The regulator of G-protein signaling RGS16 promotes insulin secretion and β-cell proliferation in rodent and human islets

Vivot, Kevin; Moullé, Valentine S.; Zarrouki, Bader; Tremblay, Caroline; Mancini, Arturo; Maachi, Hasna; Ghislain, Julien; Poitout, Vincent

doi:10.1016/j.molmet.2016.08.010

Cited by 33 publications

(32 citation statements)

References 48 publications

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“…Actually, the mRNA level of the Rgs16 was reduced in the islet of Tg mice [53], which is consistent with its reduced expression in the liver of Tg mice [15]. A recent report described that RGS16 regulates not only insulin secretion but also β -cell proliferation [63]. Consequently, disturbance in the signalling pathways mediated by RGS4 and RGS16 can cause not only insulin secretion but also the proliferation of β -cells in Tg mice.…”

Section: Characteristic Features Of Gene Expressions In the Isletsmentioning

confidence: 59%

Unique Aspects of Cryptochrome in Chronobiology and Metabolism, Pancreaticβ-Cell Dysfunction, and Regeneration: Research into Cysteine414-Alanine Mutant CRY1

Okano

2016

Journal of Diabetes Research

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Cryptochrome proteins (CRYs), which can bind noncovalently to cofactor (chromophore) flavin adenine dinucleotide (FAD), occur widely among organisms. CRYs play indispensable roles in the generation of circadian rhythm in mammals. Transgenic mice (Tg mice), ubiquitously expressing mouse CRY1 having a mutation in which cysteine414 (the zinc-binding site of CRY1) being replaced with alanine, display unique phenotypes in their circadian rhythms. Moreover, male Tg mice exhibit symptoms of diabetes characterized by beta-cell dysfunction, resembling human maturity onset diabetes of the young (MODY). The lowered proliferation of β-cells is a primary cause of age-dependent β-cell loss. Furthermore, unusually enlarged duct-like structures developed prominently in the Tg mice pancreases. The duct-like structures contained insulin-positive cells, suggesting neogenesis of β-cells in the Tg mice. This review, based mainly on the author's investigation of the unique features of Tg mice, presents reported results and recent findings related to molecular processes associated with mammalian cryptochromes, especially their involvement in the regulation of metabolism. New information is described with emphasis on the aspects of islet architecture, pancreatic β-cell dysfunction, and regeneration.

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Section: Characteristic Features Of Gene Expressions In the Isletsmentioning

confidence: 59%

Unique Aspects of Cryptochrome in Chronobiology and Metabolism, Pancreaticβ-Cell Dysfunction, and Regeneration: Research into Cysteine414-Alanine Mutant CRY1

Okano

2016

Journal of Diabetes Research

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“…Notably, bile acids have been shown to potentiate glucose-stimulated insulin secretion [37]. In addition to these transporters, Rgs16 was shown to be regulated, which has been shown to increase glucose-stimulated insulin secretion [38]. Furthermore, S100a4 and its paralog S100a6 are identified as up-regulated in the HDAC3βKO RNA-seq analysis.…”

Section: Discussionmentioning

confidence: 99%

Deletion of histone deacetylase 3 in adult beta cells improves glucose tolerance via increased insulin secretion

Remsberg

Ediger

et al. 2017

Molecular Metabolism

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ObjectiveHistone deacetylases are epigenetic regulators known to control gene transcription in various tissues. A member of this family, histone deacetylase 3 (HDAC3), has been shown to regulate metabolic genes. Cell culture studies with HDAC-specific inhibitors and siRNA suggest that HDAC3 plays a role in pancreatic β-cell function, but a recent genetic study in mice has been contradictory. Here we address the functional role of HDAC3 in β-cells of adult mice.MethodsAn HDAC3 β-cell specific knockout was generated in adult MIP-CreERT transgenic mice using the Cre-loxP system. Induction of HDAC3 deletion was initiated at 8 weeks of age with administration of tamoxifen in corn oil (2 mg/day for 5 days). Mice were assayed for glucose tolerance, glucose-stimulated insulin secretion, and islet function 2 weeks after induction of the knockout. Transcriptional functions of HDAC3 were assessed by ChIP-seq as well as RNA-seq comparing control and β-cell knockout islets.ResultsHDAC3 β-cell specific knockout (HDAC3βKO) did not increase total pancreatic insulin content or β-cell mass. However, HDAC3βKO mice demonstrated markedly improved glucose tolerance. This improved glucose metabolism coincided with increased basal and glucose-stimulated insulin secretion in vivo as well as in isolated islets. Cistromic and transcriptomic analyses of pancreatic islets revealed that HDAC3 regulates multiple genes that contribute to glucose-stimulated insulin secretion.ConclusionsHDAC3 plays an important role in regulating insulin secretion in vivo, and therapeutic intervention may improve glucose homeostasis.

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“…On the other hand, signaling via G i proteins negatively regulates β-cell proliferation and mass expansion in vivo [9]. Further, activation of the G i -coupled SST receptor inhibits ex vivo glucose-induced β-cell proliferation in mouse and human islets [10]. Thus, G i -GPCRs and G S -GPCRs can have opposing effects on β-cell function and β-cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

Opposing effects of prostaglandin E 2 receptors EP3 and EP4 on mouse and human β-cell survival and proliferation

Carboneau

Allan

Townsend

et al. 2017

Molecular Metabolism

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ObjectiveHyperglycemia and systemic inflammation, hallmarks of Type 2 Diabetes (T2D), can induce the production of the inflammatory signaling molecule Prostaglandin E2 (PGE2) in islets. The effects of PGE2 are mediated by its four receptors, E-Prostanoid Receptors 1-4 (EP1-4). EP3 and EP4 play opposing roles in many cell types due to signaling through different G proteins, Gi and GS, respectively. We previously found that EP3 and EP4 expression are reciprocally regulated by activation of the FoxM1 transcription factor, which promotes β-cell proliferation and survival. Our goal was to determine if EP3 and EP4 regulate β-cell proliferation and survival and, if so, to elucidate the downstream signaling mechanisms.Methodsβ-cell proliferation was assessed in mouse and human islets ex vivo treated with selective agonists and antagonists for EP3 (sulprostone and DG-041, respectively) and EP4 (CAY10598 and L-161,982, respectively). β-cell survival was measured in mouse and human islets treated with the EP3- and EP4-selective ligands in conjunction with a cytokine cocktail to induce cell death. Changes in gene expression and protein phosphorylation were analyzed in response to modulation of EP3 and EP4 activity in mouse islets.ResultsBlockade of EP3 enhanced β-cell proliferation in young, but not old, mouse islets in part through phospholipase C (PLC)-γ1 activity. Blocking EP3 also increased human β-cell proliferation. EP4 modulation had no effect on ex vivo proliferation alone. However, blockade of EP3 in combination with activation of EP4 enhanced human, but not mouse, β-cell proliferation. In both mouse and human islets, EP3 blockade or EP4 activation enhanced β-cell survival in the presence of cytokines. EP4 acts in a protein kinase A (PKA)-dependent manner to increase mouse β-cell survival. In addition, the positive effects of FoxM1 activation on β-cell survival are inhibited by EP3 and dependent on EP4 signaling.ConclusionsOur results identify EP3 and EP4 as novel regulators of β-cell proliferation and survival in mouse and human islets ex vivo.

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The regulator of G-protein signaling RGS16 promotes insulin secretion and β-cell proliferation in rodent and human islets

Cited by 33 publications

References 48 publications

Unique Aspects of Cryptochrome in Chronobiology and Metabolism, Pancreaticβ-Cell Dysfunction, and Regeneration: Research into Cysteine414-Alanine Mutant CRY1

Unique Aspects of Cryptochrome in Chronobiology and Metabolism, Pancreaticβ-Cell Dysfunction, and Regeneration: Research into Cysteine414-Alanine Mutant CRY1

Deletion of histone deacetylase 3 in adult beta cells improves glucose tolerance via increased insulin secretion

Opposing effects of prostaglandin E 2 receptors EP3 and EP4 on mouse and human β-cell survival and proliferation

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