The Experts below are selected from a list of 6963 Experts worldwide ranked by ideXlab platform
Nigel H Greig - One of the best experts on this subject based on the ideXlab platform.
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utility of neuronal derived exosomes to examine molecular mechanisms that affect motor function in patients with parkinson disease a secondary analysis of the exenatide pd trial
JAMA Neurology, 2019Co-Authors: Dilan Athauda, Seema Gulyani, Hanuma Kumar Karnati, David Tweedie, Maja Mustapic, Sahil Chawla, Kashfia Chowdhury, Simon S Skene, Nigel H GreigAbstract:Importance Exenatide, a Glucagon-Like peptide 1 Agonist used in type 2 diabetes, was recently found to have beneficial effects on motor function in a randomized, placebo-controlled trial in Parkinson disease (PD). Accumulating evidence suggests that impaired brain insulin and protein kinase B (Akt) signaling play a role in PD pathogenesis; however, exploring the extent to which drugs engage with putative mechnisms in vivo remains a challenge. Objective To assess whether participants in the Exenatide-PD trial have augmented activity in brain insulin and Akt signaling pathways. Design, Setting, and Participants Serum samples were collected from 60 participants in the single-center Exenatide-PD trial (June 18, 2014, to June 16, 2016), which compared patients with moderate PD randomized to 2 mg of exenatide once weekly or placebo for 48 weeks followed by a 12-week washout period. Serum extracellular vesicles, including exosomes, were extracted, precipitated, and enriched for neuronal source by anti–L1 cell adhesion molecule antibody absorption, and proteins of interest were evaluated using electrochemiluminescence assays. Statistical analysis was performed from May 1, 2017, to August 31, 2017. Main Outcomes and Measures The main outcome was augmented brain insulin signaling that manifested as a change in tyrosine phosphorylated insulin receptor substrate 1 within neuronal extracellular vesicles at the end of 48 weeks of exenatide treatment. Additional outcome measures were changes in other insulin receptor substrate proteins and effects on protein expression in the Akt and mitogen-activated protein kinase pathways. Results Sixty patients (mean [SD] age, 59.9 [8.4] years; 43 [72%] male) participated in the study: 31 in the exenatide group and 29 in the placebo group (data from 1 patient in the exenatide group were excluded). Patients treated with exenatide had augmented tyrosine phosphorylation of insulin receptor substrate 1 at 48 weeks (0.27 absorbance units [AU]; 95% CI, 0.09-0.44 AU;P = .003) and 60 weeks (0.23 AU; 95% CI, 0.05-0.41 AU;P = .01) compared with patients receiving placebo. Exenatide-treated patients had elevated expression of downstream substrates, including total Akt (0.35 U/mL; 95% CI, 0.16-0.53 U/mL;P Conclusions and Relevance The results of this study are consistent with target engagement of brain insulin, Akt, and mTOR signaling pathways by exenatide and provide a mechanistic context for the clinical findings of the Exenatide-PD trial. This study suggests the potential of using exosome-based biomarkers as objective measures of target engagement in clinical trials using drugs that target neuronal pathways.
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insulin resistance and exendin 4 treatment for multiple system atrophy
Brain, 2017Co-Authors: Fares Bassil, Nigel H Greig, Mariehelene Canron, Anne Vital, Erwan Bezard, Seema Gulyani, Dimitrios Kapogiannis, Pierreolivier Fernagut, Wassilios G MeissnerAbstract:See Stayte and Vissel (doi:10.1093/awx064) for a scientific commentary on this article. Multiple system atrophy is a fatal sporadic adult-onset neurodegenerative disorder with no symptomatic or disease-modifying treatment available. The cytopathological hallmark of multiple system atrophy is the accumulation of α-synuclein aggregates in oligodendrocytes, forming glial cytoplasmic inclusions. Impaired insulin/insulin-like growth factor-1 signalling (IGF-1) and insulin resistance (i.e. decreased insulin/IGF-1) have been reported in other neurodegenerative disorders such as Alzheimer's disease. Increasing evidence also suggests impaired insulin/IGF-1 signalling in multiple system atrophy, as corroborated by increased insulin and IGF-1 plasma concentrations in multiple system atrophy patients and reduced IGF-1 brain levels in a transgenic mouse model of multiple system atrophy. We here tested the hypothesis that multiple system atrophy is associated with brain insulin resistance and showed increased expression of the key downstream messenger insulin receptor substrate-1 phosphorylated at serine residue 312 in neurons and oligodendrocytes in the putamen of patients with multiple system atrophy. Furthermore, the expression of insulin receptor substrate 1 (IRS-1) phosphorylated at serine residue 312 was more apparent in inclusion bearing oligodendrocytes in the putamen. By contrast, it was not different between both groups in the temporal cortex, a less vulnerable structure compared to the putamen. These findings suggest that insulin resistance may occur in multiple system atrophy in regions where the neurodegenerative process is most severe and point to a possible relation between α-synuclein aggregates and insulin resistance. We also observed insulin resistance in the striatum of transgenic multiple system atrophy mice and further demonstrate that the Glucagon-Like Peptide-1 analogue exendin-4, a well-tolerated and Federal Drug Agency-approved antidiabetic drug, has positive effects on insulin resistance and monomeric α-synuclein load in the striatum, as well as survival of nigral dopamine neurons. Additionally, plasma levels of exosomal neural-derived IRS-1 phosphorylated at serine residue 307 (corresponding to serine residue 312 in humans) negatively correlated with survival of nigral dopamine neurons in multiple system atrophy mice treated with exendin-4. This finding suggests the potential for developing this peripheral biomarker candidate as an objective outcome measure of target engagement for clinical trials with Glucagon-Like Peptide-1 analogues in multiple system atrophy. In conclusion, our observation of brain insulin resistance in multiple system atrophy patients and transgenic mice together with the beneficial effects of the Glucagon-Like Peptide-1 Agonist exendin-4 in transgenic mice paves the way for translating this innovative treatment into a clinical trial.
Jingya Lyu - One of the best experts on this subject based on the ideXlab platform.
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role of atp binding cassette transporter a1 in suppressing lipid accumulation by glucagon like peptide 1 Agonist in hepatocytes
Molecular metabolism, 2020Co-Authors: Jingya Lyu, Hitomi Imachi, Kensaku Fukunaga, Seisuke Sato, Toshihiro Kobayashi, Tao Dong, Takanobu Saheki, Mari Matsumoto, Hisakazu IwamaAbstract:Abstract Objective Adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) influences hepatic cholesterol transportation. Accumulation of hepatic cholesterol leads to fatty liver disease, which is improved by Glucagon-Like peptide 1 (GLP-1) in diabetes. Therefore, we analyzed the molecular mechanism in the regulation of hepatic ABCA1 by GLP-1 analogue exendin-4. Methods Hepatic ABCA1 expression and transcription were checked by western blotting, real-time polymerase chain reaction (PCR), and luciferase assay in HepG2 cells. Chromatin immunoprecipitation (ChIP) and site-directed mutagenesis were employed to determine transcriptional regulation of the ABCA1 gene. Prolactin regulatory element-binding (PREB)-transgenic mice were generated to access the effect of exendin-4 on improving lipid accumulation caused by a high-fat diet (HFD). Results Exendin-4 stimulated hepatic ABCA1 expression and transcription via the Ca2+/calmodulin (CaM)-dependent protein kinase kinase/CaM-dependent protein kinase IV (CaMKK/CaMKIV) pathway, whereas GLP-1 receptor antAgonist exendin9-39 cancelled this effect. Therefore, exendin-4 decreased hepatic lipid content. ChIP showed that PREB could directly bind to the ABCA1 promoter, which was enhanced by exendin-4. Moreover, PREB stimulated ABCA1 promoter activity, and mutation of PREB-binding site in ABCA1 promoter cancelled exendin-4-enhanced ABCA1 promoter activity. Silencing of PREB attenuated the effect of exendin-4 and induced hepatic cholesterol accumulation. Blockade of CaMKK by STO-609 or siRNA cancelled the upregulation of ABCA1 and PREB induced by exendin-4. In vivo, exendin-4 or overexpression of PREB increased hepatic ABCA1 expression and decreased hepatic lipid accumulation and high plasma cholesterol caused by a HFD. Conclusions Our data shows that exendin-4 stimulates hepatic ABCA1 expression and decreases lipid accumulation by the CaMKK/CaMKIV/PREB pathway, suggesting that ABCA1 and PREB might be the therapeutic targets in fatty liver disease.
Laurent Demizieux - One of the best experts on this subject based on the ideXlab platform.
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liraglutide reduces postprandial hyperlipidemia by increasing apob48 apolipoprotein b48 catabolism and by reducing apob48 production in patients with type 2 diabetes mellitus
Arteriosclerosis Thrombosis and Vascular Biology, 2018Co-Authors: Bruno Vergès, Laurence Duvillard, Benjamin Bouillet, Alexia Rouland, Anne-laure Sberna, Jean-michel Petit, Pascal Degrace, Jean Paul Pais De Barros, S Baillotrudoni, Laurent DemizieuxAbstract:Objective— Treatment with liraglutide, a GLP-1 (Glucagon-Like Peptide-1) Agonist, has been shown to reduce postprandial lipidemia, an important feature of diabetic dyslipidemia. However, the underl...
Vikesh K Singh - One of the best experts on this subject based on the ideXlab platform.
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endoscopic sleeve gastroplasty plus liraglutide versus endoscopic sleeve gastroplasty alone for weight loss
Gastrointestinal Endoscopy, 2020Co-Authors: Dilhana Badurdeen, Anna Carolina Hoff, Abdellah Hedjoudje, Atif Adam, Mohamad I Itani, Jad Farha, Shahem Abbarh, Anthony N Kalloo, Mouen A Khashab, Vikesh K SinghAbstract:BACKGROUND AND AIMS The endoscopic sleeve gastroplasty (ESG) has been shown to be effective for inducing weight loss. The efficacy of liraglutide, a Glucagon-Like Peptide-1 Agonist, to augment weight loss after ESG is unknown. This study aims to evaluate the efficacy of ESG and liraglutide (ESG-L) compared with ESG alone. METHODS This was a retrospective study of prospectively collected data from patients undergoing ESG at 3 outpatient clinics in Brazil, between November 2017 and July 2018. Liraglutide was offered to all patients 5 months after ESG. Patients that opted to take liraglutide (ESG-L) were matched 1:1 to patients that declined it (ESG). Primary outcome was percent total body weight loss (%TBWL), and percent excess weight loss (%EWL) 7 months after initiation of liraglutide (12 months after ESG). Secondary outcome was change in percent body fat 12 months after ESG. ESG technique and postprocedure follow-up was identical at all 3 sites. RESULTS Propensity score matching yielded 26 matched pairs. Adjusted comparisons between the 2 groups showed that patients who opted to take liraglutide had a superior mean %TBWL 7 months after initiation of liraglutide (ESG-L) compared with those that declined it (ESG), 24.72 ± 2.12% versus 20.51 ± 1.68% (p <0.001). ESG-L had a statistically greater reduction in percent body fat compared with ESG, 7.85 ± 1.26 versus 10.54 ± 1.88 (p <0.001) at 12 months. CONCLUSION Addition of liraglutide at 5 months results in superior weight loss and improved efficacy as demonstrated by decreased body fat 12 months after the ESG. Further studies are imperative to determine optimal dose, timing, and duration of liraglutide.
Seema Gulyani - One of the best experts on this subject based on the ideXlab platform.
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utility of neuronal derived exosomes to examine molecular mechanisms that affect motor function in patients with parkinson disease a secondary analysis of the exenatide pd trial
JAMA Neurology, 2019Co-Authors: Dilan Athauda, Seema Gulyani, Hanuma Kumar Karnati, David Tweedie, Maja Mustapic, Sahil Chawla, Kashfia Chowdhury, Simon S Skene, Nigel H GreigAbstract:Importance Exenatide, a Glucagon-Like peptide 1 Agonist used in type 2 diabetes, was recently found to have beneficial effects on motor function in a randomized, placebo-controlled trial in Parkinson disease (PD). Accumulating evidence suggests that impaired brain insulin and protein kinase B (Akt) signaling play a role in PD pathogenesis; however, exploring the extent to which drugs engage with putative mechnisms in vivo remains a challenge. Objective To assess whether participants in the Exenatide-PD trial have augmented activity in brain insulin and Akt signaling pathways. Design, Setting, and Participants Serum samples were collected from 60 participants in the single-center Exenatide-PD trial (June 18, 2014, to June 16, 2016), which compared patients with moderate PD randomized to 2 mg of exenatide once weekly or placebo for 48 weeks followed by a 12-week washout period. Serum extracellular vesicles, including exosomes, were extracted, precipitated, and enriched for neuronal source by anti–L1 cell adhesion molecule antibody absorption, and proteins of interest were evaluated using electrochemiluminescence assays. Statistical analysis was performed from May 1, 2017, to August 31, 2017. Main Outcomes and Measures The main outcome was augmented brain insulin signaling that manifested as a change in tyrosine phosphorylated insulin receptor substrate 1 within neuronal extracellular vesicles at the end of 48 weeks of exenatide treatment. Additional outcome measures were changes in other insulin receptor substrate proteins and effects on protein expression in the Akt and mitogen-activated protein kinase pathways. Results Sixty patients (mean [SD] age, 59.9 [8.4] years; 43 [72%] male) participated in the study: 31 in the exenatide group and 29 in the placebo group (data from 1 patient in the exenatide group were excluded). Patients treated with exenatide had augmented tyrosine phosphorylation of insulin receptor substrate 1 at 48 weeks (0.27 absorbance units [AU]; 95% CI, 0.09-0.44 AU;P = .003) and 60 weeks (0.23 AU; 95% CI, 0.05-0.41 AU;P = .01) compared with patients receiving placebo. Exenatide-treated patients had elevated expression of downstream substrates, including total Akt (0.35 U/mL; 95% CI, 0.16-0.53 U/mL;P Conclusions and Relevance The results of this study are consistent with target engagement of brain insulin, Akt, and mTOR signaling pathways by exenatide and provide a mechanistic context for the clinical findings of the Exenatide-PD trial. This study suggests the potential of using exosome-based biomarkers as objective measures of target engagement in clinical trials using drugs that target neuronal pathways.
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insulin resistance and exendin 4 treatment for multiple system atrophy
Brain, 2017Co-Authors: Fares Bassil, Nigel H Greig, Mariehelene Canron, Anne Vital, Erwan Bezard, Seema Gulyani, Dimitrios Kapogiannis, Pierreolivier Fernagut, Wassilios G MeissnerAbstract:See Stayte and Vissel (doi:10.1093/awx064) for a scientific commentary on this article. Multiple system atrophy is a fatal sporadic adult-onset neurodegenerative disorder with no symptomatic or disease-modifying treatment available. The cytopathological hallmark of multiple system atrophy is the accumulation of α-synuclein aggregates in oligodendrocytes, forming glial cytoplasmic inclusions. Impaired insulin/insulin-like growth factor-1 signalling (IGF-1) and insulin resistance (i.e. decreased insulin/IGF-1) have been reported in other neurodegenerative disorders such as Alzheimer's disease. Increasing evidence also suggests impaired insulin/IGF-1 signalling in multiple system atrophy, as corroborated by increased insulin and IGF-1 plasma concentrations in multiple system atrophy patients and reduced IGF-1 brain levels in a transgenic mouse model of multiple system atrophy. We here tested the hypothesis that multiple system atrophy is associated with brain insulin resistance and showed increased expression of the key downstream messenger insulin receptor substrate-1 phosphorylated at serine residue 312 in neurons and oligodendrocytes in the putamen of patients with multiple system atrophy. Furthermore, the expression of insulin receptor substrate 1 (IRS-1) phosphorylated at serine residue 312 was more apparent in inclusion bearing oligodendrocytes in the putamen. By contrast, it was not different between both groups in the temporal cortex, a less vulnerable structure compared to the putamen. These findings suggest that insulin resistance may occur in multiple system atrophy in regions where the neurodegenerative process is most severe and point to a possible relation between α-synuclein aggregates and insulin resistance. We also observed insulin resistance in the striatum of transgenic multiple system atrophy mice and further demonstrate that the Glucagon-Like Peptide-1 analogue exendin-4, a well-tolerated and Federal Drug Agency-approved antidiabetic drug, has positive effects on insulin resistance and monomeric α-synuclein load in the striatum, as well as survival of nigral dopamine neurons. Additionally, plasma levels of exosomal neural-derived IRS-1 phosphorylated at serine residue 307 (corresponding to serine residue 312 in humans) negatively correlated with survival of nigral dopamine neurons in multiple system atrophy mice treated with exendin-4. This finding suggests the potential for developing this peripheral biomarker candidate as an objective outcome measure of target engagement for clinical trials with Glucagon-Like Peptide-1 analogues in multiple system atrophy. In conclusion, our observation of brain insulin resistance in multiple system atrophy patients and transgenic mice together with the beneficial effects of the Glucagon-Like Peptide-1 Agonist exendin-4 in transgenic mice paves the way for translating this innovative treatment into a clinical trial.