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World Journal of Diabetes 2023年第3期14卷 188-197页

作者： Hiroshi Nomoto Department of Rheumatology Endocrinology and NephrologyFaculty of Medicine and Graduate School of MedicineHokkaido UniversitySapporo 060-8638HokkaidoJapan

The maintenance of appropriate glycemic control is important for the prevention of diabetic complications in people with type 2 diabetes(T2D). Numerous oral antidiabetic drugs are now clinically available, but in particular, the introduction of injection regimens using insulin and/or glucagon-like peptide-1 receptor agonist(GLP-1RA)s represents promising step-up options for oral antidiabetic drug treatment. The recently licensed fixed-ratio combination(FRC) products,which comprise basal insulin and a GLP-1RA, have potent anti-hyperglycemic effects and reduce the undesirable side-effects of each component, such as body weight gain, hypoglycemia, and gastrointestinal symptoms. Two FRCs-insulin degludec/Liraglutide and insulin glargine/Lixisenatide-are now clinically available and, to date, several phase Ⅱ/Ⅲ trials have been conducted in particular groups of subjects with T2D. However, their utility in real-world clinical settings is of interest for most clinicians. Recently reported real-world clinical trials of these two FRCs in various situations have demonstrated their efficacy regarding glycemic control and the quality of life of people with T2D. Their long-term safety and efficacy require confirmation, but a treatment strategy that includes an FRC may be compatible with the concept of “well-balanced” therapy in certain groups of patients with T2D who have inadequate glycemic control.

关键词： Clinical trial Diabetes mellitus,type 2 glucagon-like peptide-1 receptor Glycemic control Insulin,long-acting Quality of life

Type-2 Diabetes Mellitus and glucagon-like peptide-1 receptor toward Predicting Possible Association

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Computational Molecular Bioscience 2023年第3期13卷 48-62页

作者： Nabaa Kamal Alshafei Intisar Hassan Saeed Mona Abdelrahman Mohamed Khaier Department of Biochemistry College of Veterinary Medicine University of Bahri Khartoum Sudan Department of Physiology College of Veterinary Medicine University of Bahri Khartoum Sudan Department of Molecular Biology and Bioinformatics College of Veterinary Medicine University of Bahri Khartoum Sudan

Aim: This study aimed to investigate the effect of non-synonymous SNPs (nsSNPs) of the glucagon-like peptide-1 receptor (GLP-1R) gene in protein function and structure using different computational software. Introduction: The GLP1R gene provides the necessary instruction for the synthesis of the insulin hormones which is needed for glucose catabolism. Polymorphisms in this gene are associated with diabetes. The protein is an important drug target for the treatment of type-2 diabetes and stroke. Material and Methods: Different nsSNPs and protein-related sequences were obtained from NCBI and ExPASY database. Gene associations and interactions were predicted using GeneMANIA software. Deleterious and damaging effects of nsSNPs were analyzed using SIFT, Provean, and Polyphen-2. The association of the nsSNPs with the disease was predicted using SNPs & GO software. Protein stability was investigated using I-Mutant and MUpro software. The structural and functional impact of point mutations was predicted using Project Hope software. Project Hope analyzes the mutations according to their size, charge, hydrophobicity, and conservancy. Results: The GLP1R gene was found to have an association with 20 other different genes. Among the most important ones is the GCG (glucagon) gene which is also a trans membrane protein. Overall 7229 variants were seen, and the missense variants or nsSNPs (146) were selected for further analysis. The total number of nsSNPs obtained in this study was 146. After being subjected to SIFT software (27 Deleterious and 119 Tolerated) were predicted. Analysis with Provean showed that (20 deleterious and 7 neutral). Analysis using Polyphen-2 revealed 17 probably damaging, 2 possibly damaging and 1 benign nsSNPs. Using two additional software SNPs & GO and PHD-SNPs showed that 14 and 17 nsSNPs had a disease effect, respectively. Project Hope software predicts the effect of the 14 nsSNPs on the protein function due to differences in charge, size, hydrophobicity, and conservancy between the wild and mutant

关键词： glucagon-like peptide-1 receptor Single Nucleotide Polymorphism Insilico Analysis Non Synonymous SNP SIFT Polyphen-2 GeneMANIA

SYNGR4 and PLEKHB1 deregulation in motor neurons of amyotrophic lateral sclerosis models: potential contributions to pathobiology

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Neural Regeneration Research 2022年第2期17卷 266-270页

作者： Rita F.Marques Kent E.Duncan Institute for Biochemistry and Molecular Biology Department of ChemistryUniversity of HamburgHamburgGermany Neuronal Translational Control Research Group Center for Molecular Neurobiology Hamburg(ZMNH)University Medical Center Hamburg-EppendorfHamburgGermany

Amyotrophic lateral sclerosis is the most common adult-onset neurodegenerative disease affecting motor neurons. Its defining feature is progressive loss of motor neuron function in the cortex, brainstem, and spinal cord, leading to paralysis and death. Despite major advances in identifying genes that can cause disease when mutated and model the disease in animals and cellular models, it still remains unclear why motor symptoms suddenly appear after a long pre-symptomatic phase of apparently normal function. One hypothesis is that age-related deregulation of specific proteins within key cell types, especially motor neurons themselves, initiates disease symptom appearance and may also drive progressive degeneration. Genome-wide in vivo cell-type-specific screening tools are enabling identification of candidates for such proteins. In this minireview, we first briefly discuss the methodology used in a recent study that applied a motor neuron-specific RNASeq screening approach to a standard model of TAR DNA-binding protein-43(TDP-43)-driven amyotrophic lateral sclerosis. A key finding of this study is that synaptogyrin-4 and pleckstrin homology domain-containing family B member 1 are also deregulated at the protein level within motor neurons of two unrelated mouse models of mutant TDP-43 driven amyotrophic lateral sclerosis. Guided by what is known about molecular and cellular functions of these proteins and their orthologs, we outline here specific hypotheses for how changes in their levels might potentially alter cellular physiology of motor neurons and detrimentally affect motor neuron function. Where possible, we also discuss how this information could potentially be used in a translational context to develop new therapeutic strategies for this currently incurable, devastating disease.

关键词： amyotrophic lateral sclerosis glucagon-like peptide-1 receptor motor neuron disease mouse model neurodegeneration phosphatidylserine pleckstrin homology domain synaptogyrin TAR DNA-binding protein-43 vesicle transport

The protective effects and underlying mechanisms of dapagliflozin on diabetes-induced testicular dysfunction

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Asian Journal of Andrology 2023年第3期25卷 331-338页

作者： Zhi-Chao Luo Zi-Run Jin Ya-Fei Jiang Tian-Jiao Wei Ya-Lei Cao Zhe Zhang Rui Wei Hui Jiang Department of Urology Peking University Third HospitalBeijing 100191China Department of Endocrinology and Metabolism Peking University Third HospitalBeijing 100191China Department of Reproductive Medicine Center Peking University Third HospitalBeijing 100191China

Male diabetic individuals present a marked impairment in fertility;however,knowledge regarding the pathogenic mechanisms and therapeutic strategies is unsatisfactory.The new hypoglycemic drug dapagliflozin has shown certain benefits,such as decreasing the risk of cardiovascular and renal events in patients with diabetes.Even so,until now,the effects and underlying mechanisms of dapagliflozin on diabetic male infertility have awaited clarification.Here,we found that dapagliflozin lowered blood glucose levels,alleviated seminiferous tubule destruction,and increased sperm concentrations and motility in leptin receptor-deficient diabetic db/db mice.Moreover,the glucagon-like peptide-1 receptor(GLP-1R)antagonist exendin(9-39)had no effect on glucose levels but reversed the protective effects of dapagliflozin on testicular structure and sperm quality in db/db mice.We also found that dapagliflozin inhibited the testicular apoptotic process by upregulating the expression of the antiapoptotic protein B-cell lymphoma 2(BCL2)and X-linked inhibitor of apoptosis protein(XIAP)and inhibiting oxidative stress by enhancing the antioxidant status,including total antioxidant capacity,total superoxide dismutase(SOD)activity,and glutathione peroxidase(GPx)activity,as well as decreasing the level of 4-hydroxynonenal(4-HNE).Exendin(9-39)administration partially reversed these effects.Furthermore,dapagliflozin upregulated the glucagon-like peptide-1(GLP-1)level in plasma and GLP-1R expression by promoting AKT8 virus oncogene cellular homolog(Akt)phosphorylation in testicular tissue.Exendin(9-39)partially inhibited Akt phosphorylation.These results suggest that dapagliflozin protects against diabetes-induced spermatogenic dysfunction via activation of the GLP-1R/phosphatidylinositol 3-kinase(PI3K)/Akt signaling pathway.Our results indicate the potential effects of dapagliflozin against diabetes-induced spermatogenic dysfunction.

关键词： dapagliflozin diabetes glucagon-like peptide-1 receptor male infertility oxidative stress

A potentially serious adverse effect of GLP-1 receptor agonists

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Acta Pharmaceutica Sinica B 2023年第5期13卷 2291-2293页

作者： Jinmiao Lu Hao Liu Qingtong Zhou Ming-Wei Wang Zhiping Li Department of Pharmacy Children's Hospital of Fudan UniversityNational Children's Medical CenterShanghai 201102China School of Medicine Ningbo UniversityNingbo 31521lChina Research Center for Deepsea Bioresources Sanya 572025China Department of Pharmacology School of Basic Medical SciencesFudan UniversityShanghai 200032China

To the Editor:glucagon-like peptide-1(GLP-1)is a small intestine-derived hormone^(1,2).Its peptidic analogs include exenatide,lixisenatide,dulaglutide,liraglutide,albiglutide,semaglutide,etc.They work as GLP-1 recepto... 详细信息

关键词： glucagon-like peptide-1 receptor Agonist Clinical trial Adverse effect Constipation

Metabolic and hepatic effects of liraglutide,obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis

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World Journal of Gastroenterology 2018年第2期24卷 179-194页

作者： Kirstine S Tolbol Maria NB Kristiansen Henrik H Hansen Sanne S Veidal Kristoffer TG Rigbolt Matthew P Gillum Jacob Jelsing Niels Vrang Michael Feigh Gubra Aps Horsholm DK-2970Denmark Department of Biomedical Sciences Faculty of Health SciencesUniversity of CopenhagenCopenhagen DK-2200Denmark Section for Metabolic Imaging and Liver Metabolism The Novo Nordisk Foundation Center for Basic Metabolic ResearchFaculty of Health SciencesUniversity of CopenhagenCopenhagen DK-2200Denmark Department of Chemistry Faculty of ScienceUniversity of CopenhagenCopenhagen DK-2200Denmark

AIM To evaluate the pharmacodynamics of compounds in clinical development for nonalcoholic steatohepatitis(NASH) in obese mouse models of biopsy-confirmedNASH.METHODS Male wild-type C57 BL/6 J mice(DIO-NASH) and Lep^(ob/ob)(ob/ob-NASH) mice were fed a diet high in trans-fat(40%), fructose(20%) and cholesterol(2%) for 30 and 21 wk, respectively. Prior to treatment, all mice underwent liver biopsy for confirmation and stratification of liver steatosis and fibrosis, using the nonalcoholic fatty liver disease activity score(NAS) and fibrosis staging system. The mice were kept on the diet and received vehicle, liraglutide(0.2 mg/kg, SC, BID), obeticholic acid(OCA, 30 mg/kg PO, QD), or elafibranor(30 mg/kg PO, QD) for eight weeks. Within-subject comparisons were performed on changes in steatosis, inflammation, ballooning degeneration, and fibrosis scores. In addition, compound effects were evaluated by quantitative liver histology, including percent fractional area of liver fat, galectin-3, and collagen 1 a1.RESULTS Liraglutide and elafibranor, but not OCA, reduced body weight in both models. Liraglutide improved steatosis scores in DIO-NASH mice only. Elafibranor and OCA reduced histopathological scores of hepatic steatosis and inflammation in both models, but only elafibranor reduced fibrosis severity. Liraglutide and OCA reduced total liver fat, collagen 1 a1, and galectin-3 content, driven by significant reductions in liver weight. The individual drug effects on NASH histological endpoints were supported by global gene expression(RNA sequencing) and liver lipid biochemistry.CONCLUSION DIO-NASH and ob/ob-NASH mouse models show distinct treatment effects of liraglutide, OCA, and elafibranor, being in general agreement with corresponding findings in clinical trials for NASH. The present data therefore further supports the clinical translatability and utility of DIO-NASH and ob/ob-NASH mouse models of NASH for probing the therapeutic efficacy of compounds in preclinical drug development for NASH.

关键词： Nonalcoholic steatohepatitis Disease models Pathology Fibrosis Liver biopsy Transcriptomics Pharmacodynamics glucagon-like peptide-1 receptor Peroxisome proliferator-activated receptor Farnesoid X receptor

Decreased ^(68)Ga-NOTA-exendin-4 renal uptake in patients pretreated with Gelofusine infusion: a randomized controlled study

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Journal of Pancreatology 2020年第3期3卷 161-166页

作者： Yaping Luo Qingqing Pan Fang Li Department of Nuclear Medicine Chinese Academy of Medical Sciences and Peking Union Medical College Hospital Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine BeijingP.R.China

Objective:glucagon-like peptide-1 receptor imaging,using 68Ga-NOTA-exendin-4 is recently established for detecting insulinomas.Owing to the highly radioactive kidneys in 68Ga-NOTA-exendin-4 PET/CT,we aimed to determine the effectiveness of Gelofusine in reducing renal uptake of 68Ga-NOTA-exendin-4.Methods:In our randomized controlled study,patients presenting for 68Ga-NOTA-exendin-4 PET/CT who were18 years and with normal renal function were enrolled,and then randomized into intervention group and control group.Patients in intervention group(group 1)underwent infusion of 500mL Gelofusine prior to PET/CT procedures:patients injected with 68Ga-NOTA-exendin-4(group 1a)immediately after 500mL Gelofusine infusion was completed;(group 1b)at the time point that 250 to 300mL Gelofusine infusion was completed;(group 1c)30minutes after completion of 500mL Gelofusine infusion.The control group(group 2)received 500mL 5%glucose saline instead.PET/CT was then performed,and SUVs of the kidneys and insulinomas were measured.Results:A total of 28 patients were recruited.There were 7 patients(14 kidneys)in each subgroup.The age,body weight,BMI,renal function,injected 68Ga-exendin-4 activity,and interval between injection of the tracer and PET/CT scan were not significantly different among the groups(P>.05).The average and maximum SUVs in the kidneys were significantly reduced in patients of intervention group compared with the control subjects(P1),and the renal uptake could be decreased by 57%with Gelofusine pretreatment.No significant difference in the renal radioactivity was found among group 1a,1b,and 1c(P=.071).The uptake of insulinomas was not significantly different between the intervention and control groups.Conclusion:Renal uptake of 68Ga-exendin-4 can be effectively reduced by pretreatment with Gelofusine.Abbreviations:GLP-1R=glucagon-like peptide-1 receptor;PRRT=peptide receptor radionuclide therapy;PET=positron emission tomography;SUV=standard uptake value.

关键词： ^(68)Ga-NOTA-exendin-4 Gelofusine glucagon-like peptide-1 receptor Kidney

GLP-1 receptors in the spinal cord mediate analgesia without producing tolerance in neuropathic pain and cancer pain

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GLP-1 receptors in the spinal cord mediate analgesia without...

Geniposide,a Novel Agonist for GLP-1 receptor,Prevents PC12 Cells from Oxidative Damage via MAP Kinase Pathway

中国药理学会第十一次全国学术会议

作者： WANG Yong-xiang,GONG Nian (King’s Lab,School of Pharmacy,Shanghai Jiaotong University,Shanghai 200240,China)

OBJECTIVE glucagon-like peptide-1(GLP-1) is an incretin hormone known to stimulate glucose-dependent insulin secretion and GLP-1 receptor belongs to Family B of G protein-coupled receptors(GPCRs).The present study examined the biological role of spinal GLP-1 receptors in pain transmission and transduction.METHODS Animal models of chronic pain,molecular biology analysis,and immunehistochemistry staining were employed in the study.RESULTS GLP-1 receptors were widely expressed in the spinal cord and dorsal root ganglia,approximately 1%and 1/10 000 of the lungs,respectively.Activation of spinal GLP-1 receptors by the peptide agonists exenatide and GLP-1,as well as small molecule agonists led to specific,efficacious and dose-dependent analgesia in chronic pain including formalin-induced tonic pain,neuropathic pain,bone cancer pain and streptozocin-induced diabetic pain,but not in acute nociception.Long-term administrations of GLP-1R agonists produced no tolerance to analgesia.Analgesic effects of exenatide and GLP-1 were blocked by the specific GLP-1R antagonist exendin(9-39).Further signal transduction analysis showed that analgesic effects of exenatide and GLP-1 were acted via the activation of adenylyl cyclase and protein kinase A,same as those in releasing insulin inβcells.CONCLUSION This study,for the first time,identified and validated spinal GLP-1 receptor as a poten- tial target molecule for the treatment of chronic pain without producing tolerance to analgesia.

关键词： glucagon-like peptide-1 receptor spinal cord chronic pain analgesia tolerance to analgesia

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Geniposide,a Novel Agonist for GLP-1 Receptor,Prevents PC12 ...