150 results match your criteria glp-1r islets


Synthesis, Optimization, and Biological Evaluation of Corrinated Conjugates of the GLP-1R Agonist Exendin-4.

J Med Chem 2021 Mar 6;64(6):3479-3492. Epub 2021 Mar 6.

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

Corrination is the conjugation of a corrin ring containing molecule, such as vitamin B (B12) or B12 biosynthetic precursor dicyanocobinamide (Cbi), to small molecules, peptides, or proteins with the goal of modifying pharmacology. Recently, a corrinated GLP-1R agonist (GLP-1RA) exendin-4 (Ex4) has been shown to have reduced penetration into the central nervous system relative to Ex4 alone, producing a glucoregulatory GLP-1RA devoid of anorexia and emesis. The study herein was designed to optimize the lead conjugate for GLP-1R agonism and binding. 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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FXR-mediated epigenetic regulation of GLP-1R expression contributes to enhanced incretin effect in diabetes after RYGB.

J Cell Mol Med 2021 Feb 21. Epub 2021 Feb 21.

Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, Shenzhen, China.

In this study, we investigated how Roux-en-Y gastric bypass (RYGB) enhances glucagon-like peptide 1 (GLP-1) response in GK rats and explored the potential link between RYGB-stimulated BAs/FXR signalling and GLP-1R-linked signalling in β-cells, a key pathway that regulates glucose-stimulated insulin secretion (GSIS). Here we show that RYGB restores GLP-1R expression in GK rat islets. This involves increased total BAs as well as chenodeoxycholic acid (CDCA), leading to FXR activation, increasing FXR binding to the promoter of Glp-1r and enhancing occupancy of histone acetyltransferase steroid receptor coactivator-1 (SRC1), thus increasing histone H3 acetylation at the promoter. Read More

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February 2021

GLP-1 receptor signaling increases PCSK1 and β cell features in human α cells.

JCI Insight 2021 Feb 8;6(3). Epub 2021 Feb 8.

Department of Biomedical Sciences and.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that potentiates glucose-stimulated insulin secretion. GLP-1 is classically produced by gut L cells; however, under certain circumstances α cells can express the prohormone convertase required for proglucagon processing to GLP-1, prohormone convertase 1/3 (PC1/3), and can produce GLP-1. However, the mechanisms through which this occurs are poorly defined. Read More

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February 2021

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

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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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

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

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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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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Human islets contain a subpopulation of glucagon-like peptide-1 secreting α cells that is increased in type 2 diabetes.

Mol Metab 2020 09 12;39:101014. Epub 2020 May 12.

Alberta Diabetes Institute and the Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Canada. Electronic address:

Objectives: Our study shows that glucagon-like peptide-1 (GLP-1) is secreted within human islets and may play an unexpectedly important paracrine role in islet physiology and pathophysiology. It is known that α cells within rodent and human pancreatic islets are capable of secreting GLP-1, but little is known about the functional role that islet-derived GLP-1 plays in human islets.

Methods: We used flow cytometry, immunohistochemistry, perifusions, and calcium imaging techniques to analyse GLP-1 expression and function in islets isolated from cadaveric human donors with or without type 2 diabetes. Read More

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September 2020

Synthesis and evaluation of F-PTTCO-Cys-Exendin-4 for PET imaging of ectopic insulinomas in rodents.

Bioorg Chem 2020 05 5;98:103718. Epub 2020 Mar 5.

Department of Translational Research and Cellular Therapeutics, Beckman Research Institute of City of Hope, Duarte, USA.

A major limitation in the development of radiolabeled Exendin-4 analogues (short half-life isotopes) is an inability to efficiently and rapidly separate final products from precursors. This is important as lack of purity in the final product decreases probe efficiency. The purpose of this study was to develop a method to prepare the high-purity imaging reagent [F] PTTCO-Cys-Exendin-4. Read More

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Chikusetsu saponin IVa protects pancreatic β cell against intermittent high glucose-induced injury by activating Wnt/β-catenin/TCF7L2 pathway.

Aging (Albany NY) 2020 01 22;12(2):1591-1609. Epub 2020 Jan 22.

Department of Chinese Medicine, School of Life Science, Northwestern University, Xi'an 710032, Shaanxi, China.

Islet β cell mass reduction induced by glucose fluctuation is crucial for the development and progression of T2DM. Chikusetsu saponin IVa (CHS) had protective effects against DM and related injuries. Here we aimed to investigate the role of CHS in β cell injuries and its possible mechanism involved. Read More

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January 2020

Targeted Optical Imaging of the Glucagonlike Peptide 1 Receptor Using Exendin-4-IRDye 800CW.

J Nucl Med 2020 07 10;61(7):1066-1071. Epub 2020 Jan 10.

Department of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.

The treatment of choice for insulinomas and focal lesions in congenital hyperinsulinism (CHI) is surgery. However, intraoperative detection can be challenging. This challenge could be overcome with intraoperative fluorescence imaging, which provides real-time lesion detection with a high spatial resolution. Read More

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Liraglutide ameliorates palmitate-induced oxidative injury in islet microvascular endothelial cells through GLP-1 receptor/PKA and GTPCH1/eNOS signaling pathways.

Peptides 2020 02 23;124:170212. Epub 2019 Nov 23.

Department of Endocrinology and Metabolism, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China. Electronic address:

In type 2 diabetes, lipotoxicity damages islet microvascular endothelial cells (IMECs), leading to pancreatic islet β cell dysfunction directly or indirectly. Glucagon-like peptide-1 (GLP-1) and its analogs have beneficial roles in endothelial cells. However, the protective effects of GLP-1 agents on IMECs and their potential mechanism remained obscure. Read More

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February 2020

PAHSAs attenuate immune responses and promote β cell survival in autoimmune diabetic mice.

J Clin Invest 2019 08 5;129(9):3717-3731. Epub 2019 Aug 5.

Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.

Palmitic acid esters of hydroxy stearic acids (PAHSAs) are endogenous antidiabetic and antiinflammatory lipids. Here, we show that PAHSAs protect against type 1 diabetes (T1D) and promote β cell survival and function. Daily oral PAHSA administration to nonobese diabetic (NOD) mice delayed the onset of T1D and markedly reduced the incidence of T1D, whether PAHSAs were started before or after insulitis was established. Read More

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Glucose, adrenaline and palmitate antagonistically regulate insulin and glucagon secretion in human pseudoislets.

Sci Rep 2019 07 16;9(1):10261. Epub 2019 Jul 16.

German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.

Isolated human islets do not always meet the quality standards required for transplant survival and reliable functional in vitro studies. The formation of pseudoislets, i.e. Read More

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Targeting Islets: Metabolic Surgery Is More than a Bariatric Surgery.

Obes Surg 2019 09;29(9):3001-3009

Department of Metabolism and Endocrinology, The Second Xiangya Hospital and Diabetes Center, Institute of Metabolism and Endocrinology and National Clinical Research Center for Metabolic Diseases, Central South University, Changsha, 410011, Hunan, China.

Metabolic surgery is an effective therapy for diabetic patients with obesity. The main mechanisms underlying the effects of metabolic surgery include food intake restriction and the accompanying reduced daily caloric intake and changes in gut hormones and bile acid. Insulin resistance and impaired β-cell function contribute to the development of type 2 diabetes. Read More

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September 2019

Nonconventional glucagon and GLP-1 receptor agonist and antagonist interplay at the GLP-1 receptor revealed in high-throughput FRET assays for cAMP.

J Biol Chem 2019 03 8;294(10):3514-3531. Epub 2019 Jan 8.

From the Departments of Medicine,

G protein-coupled receptors (GPCRs) for glucagon (GluR) and glucagon-like peptide-1 (GLP-1R) are normally considered to be highly selective for glucagon and GLP-1, respectively. However, glucagon secreted from pancreatic α-cells may accumulate at high concentrations to exert promiscuous effects at the β-cell GLP-1R, as may occur in the volume-restricted microenvironment of the islets of Langerhans. Furthermore, systemic administration of GluR or GLP-1R agonists and antagonists at high doses may lead to off-target effects at other receptors. Read More

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Evaluating the utility of human glucagon-like peptide 1 receptor gene as a novel radionuclide reporter gene: a promising molecular imaging tool.

Appl Microbiol Biotechnol 2019 Feb 18;103(3):1311-1324. Epub 2018 Dec 18.

Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 200025, People's Republic of China.

Radiolabelled ligands of glucagon-like peptide 1 receptor (GLP-1R) have been used to image the GLP-1R-expressing tissues (e.g., islets and insulinoma). Read More

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February 2019

GLP-1 Receptor in Pancreatic α-Cells Regulates Glucagon Secretion in a Glucose-Dependent Bidirectional Manner.

Diabetes 2019 01 2;68(1):34-44. Epub 2018 Nov 2.

Section of Endocrinology, Department of Medicine, Tulane University Health Science Center, New Orleans, LA

Glucagon-like peptide 1 (GLP-1) is known to suppress glucagon secretion, but the mechanism by which GLP-1 exerts this effect is unclear. In this study, we demonstrated GLP-1 receptor (GLP-1R) expression in α-cells using both antibody-dependent and antibody-independent strategies. A novel α-cell-specific GLP-1R knockout (αGLP-1R) mouse model was created and used to investigate its effects on glucagon secretion and glucose metabolism. Read More

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January 2019

Insulin Secretion Depends on Intra-islet Glucagon Signaling.

Cell Rep 2018 10;25(5):1127-1134.e2

NovoNordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

The intra-islet theory states that glucagon secretion is suppressed when insulin secretion is stimulated, but glucagon's role in intra-islet paracrine regulation is controversial. This study investigated intra-islet functions of glucagon in mice. We examined glucagon-induced insulin secretion using isolated perfused pancreata from wild-type, GLP-1 receptor (GLP-1R) knockout, diphtheria toxin-induced proglucagon knockdown, β cell-specific glucagon receptor (Gcgr) knockout, and global Gcgr knockout (Gcgr) mice. Read More

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October 2018

GLP-1 suppresses glucagon secretion in human pancreatic alpha-cells by inhibition of P/Q-type Ca channels.

Physiol Rep 2018 09;6(17):e13852

Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.

Glucagon is the body's main hyperglycemic hormone, and its secretion is dysregulated in type 2 diabetes mellitus (T2DM). The incretin hormone glucagon-like peptide-1 (GLP-1) is released from the gut and is used in T2DM therapy. Uniquely, it both stimulates insulin and inhibits glucagon secretion and thereby lowers plasma glucose levels. Read More

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September 2018

Neprilysin inhibition in mouse islets enhances insulin secretion in a GLP-1 receptor dependent manner.

Islets 2018 24;10(5):175-180. Epub 2018 Aug 24.

a Veterans Affairs Puget Sound Health Care System , Seattle , WA , USA.

Neprilysin, a widely expressed peptidase upregulated in type 2 diabetes, is capable of cleaving and inactivating the insulinotropic glucagon-like peptide-1 (GLP-1). Like dipeptidyl peptidase-4 (DPP-4), inhibition of neprilysin activity under diabetic conditions is associated with increased active GLP-1 levels and improved glycemic control. While neprilysin expression has been demonstrated in islets, its local contribution to GLP-1-mediated insulin secretion remains unknown. Read More

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The Ascending GLP-1 Road From Clinical Safety to Reduction of Cardiovascular Complications.

Authors:
Daniel J Drucker

Diabetes 2018 09;67(9):1710-1719

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

Glucagon-like peptide 1 (GLP-1) was originally identified as a gut-derived incretin hormone that lowered glycemia through potentiation of glucose-dependent insulin secretion. Subsequent studies expanded the actions of GLP-1 to include inhibition of glucagon secretion, gastric emptying, and appetite, collectively useful attributes for a glucose-lowering agent. The introduction of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes was associated with questions surrounding their safety, principally with regard to medullary thyroid cancer, pancreatitis, and pancreatic cancer, yet cardiovascular outcome trials subsequently revealed reductions in rates of stroke, myocardial infarction, and cardiovascular death with a paucity of major safety signals. Read More

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September 2018

An incretin-based tri-agonist promotes superior insulin secretion from murine pancreatic islets via PLC activation.

Cell Signal 2018 11 25;51:13-22. Epub 2018 Jul 25.

Institute of Experimental Pediatric Endocrinology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Recently, a unimolecular tri-agonist with activity at glucagon-like peptide 1 receptor (GLP-1R), glucose dependent insulinotropic receptor, and the glucagon receptor was reported to improve glycemic control in mice. Here, we defined the underlying molecular mechanisms of enhanced insulin secretion in murine pancreatic islets for a specific tri-agonist. The tri-agonist induced an increase in insulin secretion from murine islets compared to the respective mono-agonists. Read More

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November 2018

Expression kinetics reveal the self-adaptive role of β cells during the progression of diabetes.

Biomed Pharmacother 2018 Oct 11;106:472-482. Epub 2018 Jul 11.

Department of Medicinal Chemistry, Institute of Medical Sciences, Banaras Hindu University, India. Electronic address:

Objective: To determine the histopathological and molecular changes in β-cells at different time intervals following streptozotocin (STZ)-induced diabetes.

Methods: STZ (65 mg/kg body weight) was given to overnight fasted rats that were sacrificed after 1, 3, and 10 days of injection. Changes in islet morphology and in the expression of various factors involved in β-cell proliferation, inflammation and apoptosis were analyzed. Read More

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October 2018

Enhanced Glucose Control Following Vertical Sleeve Gastrectomy Does Not Require a β-Cell Glucagon-Like Peptide 1 Receptor.

Diabetes 2018 08 14;67(8):1504-1511. Epub 2018 May 14.

Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC.

Bariatric surgeries, including vertical sleeve gastrectomy (VSG), resolve diabetes in 40-50% of patients. Studies examining the molecular mechanisms underlying this effect have centered on the role of the insulinotropic glucagon-like peptide 1 (GLP-1), in great part because of the ∼10-fold rise in its circulating levels after surgery. However, there is currently debate over the role of direct β-cell signaling by GLP-1 to mediate improved glucose tolerance following surgery. Read More

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The LIM homeodomain protein ISL1 mediates the function of TCF7L2 in pancreatic beta cells.

J Mol Endocrinol 2018 07 20;61(1):1-12. Epub 2018 Apr 20.

Division of Advanced DiagnosticsToronto General Research Institute, University Health Network, Toronto, Ontario, Canada

Pancreatic β-cell deletion or its functional knockdown suggested the essential role of this Wnt pathway effector in controlling insulin secretion, glucose homeostasis and β-cell gene expression. As the LIM homeodomain protein ISL1 is a suggested Wnt pathway downstream target, we hypothesize that it mediates metabolic functions of TCF7L2. We aimed to determine the role of ISL1 in mediating the function of TCF7L2 and the incretin hormone GLP-1 in pancreatic β-cells. Read More

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