GLP-1 Analog Liraglutide Enhances Proinsulin Processing in Pancreatic β-Cells via a PKA-Dependent Pathway

Wang, Liang; Liu, Ye; Yang, Jin; Zhao, Hejun; Ke, Jing; Tian, Qing; Zhang, Lin; Wen, Jinhua; Wei, Rui; Hong, Tianpei

doi:10.1210/en.2014-1218

Cited by 20 publications

(24 citation statements)

References 59 publications

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“…Previous reports already showed contradictory results in terms of GLP-1R expression within the liver 4, 5 , and we are not totally convinced that the band detected by the antibody in human samples really corresponds to GLP-1R (as it is contradictory to the two specific mRNA TaqMan probes). In agreement, additional experiments showed lack of protein kinase A phosphorylation (marker of GLP-1R activation) 31, 32 in response to liraglutide, and no differences in liraglutide-mediated HSC de-activation and proliferation when an antagonist of GLP-1R was used. Secondly, we analyzed the expression of the transcription factor Kruppel-like factor 2 (KLF2) in response to liraglutide since the effects of liraglutide on HSC were quite similar to those previously observed using statins 26, 33–35 .…”

Section: Discussionsupporting

confidence: 72%

Liraglutide improves liver microvascular dysfunction in cirrhosis: Evidence from translational studies

Mesquita

Guixé‐Muntet

Fernández‐Iglesias

et al. 2017

Sci Rep

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1Hepatic stellate cells (HSC) play a key role in the development of chronic liver disease (CLD). Liraglutide, well-established in type 2 diabetes, showed anti-inflammatory and anti-oxidant properties. We evaluated the effects of liraglutide on HSC phenotype and hepatic microvascular function using diverse pre-clinical models of CLD. Human and rat HSC were in vitro treated with liraglutide, or vehicle, and their phenotype, viability and proliferation were evaluated. In addition, liraglutide or vehicle was administered to rats with CLD. Liver microvascular function, fibrosis, HSC phenotype and sinusoidal endothelial phenotype were determined. Additionally, the effects of liraglutide on HSC phenotype were analysed in human precision-cut liver slices. Liraglutide markedly improved HSC phenotype and diminished cell proliferation. Cirrhotic rats receiving liraglutide exhibited significantly improved liver microvascular function, as evidenced by lower portal pressure, improved intrahepatic vascular resistance, and marked ameliorations in fibrosis, HSC phenotype and endothelial function. The antifibrotic effects of liraglutide were confirmed in human liver tissue and, although requiring further investigation, its underlying molecular mechanisms suggested a GLP1-R-independent and NF-κB-Sox9-dependent one. This study demonstrates for the first time that liraglutide improves the liver sinusoidal milieu in pre-clinical models of cirrhosis, encouraging its clinical evaluation in the treatment of chronic liver disease.Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RA) are a new class of anti-diabetic medications that mimic the effects of incretin hormones 1 . As an incretin hormone, which is synthesized in response to food intake, GLP-1 can stimulate insulin release by pancreatic β-cells in a glucose-dependent manner and suppress glucagon secretion from α-cells 2 . The favourable actions of GLP-1 on glucose homeostasis are mediated through GLP-1 receptors. However, native GLP-1 is rapidly degraded in circulation 3 . Liraglutide, a synthetic GLP-1RA that shares 97% homology with the structure of human GLP-1, possesses a much longer circulating half-life, thereby making it a novel anti-diabetic drug suitable for once-daily injection 1 . Apart from the pancreatic islets, GLP-1 receptors are present in many other tissues and, although its expression within the liver is not clear 4,5 , recent studies demonstrated efficacy of GLP-1RA in liver diseases, such as NAFLD 6,7 . In this regard, studies showed other beneficial properties for this type of drugs, including anti-inflammatory and anti-oxidant 8,9 , which are also important for the resolution of chronic liver disease (CLD).Cirrhosis is the end stage of CLD that starts with deregulations in the phenotype of all hepatic cells leading to parenchymal and sinusoidal dysfunction 10 . In CLD, both architectural alterations of the liver parenchyma and

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Section: Discussionsupporting

confidence: 72%

Liraglutide improves liver microvascular dysfunction in cirrhosis: Evidence from translational studies

Mesquita

Guixé‐Muntet

Fernández‐Iglesias

et al. 2017

Sci Rep

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“…The present results support this hypothesis, as we showed that the effect of liraglutide on reversing AGEs-induced ROS production, pro-inflammatory cytokine secretion, and cell viability were mediated by the activation of cAMP/PKA signaling. Liraglutide was previously shown to upregulate the prohormone converting enzymes PC1/3, which process proinsulin to insulin in pancreatic β-cells, in vitro and in vivo through the activation of the GLP-1R/cAMP/PKA pathway [48]. In a mouse model of diabetic nephropathy, liraglutide showed a protective role against renal oxidative stress triggered by hyperglycemia mediated by cAMP/PKA activation [49].…”

Section: Bao Et Al: Relation Of Liraglutide and Glp-1r In Neuroprotementioning

confidence: 99%

The Neuroprotective Effect of Liraglutide is Mediated by Glucagon-Like Peptide 1 Receptor-Mediated Activation of cAMP/PKA/CREB Pathway

Bao

Jiang

Chen

et al. 2015

Cell Physiol Biochem

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Background/Aims: Glucagon-like peptide-1 (GLP-1)-based drugs are being used to achieve better glucose control in patients with type 2 diabetes, and GLP-1 mimetics such as liraglutide have shown therapeutic potential in preventing diabetes-related microvascular and macrovascular complications as well as comorbidities such as neurodegenerative disorders. In the present study, we investigated the effects of liraglutide on primary rat cortical astrocytes treated with advanced glycation end-products (AGEs). Methods: Gene and protein expression was analyzed by quantitative real time PCR, western blots, and enzyme-linked immunosorbent assay. The caspase-3 activity was assessed using a caspase-3 colorimetric assay kit. The ROS production was measured with CM-H2DCFDA staining. The cell viability of rat astrocytes was determined using MTT assay. Results: Liraglutide ameliorated AGEs-induced oxidative stress, inflammatory cytokine secretion, caspase activation, and cell death in astrocytes, and reversed the AGEs mediated reduction in intracellular cyclic AMP (cAMP) levels, protein kinase A (PKA) activity, and the phosphorylation of the cAMP response element-binding (CREB) protein. The protective effects of liraglutide against AGEs-mediated toxicity were abolished by GLP-1 receptor (GLP-1R) knockdown or pretreatment of cells with the adenylyl cyclase inhibitor SQ22536 or the PKA inhibitor Rp-cAMP. Conclusions: Liraglutide exerts its neuroprotective effects via the GLP-1R-mediated activation of the cAMP/PKA/CREB pathway. The results of the present study support the therapeutic potential of liraglutide for the treatment of neurodegenerative disorders.

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“…Nevertheless, the underlying mechanism was still unclear. Otherwise, some data confirmed that GLP-1 possess a potent anti-inflammatory property through a PKA-dependent signaling pathway [ 19 , 20 , 21 , 22 , 23 , 24 ]. Arakawa et al [ 24 ] showed that LPS-induced macrophage activation and TNF-α expression was significantly reduced by GLP-1 analog exendin-4 through PKA/NF-κB signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Glucagon Like Peptide-1 (GLP-1) Modulates OVA-Induced Airway Inflammation and Mucus Secretion Involving a Protein Kinase A (PKA)-Dependent Nuclear Factor-κB (NF-κB) Signaling Pathway in Mice

Zhu

Zhang

et al. 2015

IJMS

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Asthma is a common chronic pulmonary inflammatory disease, featured with mucus hyper-secretion in the airway. Recent studies found that glucagon like peptide-1 (GLP-1) analogs, including liraglutide and exenatide, possessed a potent anti-inflammatory property through a protein kinase A (PKA)-dependent signaling pathway. Therefore, the aim of current study was to investigate the value of GLP-1 analog therapy liraglutide in airway inflammation and mucus secretion in a murine model of ovalbumin (OVA)-induced asthma, and its underlying molecular mechanism. In our study, BALB/c mice were sensitized and challenged by OVA to induce chronic asthma. Pathological alterations, the number of cells and the content of inflammatory mediators in bronchoalveolar lavage fluid (BALF), and mucus secretion were observed and measured. In addition, the mRNA and protein expression of E-selectin and MUC5AC were analyzed by qPCR and Western blotting. Then, the phosphorylation of PKA and nuclear factor-κB (NF-κB) p65 were also measured by Western blotting. Further, NF-κB p65 DNA binding activity was detected by ELISA. OVA-induced airway inflammation, airway mucus hyper-secretion, the up-regulation of E-selectin and MUC5AC were remarkably inhibited by GLP-1 in mice (all p < 0.01). Then, we also found that OVA-reduced phosphorylation of PKA, and OVA-enhanced NF-κB p65 activation and NF-κB p65 DNA binding activity were markedly improved by GLP-1 (all p < 0.01). Furthermore, our data also figured out that these effects of GLP-1 were largely abrogated by the PKA inhibitor H-89 (all p < 0.01). Taken together, our results suggest that OVA-induced asthma were potently ameliorated by GLP-1 possibly through a PKA-dependent inactivation of NF-κB in mice, indicating that GLP-1 analogs may be considered an effective and safe drug for the potential treatment of asthma in the future.

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GLP-1 Analog Liraglutide Enhances Proinsulin Processing in Pancreatic β-Cells via a PKA-Dependent Pathway

Cited by 20 publications

References 59 publications

Liraglutide improves liver microvascular dysfunction in cirrhosis: Evidence from translational studies

Liraglutide improves liver microvascular dysfunction in cirrhosis: Evidence from translational studies

The Neuroprotective Effect of Liraglutide is Mediated by Glucagon-Like Peptide 1 Receptor-Mediated Activation of cAMP/PKA/CREB Pathway

Glucagon Like Peptide-1 (GLP-1) Modulates OVA-Induced Airway Inflammation and Mucus Secretion Involving a Protein Kinase A (PKA)-Dependent Nuclear Factor-κB (NF-κB) Signaling Pathway in Mice

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