405 results match your criteria pancreatic glp-1r

GLP-1 peptide analogs for targeting pancreatic beta cells.

Drug Discov Today 2021 Apr 8. Epub 2021 Apr 8.

Department of Microbiology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran. Electronic address:

Loss or dysfunction of the pancreatic beta cells or insulin receptors leads to diabetes mellitus (DM). This usually occurs over many years; therefore, the development of methods for the timely detection and clinical intervention are vital to prevent the development of this disease. Glucagon-like peptide-1 receptor (GLP-1R) is the receptor of GLP-1, an incretin hormone that causes insulin secretion in a glucose-dependent manner. Read More

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Exendin-4 Promotes Schwann Cell Survival/Migration and Myelination In Vitro.

Int J Mol Sci 2021 Mar 15;22(6). Epub 2021 Mar 15.

Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.

Besides its insulinotropic actions on pancreatic β cells, neuroprotective activities of glucagon-like peptide-1 (GLP-1) have attracted attention. The efficacy of a GLP-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) for functional repair after sciatic nerve injury and amelioration of diabetic peripheral neuropathy (DPN) has been reported; however, the underlying mechanisms remain unclear. In this study, the bioactivities of Ex-4 on immortalized adult rat Schwann cells IFRS1 and adult rat dorsal root ganglion (DRG) neuron-IFRS1 co-culture system were investigated. Read More

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Feasibility of a scale-down production of [68Ga]Ga-NODAGA-Exendin-4 in a hospital based radiopharmacy.

Curr Radiopharm 2021 Mar 9. Epub 2021 Mar 9.

Nuclear Medicine and Molecular Imaging Department, University Hospital of Parma, via Gramsci 14, 43126 Parma. Italy.

Background: Glucagon-like peptide 1 receptor (GLP-1R) is preferentially expressed in β-cells, but it is highly expressed in human insulinomas and gastrinomas. Several GLP-1 receptor-avid radioligands have been developed to image insulin-secreting tumors or to provide a quantitative in vivo biomarker of pancreatic β-cell mass. Exendin-4 is a high affinity ligand of the GLP1-R, which is a candidate for being labeled with a PET isotope and used for imaging purposes. Read More

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GRK2 regulates GLP-1R-mediated early phase insulin secretion in vivo.

BMC Biol 2021 Mar 3;19(1):40. Epub 2021 Mar 3.

Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (CBMSO) UAM-CSIC; Instituto de Investigación Sanitaria Hospital Universitario La Princesa; CIBER de Enfermedades Cardiovasculares (CIBERCV), UNIVERSIDAD AUTONOMA DE MADRID and Instituto de Salud Carlos III, Madrid, Spain.

Background: Insulin secretion from the pancreatic β-cell is finely modulated by different signals to allow an adequate control of glucose homeostasis. Incretin hormones such as glucagon-like peptide-1 (GLP-1) act as key physiological potentiators of insulin release through binding to the G protein-coupled receptor GLP-1R. Another key regulator of insulin signaling is the Ser/Thr kinase G protein-coupled receptor kinase 2 (GRK2). Read More

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GLP-1 Val8: A Biased GLP-1R Agonist with Altered Binding Kinetics and Impaired Release of Pancreatic Hormones in Rats.

ACS Pharmacol Transl Sci 2021 Feb 19;4(1):296-313. Epub 2021 Jan 19.

Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.

Biased ligands that selectively confer activity in one pathway over another are pharmacologically important because biased signaling may reduce on-target side effects and improve drug efficacy. Here, we describe an N-terminal modification in the incretin hormone glucagon-like peptide (GLP-1) that alters the signaling capabilities of the GLP-1 receptor (GLP-1R) by making it G protein biased over internalization but was originally designed to confer DPP-4 resistance and thereby prolong the half-life of GLP-1. Despite similar binding affinity, cAMP production, and calcium mobilization, substitution of a single amino acid (Ala8 to Val8) in the N-terminus of GLP-1(7-36)NH (GLP-1 Val8) severely impaired its ability to internalize GLP-1R compared to endogenous GLP-1. Read More

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February 2021

Continuous stimulation of dual-function peptide PGLP-1-VP inhibits the morbidity and mortality of NOD mice through anti-inflammation and immunoregulation.

Sci Rep 2021 Feb 11;11(1):3593. Epub 2021 Feb 11.

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.

Multiple animal and human studies have shown that administration of GLP-1RA can enhance β-cell recovery, reduce insulin dosage, reduce HbA1c content in the blood, reduce the risk of hypoglycemia and reduce inflammation. In the NOD mouse model, peptide VP treatment can prevent and treat type 1 diabetes through immunomodulation. Therefore, we designed a new dual-functional PGLP-1-VP, which is expected to combine the anti-inflammatory effect of PGLP-1 and the immunomodulatory effect of VP peptide. Read More

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February 2021

Using a Reporter Mouse to Map Known and Novel Sites of GLP-1 Receptor Expression in Peripheral Tissues of Male Mice.

Endocrinology 2021 Mar;162(3)

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Panum Institute, Copenhagen, Denmark.

Glucagon-like peptide-1 receptor (GLP-1R) activation is used in the treatment of diabetes and obesity; however, GLP-1 induces many other physiological effects with unclear mechanisms of action. To identify the cellular targets of GLP-1 and GLP-1 analogues, we generated a Glp1r.tdTomato reporter mouse expressing the reporter protein, tdTomato, in Glp1r-expressing cells. Read More

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Glucagon-like peptide-1 receptor is expressed in human and rodent testis.

Andrology 2020 11 11;8(6):1935-1945. Epub 2020 Aug 11.

Department of Experimental and Clinical Medicine, University of Catania, Catania, Italy.

Background: The incretin hormone glucagon-like peptide-l (GLP-1) is an important regulator of post-prandial insulin secretion, acting through a G protein-coupled cell surface receptor (GLP-1R). In addition to its expression in pancreatic β-cells, several studies suggested that GLP-1R is located in extra-pancreatic tissues.

Objectives: In this study, we examined for the first time the testicular distribution of the GLP-1R, both in normal human and neoplastic testicular tissues as well as in rodent testis and rodent testicular cell lines. Read More

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November 2020

Design and Evaluation of Peptide Dual-Agonists of GLP-1 and NPY2 Receptors for Glucoregulation and Weight Loss with Mitigated Nausea and Emesis.

J Med Chem 2021 01 15;64(2):1127-1138. Epub 2021 Jan 15.

Department of Chemistry, Syracuse University, 111 College Place, Syracuse, New York 13244, United States.

There is a critical unmet need for therapeutics to treat the epidemic of comorbidities associated with obesity and type 2 diabetes, ideally devoid of nausea/emesis. This study developed monomeric peptide agonists of glucagon-like peptide 1 receptor (GLP-1R) and neuropeptide Y2 receptor (Y2-R) based on exendin-4 (Ex-4) and PYY. A novel peptide, GEP44, was obtained via receptor screens, insulin secretion in islets, stability assays, and rat and shrew studies of glucoregulation, weight loss, nausea, and emesis. Read More

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January 2021

Antagonizing somatostatin receptor subtype 2 and 5 reduces blood glucose in a gut- and GLP-1R-dependent manner.

JCI Insight 2021 Feb 22;6(4). Epub 2021 Feb 22.

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Somatostatin (SS) inhibits glucagon-like peptide-1 (GLP-1) secretion in a paracrine manner. We hypothesized that blocking somatostatin subtype receptor 2 (SSTR2) and 5 (SSTR5) would improve glycemia by enhancing GLP-1 secretion. In the perfused mouse small intestine, the selective SSTR5 antagonist (SSTR5a) stimulated glucose-induced GLP-1 secretion to a larger degree than the SSTR2 antagonist (SSTR2a). Read More

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February 2021

ι-Carrageenan Tetrasaccharide from ι-Carrageenan Inhibits Islet β Cell Apoptosis Via the Upregulation of GLP-1 to Inhibit the Mitochondrial Apoptosis Pathway.

J Agric Food Chem 2021 Jan 22;69(1):212-222. Epub 2020 Dec 22.

College of Food Science and Engineering, Ocean University of China, Qingdao 266003, China.

ι-Carrageenan performs diversified biological activities but has low bioavailability. ι-Carrageenan tetrasaccharide (ιCTs), a novel marine oligosaccharide prepared by the marine enzyme , was investigated for its effects on insulin resistance in high-fat and high-sucrose diet mice. Oral administration of ιCTs (ιCTs-L 30. Read More

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January 2021

Novel peptidic dual GLP-1/glucagon receptor agonist alleviates diabetes and diabetic complications in combination with low-intensity ultrasound.

Eur Rev Med Pharmacol Sci 2020 12;24(23):12423-12436

The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang Province, China.

Objective: To design and evaluate a novel oxyntomodulin (OXM) derivative with albumin-binding helix domain and dual GLP-1 receptor (GLP-1R) and glucagon receptor (GcgR) activation activity to achieve metabolize improvement on the diabetes-related complication.

Materials And Methods: Mutation (D-Ser2) on OXM was performed and then different helix albumin-binding domains were fused to the mutated OXM via a thrombin-cleavable linker to generate seven fusion peptides, named LM01-LM07. Seven LM peptides were synthesized and screened via in vitro receptor activation test, albumin binding measurement and protease cleavage assay to select potent candidate peptide for further in vivo study. Read More

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December 2020

Revisiting the Complexity of GLP-1 Action from Sites of Synthesis to Receptor Activation.

Endocr Rev 2021 Mar;42(2):101-132

Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Ontario, Canada.

Glucagon-like peptide-1 (GLP-1) is produced in gut endocrine cells and in the brain, and acts through hormonal and neural pathways to regulate islet function, satiety, and gut motility, supporting development of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes and obesity. Classic notions of GLP-1 acting as a meal-stimulated hormone from the distal gut are challenged by data supporting production of GLP-1 in the endocrine pancreas, and by the importance of brain-derived GLP-1 in the control of neural activity. Moreover, attribution of direct vs indirect actions of GLP-1 is difficult, as many tissue and cellular targets of GLP-1 action do not exhibit robust or detectable GLP-1R expression. Read More

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Ileal interposition improves metabolic syndrome parameters in a rat model of metabolic syndrome induced by monosodium glutamate.

Life Sci 2021 Feb 9;266:118846. Epub 2020 Dec 9.

Pamukkale University Medical Faculty Department of Physiology, Denizli 20160, Turkey. Electronic address:

Aims: Metabolic syndrome (MetS) is a cluster of metabolic abnormalities. Anatomically restructuring of the gastrointestinal system has recently been an important subject of research in the treatment of MetS and closely related diseases. The aim of this study is to ensure the remission of parameters that define MetS by ileal interposition (IT) and to examine the effect of IT on plasma total GLP-1 and pancreatic GLP-1R expression. Read More

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February 2021

Identification of N-Terminally Diversified GLP-1R Agonists Using Saturation Mutagenesis and Chemical Design.

ACS Chem Biol 2021 01 14;16(1):58-66. Epub 2020 Dec 14.

Department of Bioengineering, Stanford University, Shriram Center, 443 Via Ortega, Stanford, California 94305, United States.

The glucagon-like peptide 1 receptor (GLP-1R) is a class B G-protein coupled receptor (GPCR) and diabetes drug target expressed mainly in pancreatic β-cells that, when activated by its agonist glucagon-like peptide 1 (GLP-1) after a meal, stimulates insulin secretion and β-cell survival and proliferation. The N-terminal region of GLP-1 interacts with membrane-proximal residues of GLP-1R, stabilizing its active conformation to trigger intracellular signaling. The best-studied agonist peptides, GLP-1 and exendin-4, share sequence homology at their N-terminal region; however, modifications that can be tolerated here are not fully understood. Read More

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January 2021

Role of PET/CT and Therapy Management of Pancreatic Neuroendocrine Tumors.

Diagnostics (Basel) 2020 Dec 7;10(12). Epub 2020 Dec 7.

Department of Nuclear Medicine, IRCCS Azienda Ospedaliera-Universitaria di Bologna, 40138 Bologna, Italy.

Pancreatic neuroendocrine neoplasms (panNENs) are heterogeneous neoplasms with neuroendocrine differentiation that show peculiar clinical and histomorphological features, with variable prognosis. In recent years, advances in knowledge regarding the pathophysiology and heterogeneous clinical presentation, as well as the availability of different diagnostic procedures for panNEN diagnosis and novel therapeutic options for patient clinical management, has led to the recognition of the need for an active multidisciplinary discussion for optimal patient care. Molecular imaging with positron emission tomography/computed tomography (PET/CT) has become indispensable for the management of panNENs. Read More

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December 2020

Ligand-Specific Factors Influencing GLP-1 Receptor Post-Endocytic Trafficking and Degradation in Pancreatic Beta Cells.

Int J Mol Sci 2020 Nov 9;21(21). Epub 2020 Nov 9.

Section of Endocrinology and Investigative Medicine, Imperial College London, London W12 0NN, UK.

The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of blood glucose homeostasis. Ligand-specific differences in membrane trafficking of the GLP-1R influence its signalling properties and therapeutic potential in type 2 diabetes. Here, we have evaluated how different factors combine to control the post-endocytic trafficking of GLP-1R to recycling versus degradative pathways. Read More

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November 2020

Pancreatic GLP-1r binding potential is reduced in insulin-resistant pigs.

BMJ Open Diabetes Res Care 2020 11;8(2)

Center of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, South Australia, Australia.

Introduction: The insulinotropic capacity of exogenous glucagon like peptide-1 (GLP-1) is reduced in type 2 diabetes and the insulin-resistant obese. We have tested the hypothesis that this response is the consequence of a reduced pancreatic GLP-1 receptor (GLP-1r) density in insulin-resistant obese animals.

Research Design And Methods: GLP-1r density was measured in lean and insulin-resistant adult miniature pigs after the administration of a Ga-labeled GLP-1r agonist. Read More

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November 2020

Stapled and Glucagon-Like Peptide 1 (GLP-1)-Based Dual GLP-1/Gastrin Receptor Agonists with Improved Metabolic Benefits in Rodent Models of Obesity and Diabetes.

J Med Chem 2020 11 30;63(21):12595-12613. Epub 2020 Oct 30.

School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou 221116, PR China.

Diabetes is characterized by pancreas dysfunction and is commonly associated with obesity. Hypoglycemic agents capable of improving β-cell function and reducing body weight therefore are gaining increasing interest. Though glucagon-like peptide 1 receptor (GLP-1R)/cholecystokinin 2 receptor (CCK-2R) dual agonist ZP3022 potently increases β-cell mass and improves glycemic control in diabetic db/db mice, the in vivo half-life () is short, and its body weight reducing activity is limited. Read More

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November 2020

Optoacoustic imaging of Glucagon-like Peptide 1 Receptor with a near-infrared exendin-4 analog.

J Nucl Med 2020 Oct 23. Epub 2020 Oct 23.

Memorial Sloan Kettering Cancer Center, United States.

Limitations in current imaging tools have long challenged the imaging of small pancreatic islets in animal models. Here, we report the first development and in vivo validation testing of a broad spectrum and high absorbance near infrared optoacoustic contrast agent, E4-Cy7. Our near infrared tracer (E4-Cy7) is based on the amino acid sequence of exendin-4 and targets the glucagon-like peptide-1 receptor (GLP-1R). Read More

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October 2020

Indirectly radioiodinated exendin-4 as an analytical tool for in vivo detection of glucagon-like peptide-1 receptor in a disease setting.

Ann Nucl Med 2021 Jan 16;35(1):83-91. Epub 2020 Oct 16.

Department of Biofunctional Analysis, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan.

Objective: Glucagon-like peptide-1 receptor agonist (GLP-1RA) has been reported to have therapeutic effects on diabetes and various diseases. Precise detection of GLP-1 receptor (GLP-1R) can be useful to diagnose and elucidate the mechanism of such diseases. Here we aimed to develop an imaging probe based on GLP-1RA that has high molar activity and sensitivity for detection of low-level GLP-1R expression in non-pancreatic diseases. Read More

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January 2021

Receptor occupancy of dual glucagon-like peptide 1/glucagon receptor agonist SAR425899 in individuals with type 2 diabetes.

Sci Rep 2020 10 7;10(1):16758. Epub 2020 Oct 7.

Translational Medicine, Sanofi, Frankfurt, Germany.

Unimolecular dual agonists for the glucagon-like peptide 1 receptor (GLP1R) and glucagon receptor (GCGR) are emerging as a potential new class of important therapeutics in type 2 diabetes (T2D). Reliable and quantitative assessments of in vivo occupancy on each receptor would improve the understanding of the efficacy of this class of drugs. In this study we investigated the target occupancy of the dual agonist SAR425899 at the GLP1R in pancreas and GCGR in liver by Positron Emission Tomography/Computed Tomography (PET/CT). Read More

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October 2020

Effect of dulaglutide on liver fat in patients with type 2 diabetes and NAFLD: randomised controlled trial (D-LIFT trial).

Diabetologia 2020 11 31;63(11):2434-2445. Epub 2020 Aug 31.

Division of Endocrinology and Diabetes, Medanta-The Medicity Hospital, Haryana, India.

Aims/hypothesis: Liraglutide, a daily injectable glucagon-like peptide-1 receptor (GLP-1r) agonist, has been shown to reduce liver fat content (LFC) in humans. Data regarding the effect of dulaglutide, a once-weekly GLP-1r agonist, on human LFC are scarce. This study examined the effect of dulaglutide on LFC in individuals with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Read More

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November 2020

Noninvasive Monitoring of Glycemia-Induced Regulation of GLP-1R Expression in Murine and Human Islets of Langerhans.

Diabetes 2020 11 25;69(11):2246-2252. Epub 2020 Aug 25.

Department of Radiology and Nuclear Medicine, Radboudumc, Nijmegen, the Netherlands.

Glucagon-like peptide 1 receptor (GLP-1R) imaging with radiolabeled exendin has proven to be a powerful tool to quantify β-cell mass (BCM) in vivo. As GLP-1R expression is thought to be influenced by glycemic control, we examined the effect of blood glucose (BG) levels on GLP-1R-mediated exendin uptake in both murine and human islets and its implications for BCM quantification. Periods of hyperglycemia significantly reduced exendin uptake in murine and human islets, which was paralleled by a reduction in GLP-1R expression. Read More

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November 2020

Glucagon-like peptide-1 receptor mediates the beneficial effect of liraglutide in an acute lung injury mouse model involving the thioredoxin-interacting protein.

Am J Physiol Endocrinol Metab 2020 09 29;319(3):E568-E578. Epub 2020 Jul 29.

Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.

Repurposing clinically used drugs is among the important strategies in drug discovery. Glucagon-like peptide-1 (GLP-1) and its diabetes-based drugs, such as liraglutide, possess a spectrum of extra-pancreatic functions, while GLP-1 receptor (GLP-1R) is most abundantly expressed in the lung. Recent studies have suggested that GLP-1-based drugs exert beneficial effects in chronic, as well as acute, lung injury rodent models. Read More

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September 2020

Discordance between GLP-1R gene and protein expression in mouse pancreatic islet cells.

J Biol Chem 2020 08 18;295(33):11529-11541. Epub 2020 Jun 18.

Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA

The insulinotropic actions of glucagon-like peptide 1 receptor (GLP-1R) in β-cells have made it a useful target to manage type 2 diabetes. Metabolic stress reduces β-cell sensitivity to GLP-1, yet the underlying mechanisms are unknown. We hypothesized that expression is heterogeneous among β-cells and that metabolic stress decreases the number of GLP-1R-positive β-cells. Read More

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GABA requires GLP-1R to exert its pancreatic function during STZ challenge.

J Endocrinol 2020 09;246(3):207-222

Divsion of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada.

Gamma-aminobutyric acid (GABA) administration attenuates streptozotocin (STZ)-induced diabetes in rodent models with unclear underlying mechanisms. We found that GABA and Sitagliptin possess additive effect on pancreatic β-cells, which prompted us to ask the existence of common or unique targets of GLP-1 and GABA in pancreatic β-cells. Effect of GABA on expression of thioredoxin-interacting protein (TxNIP) was assessed in the INS-1 832/13 (INS-1) cell line, WT and GLP-1R-/- mouse islets. Read More

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September 2020

Microwell-based pancreas-on-chip model enhances genes expression and functionality of rat islets of Langerhans.

Mol Cell Endocrinol 2020 08 9;514:110892. Epub 2020 Jun 9.

Université de technologie de Compiègne, CNRS, Biomechanics and Bioengineering, Centre de recherche Royallieu, CS 60319, 60203, Compiègne Cedex, France; CNRS UMI 2820, Laboratory for Integrated Micro Mechatronic Systems, Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8505, Japan. Electronic address:

Organ-on-chip technology is a promising tool for investigating physiological in vitro responses in drug screening development, and in advanced disease models. Within this framework, we investigated the behavior of rat islets of Langerhans in an organ-on-chip model. The islets were trapped by sedimentation in a biochip with a microstructure based on microwells, and perfused for 5 days of culture. Read More

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Everestmab, a novel long-acting GLP-1/anti GLP-1R nanobody fusion protein, exerts potent anti-diabetic effects.

Artif Cells Nanomed Biotechnol 2020 Dec;48(1):854-866

Department of Laboratory Medicine, Tongji Hospital of Tongji University, Shanghai, P. R. China.

In the present study, a novel single domain antibody (sdAb) fusion protein, named everestmab, composing of a mutated GLP-1(A8G) fused to the tandem bispecific humanized GLP-1R-targeting and albumin-binding nanobodies was designed and characterized for the therapies for type 2 diabetes mellitus (T2DM). Surface plasmon resonance (SPR) measurements demonstrated everestmab associates with serum albumins of rat and monkey species with high affinity, and tends to be cross-reactive with rat and monkey species. GLP-1R binding and activation assays revealed that everestmab can specifically activate the GLP-1R, and the antagonist exendin-4 (9-39) did not inhibit the activation yet. Read More

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December 2020

Alterations in pancreatic islet cell function in response to small bowel resection.

Am J Physiol Gastrointest Liver Physiol 2020 07 28;319(1):G36-G42. Epub 2020 May 28.

Division of Pediatric Surgery, Department of Surgery, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, Missouri.

After 50% proximal small bowel resection (SBR) in mice, we have demonstrated hepatic steatosis, impaired glucose metabolism without insulin resistance, and increased pancreatic islet area. We sought to determine the consequences of SBR on pancreatic β-cell morphology, proliferation, and expression of a key regulatory hormone, glucagon-like peptide-1 (GLP-1). C57BL/6 mice underwent 50% SBR or sham operation. Read More

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