activity at unphysiologically high glucose levels

et al. 2022

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“…Activators and inhibitors that activate G-protein signaling pathways, or enhance cell secretion through other mechanisms, were selected for application to the L-cell-enriched monolayers to assess whether GLP-1 secretion could be measured. − The test compounds were added to the luminal reservoir and the secretion of GLP-1 into the basal compartment was measured (Figure A). Forskolin, l -lysine, and bombesin significantly increased GLP-1 secretion relative to that of control cells (Figure B).…”

Section: Resultsmentioning

confidence: 99%

Development of a Primary Human Intestinal Epithelium Enriched in L-Cells for Assay of GLP-1 Secretion

Villegas-Novoa

Wang

Sims³

et al. 2022

Anal. Chem.

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Type 2 diabetes mellitus is a chronic disease associated with obesity and dysregulated human feeding behavior. The hormone glucagonlike peptide 1 (GLP-1), a critical regulator of body weight, food intake, and blood glucose levels, is secreted by enteroendocrine L-cells. The paucity of Lcells in primary intestinal cell cultures including organoids and monolayers has made assays of GLP-1 secretion from primary human cells challenging. In the current paper, an analytical assay pipeline consisting of an optimized human intestinal tissue construct enriched in L-cells paired with standard antibody-based GLP-1 assays was developed to screen compounds for the development of pharmaceuticals to modulate L-cell signaling. The addition of the serotonin receptor agonist Bimu 8, optimization of R-spondin and Noggin concentrations, and utilization of vasoactive intestinal peptide (VIP) increased the density of L-cells in a primary human colonic epithelial monolayer. Additionally, the incorporation of an air−liquid interface culture format increased the L-cell number so that the signal-to-noise ratio of conventional enzyme-linked immunoassays could be used to monitor GLP-1 secretion in compound screens. To demonstrate the utility of the optimized analytical method, 21 types of beverage sweeteners were screened for their ability to stimulate GLP-1 secretion. Stevioside and cyclamate were found to be the most potent inducers of GLP-1 secretion. This platform enables the quantification of GLP-1 secretion from human primary L-cells and will have broad application in understanding L-cell formation and physiology and will improve the identification of modulators of human feeding behavior.

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“…Thus, our studies using LY2786890 and isolated islets more clearly substantiate an ability of intra-islet glucagon to confer β-cell glucose competence for first-phase GSIS in a GcgR-mediate manner. Finally, controversy exists concerning whether Ex[9–39] acts as a pure antagonist or instead as an inverse agonist at the GLP-1R ( 14 , 43 , 75 ). If Ex[9–39] possesses such inverse agonist properties, it may directly block first-phase insulin secretion in a manner that is independent of any action of intra-islet glucagon at the GLP-1R.…”

Section: Discussionmentioning

confidence: 99%

Intra-islet glucagon confers β-cell glucose competence for first-phase insulin secretion and favors GLP-1R stimulation by exogenous glucagon

Cabrera¹,

Ficorilli²,

Shaw³

et al. 2022

Journal of Biological Chemistry

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Glucose‐induced cAMP elevation in β‐cells involves amplification of constitutive and glucagon‐activated GLP‐1 receptor signalling

Cited by 17 publications

References 60 publications

Physiological levels of adrenaline fail to stop pancreatic beta cell activity at unphysiologically high glucose levels

Physiological levels of adrenaline fail to stop pancreatic beta cell activity at unphysiologically high glucose levels

Development of a Primary Human Intestinal Epithelium Enriched in L-Cells for Assay of GLP-1 Secretion

Intra-islet glucagon confers β-cell glucose competence for first-phase insulin secretion and favors GLP-1R stimulation by exogenous glucagon

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