Imperial College London

DrDavidHodson

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Honorary Senior Lecturer (non-clinical)
 
 
 
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Contact

 

+44 (0)20 7594 1713d.hodson Website

 
 
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Location

 

329ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

110 results found

Trumpp M, Oliveras A, Gonschior H, Ast J, Hodson DJ, Knaus P, Lehmann M, Birol M, Broichhagen Jet al., 2022, Enzyme self-label-bound ATTO700 in single-molecule and super-resolution microscopy., Chem Commun (Camb)

Herein, we evaluate near-infrared ATTO700 as an acceptor in SNAP- and Halo-tag protein labelling for Förster Resonance Energy Transfer (FRET) by ensemble and single molecule measurements. Microscopy of cell surface proteins in live cells is perfomed including super-resolution stimulated emission by depletion (STED) nanoscopy.

Journal article

Allen SL, Seabright AP, Quinlan J, Dhaliwal A, Williams FR, Fine NHF, Hodson DJ, Armstrong MJ, Elsharkaway AM, Greig CA, Lai Y-C, Lord JM, Lavery GG, Breen Let al., 2022, The Effect of Ex Vivo Human Serum from Liver Disease Patients on Cellular Protein Synthesis and Growth, CELLS, Vol: 11

Journal article

Karsai M, Zuellig RA, Lehmann R, Cuozzo F, Nasteska D, Luca E, Hantel C, Hodson DJ, Spinas GA, Rutter GA, Gerber PAet 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

Journal article

Pauza AG, Thakkar P, Tasic T, Felippe I, Bishop P, Greenwood MP, Rysevaite-Kyguoliene K, Ast J, Broichhagen J, Hodson DJ, Salgado HC, Pauza DH, Japundzic-Zigon N, Paton JFR, Murphy Det al., 2022, GLP1R Attenuates Sympathetic Response to High Glucose via Carotid Body Inhibition, CIRCULATION RESEARCH, Vol: 130, Pages: 694-707, ISSN: 0009-7330

Journal article

Birke R, Ast J, Roosen DA, Lee J, Rossmann K, Huhn C, Mathes B, Lisurek M, Bushiri D, Sun H, Jones B, Lehmann M, Levitz J, Haucke V, Hodson DJ, Broichhagen Jet 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

Journal article

Westbrook RL, Bridges E, Roberts J, Escribano-Gonzalez C, Eales KL, Vettore LA, Walker PD, Vera-Siguenza E, Rana H, Cuozzo F, Eskla K-L, Vellama H, Shaaban A, Nixon C, Luuk H, Lavery GG, Hodson DJ, Harris AL, Tennant DAet al., 2022, Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions., Cell Rep, Vol: 38

The demands of cancer cell proliferation alongside an inadequate angiogenic response lead to insufficient oxygen availability in the tumor microenvironment. Within the mitochondria, oxygen is the major electron acceptor for NADH, with the result that the reducing potential produced through tricarboxylic acid (TCA) cycle activity and mitochondrial respiration are functionally linked. As the oxidizing activity of the TCA cycle is required for efficient synthesis of anabolic precursors, tumoral hypoxia could lead to a cessation of proliferation without another means of correcting the redox imbalance. We show that in hypoxic conditions, mitochondrial pyrroline 5-carboxylate reductase 1 (PYCR1) activity is increased, oxidizing NADH with the synthesis of proline as a by-product. We further show that PYCR1 activity is required for the successful maintenance of hypoxic regions by permitting continued TCA cycle activity, and that its loss leads to significantly increased hypoxia in vivo and in 3D culture, resulting in widespread cell death.

Journal article

Hoang M, Jentz E, Janssen SM, Nasteska D, Cuozzo F, Hodson DJ, Tupling AR, Fong G-H, Joseph JWet al., 2022, Isoform-specific Roles of Prolyl Hydroxylases in the Regulation of Pancreatic beta-Cell Function, ENDOCRINOLOGY, Vol: 163, ISSN: 0013-7227

Journal article

Costa A, Ai M, Nunn N, Culotta I, Hunter J, Boudjadja MB, Valencia-Torres L, Aviello G, Hodson DJ, Snider BM, Coskun T, Emmerson PJ, Luckman SM, D'Agostino Get al., 2021, 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

Journal article

Ast J, Broichhagen J, Hodson DJ, 2021, Reagents and models for detecting endogenous GLP1R and GIPR, EBIOMEDICINE, Vol: 74, ISSN: 2352-3964

Journal article

Pickford P, Lucey M, Rujan R-M, McGlone ER, Bitsi S, Ashford FB, Corrêa IR, Hodson DJ, Tomas A, Deganutti G, Reynolds CA, Owen BM, Tan TM, Minnion J, Jones B, Bloom SRet 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.

Journal article

Ast J, Novak AN, Podewin T, Fine NHF, Jones B, Tomas Catala A, Birke R, Roßmann K, Mathes B, Eichhorst J, Lehmann M, Linnemann AK, Hodson DJ, Broichhagen Jet al., 2021, An expanded LUXendin color palette for GLP1R detection and visualization in vitro and in vivo, Publisher: ChemRxiv

The glucagon-like peptide-1 receptor (GLP1R) is expressed in peripheral tissues and the brain, where it exerts pleiotropic actions on metabolic and inflammatory processes. Detection and visualization of GLP1R remains challenging, partly due to a lack of validated reagents. Previously, we generated LUXendins, antagonistic red and far-red fluorescent probes for specific labeling of GLP1R in live and fixed cells/tissue. We now extend this concept to the green and near-infrared color ranges by synthesizing and testing LUXendin492, LUXendin551, LUXendin615 and LUXendin762. All four probes brightly and specifically label GLP1R in cells and pancreatic islets. Further, LUXendin551 acts as chemical beta cell reporter in preclinical rodent models, while LUXendin762 allows non-invasive imaging, highlighting differentially-accessible GLP1R populations. We thus expand the color palette of LUXendins to seven different spectra, opening up a range of experiments using widefield microscopy available in most labs through super-resolution imaging and whole animal imaging. With this, we expect that LUXendins will continue to generate novel and specific insight into GLP1R biology.

Working paper

Nasteska D, Fine NHF, Ashford FB, Cuozzo F, Viloria K, Smith G, Dahir A, Dawson PWJ, Lai Y-C, Bastidas-Ponce A, Bakhti M, Rutter GA, Fiancette R, Nano R, Piemonti L, Lickert H, Zhou Q, Akerman I, Hodson DJet al., 2021, PDX1(LOW) MAFA(LOW) beta-cells contribute to islet function and insulin release (vol 12, 674, 2021), NATURE COMMUNICATIONS, Vol: 12, ISSN: 2041-1723

Journal article

Viloria K, Hewison M, Hodson DJ, 2021, 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

Journal article

McLean BA, Wong CK, Campbell JE, Hodson DJ, Trapp S, Drucker DJet al., 2021, Revisiting the Complexity of GLP-1 Action from Sites of Synthesis to Receptor Activation, ENDOCRINE REVIEWS, Vol: 42, Pages: 101-132, ISSN: 0163-769X

Journal article

Nasteska D, Fine NHF, Ashford FB, Cuozzo F, Viloria K, Smith G, Dahir A, Dawson PWJ, Lai Y-C, Bastidas-Ponce A, Bakhti M, Rutter GA, Fiancette R, Nano R, Piemonti L, Lickert H, Zhou Q, Akerman I, Hodson DJet al., 2021, PDX1(LOW) MAFA(LOW) beta-cells contribute to islet function and insulin release, NATURE COMMUNICATIONS, Vol: 12

Journal article

Jones B, Fang Z, Chen S, Manchanda Y, Bitsi S, Pickford P, David A, Shchepinova MM, Corrêa Jr IR, Hodson DJ, Broichhagen J, Tate EW, Reimann F, Salem V, Rutter GA, Tan T, Bloom SR, Tomas Aet al., 2020, Ligand-specific factors influencing GLP-1 receptor post-endocytic trafficking and degradation in pancreatic beta cells, International Journal of Molecular Sciences, Vol: 212, Pages: 1-24, ISSN: 1422-0067

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. Experiments were performed in primary islet cells, INS-1 832/3 clonal beta cells and HEK293 cells, using biorthogonal labelling of GLP-1R to determine its localisation and degradation after treatment with GLP-1, exendin-4 and several further GLP-1R agonist peptides. We also characterised the effect of a rare GLP1R coding variant, T149M, and the role of endosomal peptidase endothelin-converting enzyme-1 (ECE-1), in GLP1R trafficking. Our data reveal how treatment with GLP-1 versus exendin-4 is associated with preferential GLP-1R targeting towards a recycling pathway. GLP-1, but not exendin-4, is a substrate for ECE-1, and the resultant propensity to intra-endosomal degradation, in conjunction with differences in binding affinity, contributes to alterations in GLP-1R trafficking behaviours and degradation. The T149M GLP-1R variant shows reduced signalling and internalisation responses, which is likely to be due to disruption of the cytoplasmic region that couples to intracellular effectors. These observations provide insights into how ligand- and genotype-specific factors can influence GLP-1R trafficking.

Journal article

Ast J, Arvaniti A, Fine NHF, Nasteska D, Ashford FB, Stamataki Z, Koszegi Z, Bacon A, Jones BJ, Lucey MA, Sasaki S, Brierley DI, Hastoy B, Tomas A, D'Agostino G, Reimann F, Lynn FC, Reissaus CA, Linnemann AK, D'Este E, Calebiro D, Trapp S, Johnsson K, Podewin T, Broichhagen J, Hodson DJet al., 2020, Author Correction: Super-resolution microscopy compatible fluorescent probes reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics., Nature Communications, Vol: 11, Pages: 1-1, ISSN: 2041-1723

Correction to: Nature Communications https://doi.org/10.1038/s41467-020-14309-w, published online 24 January 2020.

Journal article

Rutter GA, Ninov N, Salem V, Hodson DJet al., 2020, Comment on Satin et al. "Take Me To Your Leader": An Electrophysiological Appraisal of the Role of Hub Cells in Pancreatic Islets. Diabetes 2020;69:830-836, DIABETES, Vol: 69, Pages: E10-E11, ISSN: 0012-1797

Journal article

Poc P, Gutzeit VA, Ast J, Lee J, Jones BJ, D'Este E, Mathes B, Lehmann M, Hodson DJ, Levitz J, Broichhagen Jet al., 2020, Interrogating surfaceversusintracellular transmembrane receptor populations using cell-impermeable SNAP-tag substrates, Chemical Science, Vol: 11, Pages: 7871-7883, ISSN: 2041-6520

Employing self-labelling protein tags for the attachment of fluorescent dyes has become a routine and powerful technique in optical microscopy to visualize and track fused proteins. However, membrane permeability of the dyes and the associated background signals can interfere with the analysis of extracellular labelling sites. Here we describe a novel approach to improve extracellular labelling by functionalizing the SNAP-tag substrate benzyl guanine (“BG”) with a charged sulfonate (“SBG”). This chemical manipulation can be applied to any SNAP-tag substrate, improves solubility, reduces non-specific staining and renders the bioconjugation handle impermeable while leaving its cargo untouched. We report SBG-conjugated fluorophores across the visible spectrum, which cleanly label SNAP-fused proteins in the plasma membrane of living cells. We demonstrate the utility of SBG-conjugated fluorophores to interrogate class A, B and C G protein-coupled receptors (GPCRs) using a range of imaging approaches including nanoscopic superresolution imaging, analysis of GPCR trafficking from intra- and extracellular pools, in vivo labelling in mouse brain and analysis of receptor stoichiometry using single molecule pull down.

Journal article

Kemkem Y, Nasteska D, de Bray A, Bargi-Souza P, Peliciari-Garcia RA, Guillou A, Mollard P, Hodson DJ, Schaeffer Met al., 2020, Maternal hypothyroidism in mice influences glucose metabolism in adult offspring, DIABETOLOGIA, Vol: 63, Pages: 1822-1835, ISSN: 0012-186X

Journal article

Hodson DJ, Rorsman P, 2020, A Variation on the Theme: SGLT2 Inhibition and Glucagon Secretion in Human Islets, DIABETES, Vol: 69, Pages: 864-866, ISSN: 0012-1797

Journal article

Fang Z, Chen S, Pickford P, Broichhagen J, Hodson DJ, Corrêa IR, Kumar S, Görlitz F, Dunsby C, French PMW, Rutter GA, Tan T, Bloom SR, Tomas A, Jones Bet al., 2020, The influence of peptide context on signaling and trafficking of glucagon-like peptide-1 receptor biased agonists, ACS Pharmacology & Translational Science, Vol: 3, Pages: 345-360, ISSN: 2575-9108

Signal bias and membrane trafficking have recently emerged as important considerations in the therapeutic targeting of the glucagon-like peptide-1 receptor (GLP-1R) in type 2 diabetes and obesity. In the present study, we have evaluated a peptide series with varying sequence homology between native GLP-1 and exendin-4, the archetypal ligands on which approved GLP-1R agonists are based. We find notable differences in agonist-mediated cyclic AMP signaling, recruitment of β-arrestins, endocytosis, and recycling, dependent both on the introduction of a His → Phe switch at position 1 and the specific midpeptide helical regions and C-termini of the two agonists. These observations were linked to insulin secretion in a beta cell model and provide insights into how ligand factors influence GLP-1R function at the cellular level.

Journal article

Carrat GR, Haythorne E, Tomas A, Haataja L, Müller A, Arvan P, Piunti A, Cheng K, Huang M, Pullen TJ, Georgiadou E, Stylianides T, Amirruddin NS, Salem V, Distaso W, Cakebread A, Heesom KJ, Lewis PA, Hodson DJ, Briant LJ, Fung ACH, Sessions RB, Alpy F, Kong APS, Benke PI, Torta F, Teo AKK, Leclerc I, Solimena M, Wigley DB, Rutter GAet al., 2020, The type 2 diabetes gene product STARD10 is a phosphoinositide binding protein that controls insulin secretory granule biogenesis, Publisher: Cold Spring Harbor Laboratory

<jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>Risk alleles for type 2 diabetes at the<jats:italic>STARD10</jats:italic>locus are associated with lowered<jats:italic>STARD10</jats:italic>expression in the β-cell, impaired glucose-induced insulin secretion and decreased circulating proinsulin:insulin ratios. Although likely to serve as a mediator of intracellular lipid transfer, the identity of the transported lipids, and thus the pathways through which STARD10 regulates β-cell function, are not understood. The aim of this study was to identify the lipids transported and affected by STARD10 in the β-cell and its effect on proinsulin processing and insulin granule biogenesis and maturation.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We used isolated islets from mice deleted selectively in the β-cell for<jats:italic>Stard10</jats:italic>(β<jats:italic>StarD10</jats:italic>KO) and performed electron microscopy, pulse-chase, RNA sequencing and lipidomic analyses. Proteomic analysis of STARD10 binding partners was executed in INS1 (832/13) cell line. X-ray crystallography followed by molecular docking and lipid overlay assay were performed on purified STARD10 protein.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>β<jats:italic>StarD10</jats:italic>KO islets had a sharply altered dense core granule appearance, with a dramatic increase in the number of “rod-like” dense cores. Correspondingly, basal secretion of proinsulin was increased. Amongst the differentially expressed genes in β<jats:italic>StarD10</jats:italic>KO islets, expression of the phosphoinositide binding proteins<jats:italic>Pirt</jats:italic>and<jats:italic>Synaptotagmin 1</jats:

Working paper

Nasteska D, Hodson DJ, 2020, GPR119 Agonism Revisited: A Novel Target for Increasing beta-Cell Mass?, ENDOCRINOLOGY, Vol: 161, ISSN: 0013-7227

Journal article

Poc P, Gutzeit VA, Ast J, Lee J, Jones BJ, DEste E, Mathes B, Hodson DJ, Levitz J, Broichhagen Jet al., 2020, Interrogating surface versus intracellular transmembrane receptor populations using cell-impermeable SNAP-tag substrates

<jats:title>Abstract</jats:title><jats:p>Employing self-labelling protein tags for the attachment of fluorescent dyes has become a routine and powerful technique in optical microscopy to visualize and track fused proteins. However, membrane permeability of the dyes and the associated background signals can interfere with the analysis of extracellular labeling sites. Here we describe a novel approach to improve extracellular labeling by functionalizing the SNAP-tag substrate benzyl guanine (“BG”) with a charged sulfonate (“SBG”). This chemical manipulation improves solubility, reduces non-specific staining and renders the bioconjugation handle impermeable while leaving its cargo untouched. We report SBG-conjugated fluorophores across the visible spectrum, which cleanly label SNAP-fused proteins in the plasma membrane of living cells. We demonstrate the utility of SBG-conjugated fluorophores to interrogate class A, B and C G protein-coupled receptors (GPCRs) using a range of imaging approaches including nanoscopic super-resolution imaging, analysis of GPCR trafficking from intra- and extracellular pools, <jats:italic>in vivo</jats:italic> labelling in mouse brain and analysis of receptor stoichiometry using single molecule pull down.</jats:p>

Journal article

Ast J, Arvaniti A, Fine NHF, Nasteska D, Ashford FB, Stamataki Z, Koszegi Z, Bacon A, Jones BJ, Lucey MA, Sasaki S, Brierley DI, Hastoy B, Tomas A, D'Agostino G, Reimann F, Lynn FC, Reissaus CA, Linnemann AK, D'Este E, Calebiro D, Trapp S, Johnsson K, Podewin T, Broichhagen J, Hodson DJet al., 2020, Super-resolution microscopy compatible fluorescent probes reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics, Nature Communications, Vol: 11, ISSN: 2041-1723

The glucagon-like peptide-1 receptor (GLP1R) is a class B G protein-coupled receptor (GPCR) involved in metabolism. Presently, its visualization is limited to genetic manipulation, antibody detection or the use of probes that stimulate receptor activation. Herein, we present LUXendin645, a far-red fluorescent GLP1R antagonistic peptide label. LUXendin645 produces intense and specific membrane labeling throughout live and fixed tissue. GLP1R signaling can additionally be evoked when the receptor is allosterically modulated in the presence of LUXendin645. Using LUXendin645 and LUXendin651, we describe islet, brain and hESC-derived β-like cell GLP1R expression patterns, reveal higher-order GLP1R organization including membrane nanodomains, and track single receptor subpopulations. We furthermore show that the LUXendin backbone can be optimized for intravital two-photon imaging by installing a red fluorophore. Thus, our super-resolution compatible labeling probes allow visualization of endogenous GLP1R, and provide insight into class B GPCR distribution and dynamics both in vitro and in vivo.

Journal article

Viloria K, Nasteska D, Briant LJB, Heising S, Larner D, Fine NHF, Ashford FB, Silva Xavier GD, Ramos MJ, Manning Fox JE, MacDonald PE, Akerman I, Lavery GG, Flaxman C, Morgan NG, Richardson SJ, Hewison M, Hodson DJet al., 2019, Vitamin D-binding protein is required for the maintenance of α-cell function and glucagon secretion

<jats:title>ABSTRACT</jats:title><jats:p>Vitamin D-binding protein (DBP) or GC-globulin carries vitamin D metabolites from the circulation to target tissues. DBP expression is highly-localized to the liver and pancreatic α-cells. While DBP serum levels, gene polymorphisms and autoantigens have all been associated with diabetes risk, the underlying mechanisms remain unknown. Here, we show that DBP regulates α-cell morphology, α-cell function and glucagon secretion. Deletion of DBP led to smaller and hyperplastic α-cells, altered Na<jats:sup>+</jats:sup>channel conductance, impaired α-cell activation by low glucose, and reduced rates of glucagon secretion. Mechanistically, this involved reversible changes in islet microfilament abundance and density, as well as changes in glucagon granule distribution. Defects were also seen in β-cell and δ-cell function. Immunostaining of human pancreata revealed generalized loss of DBP expression as a feature of late-onset and longstanding, but not early-onset type 1 diabetes. Thus, DBP is a critical regulator of α-cell phenotype, with implications for diabetes pathogenesis.</jats:p><jats:sec><jats:title>HIGHLIGHTS</jats:title><jats:p><jats:list list-type="bullet"><jats:list-item><jats:p>DBP expression is highly-localized to mouse and human α-cells</jats:p></jats:list-item><jats:list-item><jats:p>Loss of DBP increases α-cell number, but decreases α-cell size</jats:p></jats:list-item><jats:list-item><jats:p>α-cells in DBP knockout islets are dysfunctional and secrete less glucagon</jats:p></jats:list-item><jats:list-item><jats:p>DBP expression is decreased in α-cells of donors with late-onset or longstanding type 1 diabetes</jats:p></jats:list-item></jats:list></jats:p></jat

Journal article

Frank JA, Broichhagen J, Yushchenko DA, Trauner D, Schultz C, Hodson DJet al., 2018, Optical tools for understanding the complexity of beta-cell signalling and insulin release, NATURE REVIEWS ENDOCRINOLOGY, Vol: 14, Pages: 721-737, ISSN: 1759-5029

Journal article

Janjuha S, Singh SP, Tsakmaki A, Mousavy Gharavy NS, Murawala P, Konantz J, Birke S, Hodson DJ, Rutter GA, Bewick GAet al., 2018, Age-related islet inflammation marks the proliferative decline of pancreatic beta-cells in zebrafish, eLife, Vol: 7, ISSN: 2050-084X

The pancreatic islet, a cellular community harboring the insulin-producing beta-cells, is known to undergo age-related alterations. However, only a handful of signals associated with aging have been identified. By comparing beta-cells from younger and older zebrafish, here we show that the aging islets exhibit signs of chronic inflammation. These include recruitment of tnfα-expressing macrophages and the activation of NF-kB signaling in beta-cells. Using a transgenic reporter, we show that NF-kB activity is undetectable in juvenile beta-cells, whereas cells from older fish exhibit heterogeneous NF-kB activity. We link this heterogeneity to differences in gene expression and proliferation. Beta-cells with high NF-kB signaling proliferate significantly less compared to their neighbors with low activity. The NF-kB signalinghi cells also exhibit premature upregulation of socs2, an age-related gene that inhibits beta-cell proliferation. Together, our results show that NF-kB activity marks the asynchronous decline in beta-cell proliferation with advancing age.

Journal article

Benninger RKP, Hodson DJ, 2018, New Understanding of beta-Cell Heterogeneity and In Situ Islet Function, DIABETES, Vol: 67, Pages: 537-547, ISSN: 0012-1797

Journal article

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