Publications
164 results found
Shilleh AH, Viloria K, Broichhagen J, et al., 2024, GLP1R and GIPR expression and signaling in pancreatic alpha cells, beta cells and delta cells, Peptides, Vol: 175, Pages: 171179-171179, ISSN: 0196-9781
Peercy BE, Hodson DJ, 2024, Synchronizing beta cells in the pancreas., Elife, Vol: 13
The secretion of insulin from the pancreas relies on both gap junctions and subpopulations of beta cells with specific intrinsic properties.
Rueckert A-K, Ast J, Hasib A, et al., 2023, Fine-tuned photochromic sulfonylureas for optical control of beta cell Ca<SUP>2+</SUP> fluxes, DIABETIC MEDICINE, ISSN: 0742-3071
Xu W, Qadir MMF, Nasteska D, et al., 2023, Architecture of androgen receptor pathways amplifying glucagon-like peptide-1 insulinotropic action in male pancreatic β cells, Cell Reports, Vol: 42, Pages: 1-29, ISSN: 2211-1247
Male mice lacking the androgen receptor (AR) in pancreatic β cells exhibit blunted glucose-stimulated insulin secretion (GSIS), leading to hyperglycemia. Testosterone activates an extranuclear AR in β cells to amplify glucagon-like peptide-1 (GLP-1) insulinotropic action. Here, we examined the architecture of AR targets that regulate GLP-1 insulinotropic action in male β cells. Testosterone cooperates with GLP-1 to enhance cAMP production at the plasma membrane and endosomes via: (1) increased mitochondrial production of CO2, activating the HCO3--sensitive soluble adenylate cyclase; and (2) increased Gαs recruitment to GLP-1 receptor and AR complexes, activating transmembrane adenylate cyclase. Additionally, testosterone enhances GSIS in human islets via a focal adhesion kinase/SRC/phosphatidylinositol 3-kinase/mammalian target of rapamycin complex 2 actin remodeling cascade. We describe the testosterone-stimulated AR interactome, transcriptome, proteome, and metabolome that contribute to these effects. This study identifies AR genomic and non-genomic actions that enhance GLP-1-stimulated insulin exocytosis in male β cells.
Adriaenssens A, Broichhagen J, de Bray A, et al., 2023, Hypothalamic and brainstem glucose- dependent insulinotropic polypeptide receptor neurons employ distinct mechanisms to affect feeding, JCI INSIGHT, Vol: 8
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- Citations: 1
Mendive-Tapia L, Miret-Casals L, Barth ND, et al., 2023, Acid-Resistant BODIPY Amino Acids for Peptide-Based Fluorescence Imaging of GPR54 Receptors in Pancreatic Islets, ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, Vol: 62, ISSN: 1433-7851
Pezhman L, Hopkin SJ, Begum J, et al., 2023, PEPITEM modulates leukocyte trafficking to reduce obesity-induced inflammation, CLINICAL AND EXPERIMENTAL IMMUNOLOGY, Vol: 212, Pages: 1-10, ISSN: 0009-9104
Romano N, Lafont C, Campos P, et al., 2023, Median eminence blood flow influences food intake by regulating ghrelin access to the metabolic brain, JCI INSIGHT, Vol: 8
Viloria K, Nasteska D, Ast J, et al., 2023, GC-Globulin/Vitamin D-Binding Protein Is Required for Pancreatic α-Cell Adaptation to Metabolic Stress, DIABETES, Vol: 72, Pages: 275-289, ISSN: 0012-1797
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- Citations: 1
Ast J, Nasteska D, Fine NHF, et al., 2023, Revealing the tissue-level complexity of endogenous glucagon-like peptide-1 receptor expression and signaling, NATURE COMMUNICATIONS, Vol: 14
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- Citations: 1
Trumpp M, Oliveras A, Gonschior H, et al., 2022, Enzyme self-label-bound ATTO700 in single-molecule and super-resolution microscopy, CHEMICAL COMMUNICATIONS, Vol: 58, Pages: 13724-13727, ISSN: 1359-7345
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- Citations: 2
Kravets V, Dwulet JM, Schleicher WE, et al., 2022, Functional architecture of pancreatic islets identifies a population of first responder cells that drive the first-phase calcium response, PLOS BIOLOGY, Vol: 20, ISSN: 1544-9173
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- Citations: 8
Birke R, Ast J, Roosen DA, et al., 2022, Sulfonated red and far-red rhodamines to visualize SNAP- and Halo-tagged cell surface proteins, ORGANIC & BIOMOLECULAR CHEMISTRY, Vol: 20, Pages: 5967-5980, ISSN: 1477-0520
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- Citations: 7
Cahil KN, Amin T, Boutaud O, et al., 2022, Glucagon-Like Peptide-1 Receptor Regulates Thromboxane-Induced Activation, JACC-BASIC TO TRANSLATIONAL SCIENCE, Vol: 7, Pages: 713-715, ISSN: 2452-302X
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- Citations: 7
Michau A, Lafont C, Bargi-Souza P, et al., 2022, Metabolic Stress Impairs Pericyte Response to Optogenetic Stimulation in Pancreatic Islets, FRONTIERS IN ENDOCRINOLOGY, Vol: 13, ISSN: 1664-2392
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- Citations: 2
Mugabo Y, Zhao C, Tan JJ, et al., 2022, 14-3-3σ Constrains insulin secretion by regulating mitochondrial function in pancreatic β cells, JCI INSIGHT, Vol: 7
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- Citations: 7
Allen SL, Seabright AP, Quinlan J, et al., 2022, The Effect of Ex Vivo Human Serum from Liver Disease Patients on Cellular Protein Synthesis and Growth, CELLS, Vol: 11
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- Citations: 3
Karsai M, Zuellig RA, Lehmann R, et al., 2022, Lack of ZnT8 protects pancreatic islets from hypoxia- and cytokine-induced cell death, JOURNAL OF ENDOCRINOLOGY, Vol: 253, Pages: 1-11, ISSN: 0022-0795
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- Citations: 5
Guerineau NC, Campos P, Le Tissier PR, et al., 2022, Cell Networks in Endocrine/Neuroendocrine Gland Function, COMPREHENSIVE PHYSIOLOGY, Vol: 12, Pages: 3371-3415, ISSN: 2040-4603
Pauza AG, Thakkar P, Tasic T, et al., 2022, GLP1R Attenuates Sympathetic Response to High Glucose via Carotid Body Inhibition, CIRCULATION RESEARCH, Vol: 130, Pages: 694-707, ISSN: 0009-7330
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- Citations: 23
Viloria K, Hewison M, Hodson DJ, 2022, Vitamin D binding protein/GC-globulin: a novel regulator of alpha cell function and glucagon secretion, JOURNAL OF PHYSIOLOGY-LONDON, Vol: 600, Pages: 1119-1133, ISSN: 0022-3751
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- Citations: 4
Westbrook RL, Bridges E, Roberts J, et al., 2022, Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions, CELL REPORTS, Vol: 38, ISSN: 2211-1247
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- Citations: 15
Hoang M, Jentz E, Janssen SM, et al., 2022, Isoform-specific Roles of Prolyl Hydroxylases in the Regulation of Pancreatic beta-Cell Function, ENDOCRINOLOGY, Vol: 163, ISSN: 0013-7227
Costa A, Ai M, Nunn N, et al., 2022, Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation, MOLECULAR METABOLISM, Vol: 55, ISSN: 2212-8778
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- Citations: 17
Ast J, Broichhagen J, Hodson DJ, 2021, Reagents and models for detecting endogenous GLP1R and GIPR, EBIOMEDICINE, Vol: 74, ISSN: 2352-3964
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- Citations: 9
Olaniru OE, Cheng J, Ast J, et al., 2021, SNAP-tag-enabled super-resolution imaging reveals constitutive and agonist-dependent trafficking of GPR56 in pancreatic -cells, MOLECULAR METABOLISM, Vol: 53, ISSN: 2212-8778
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- Citations: 4
Lucey M, Ashik T, Marzook A, et al., 2021, Acylation of the incretin peptide exendin-4 directly impacts GLP-1 receptor signalling and trafficking, Molecular Pharmacology, Vol: 100, Pages: 319-334, ISSN: 0026-895X
The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor and mainstay therapeutic target for the treatment of type 2 diabetes and obesity. Recent reports have highlighted how biased agonism at the GLP-1R affects sustained glucose-stimulated insulin secretion through avoidance of desensitisation and downregulation. A number of GLP-1R agonists (GLP-1RAs) feature a fatty acid moiety to prolong their pharmacokinetics via increased albumin binding, but the potential for these chemical changes to influence GLP-1R function has rarely been investigated beyond potency assessments for cyclic adenosine monophosphate (cAMP). Here we directly compare the prototypical GLP-1RA exendin-4 with its C-terminally acylated analogue, exendin-4-C16. We examine relative propensities of each ligand to recruit and activate G proteins and β-arrestins, endocytic and post-endocytic trafficking profiles, and interactions with model and cellular membranes in HEK293 and HEK293T cells. Both ligands had similar cAMP potency but exendin-4-C16 showed ~2.5-fold bias towards G protein recruitment and a ~60% reduction in β-arrestin-2 recruitment efficacy compared to exendin-4, as well as reduced GLP-1R endocytosis and preferential targeting towards recycling pathways. These effects were associated with reduced movement of the GLP-1R extracellular domain measured using a conformational biosensor approach, and a ~70% increase in insulin secretion in INS-1 832/3 cells. Interactions with plasma membrane lipids were enhanced by the acyl chain. Exendin-4-C16 showed extensive albumin binding and was highly effective for lowering of blood glucose in mice over at least 72 hours. Our study highlights the importance of a broad approach to the evaluation of GLP-1RA pharmacology.
Cartwright DM, Oakey LA, Fletcher RS, et al., 2021, Nicotinamide riboside has minimal impact on energy metabolism in mouse models of mild obesity, JOURNAL OF ENDOCRINOLOGY, Vol: 251, Pages: 111-123, ISSN: 0022-0795
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- Citations: 10
Pickford P, Lucey M, Rujan R-M, et al., 2021, Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist, Molecular Metabolism, Vol: 51, ISSN: 2212-8778
OBJECTIVE: Glucagon-like peptide-1 and glucagon receptor (GLP-1R/GCGR) co-agonism can maximise weight loss and improve glycaemic control in type 2 diabetes and obesity. In this study we investigated the cellular and metabolic effects of modulating the balance between G protein and β-arrestin-2 recruitment at GLP-1R and GCGR using oxyntomodulin (OXM)-derived co-agonists. This strategy has been previously shown to improve the duration of action of GLP-1R mono-agonists by reducing target desensitisation and downregulation. METHODS: Dipeptidyl dipeptidase-4 (DPP-4)-resistant OXM analogues were generated and assessed for a variety of cellular readouts. Molecular dynamic simulations were used to gain insights into the molecular interactions involved. In vivo studies were performed in mice to identify effects on glucose homeostasis and weight loss. RESULTS: Ligand-specific reductions in β-arrestin-2 recruitment were associated with slower GLP-1R internalisation and prolonged glucose-lowering action in vivo. The putative benefits of GCGR agonism were retained, with equivalent weight loss compared to the GLP-1R mono-agonist liraglutide in spite of a lesser degree of food intake suppression. The compounds tested showed only a minor degree of biased agonism between G protein and β-arrestin-2 recruitment at both receptors and were best classified as partial agonists for the two pathways measured. CONCLUSIONS: Diminishing β-arrestin-2 recruitment may be an effective way to increase the therapeutic efficacy of GLP-1R/GCGR co-agonists. These benefits can be achieved by partial rather than biased agonism.
Nasteska D, Cuozzo F, Viloria K, et al., 2021, Prolyl-4-hydroxylase 3 maintains β cell glucose metabolism during fatty acid excess in mice, JCI INSIGHT, Vol: 6
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- Citations: 4
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