Publications
164 results found
Yip SH, Romano N, Gustafson P, et al., 2019, Elevated Prolactin during Pregnancy Drives a Phenotypic Switch in Mouse Hypothalamic Dopaminergic Neurons, CELL REPORTS, Vol: 26, Pages: 1787-+, ISSN: 2211-1247
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- Citations: 26
Frank JA, Broichhagen J, Yushchenko DA, et al., 2018, Optical tools for understanding the complexity of β-cell signalling and insulin release, NATURE REVIEWS ENDOCRINOLOGY, Vol: 14, Pages: 721-737, ISSN: 1759-5029
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- Citations: 27
Salem V, Silva LD, Suba K, et al., 2018, Glucose regulates pancreatic islet beta cell calcium dynamics and intercellular connectivity in vivo, 54th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S18-S18, ISSN: 0012-186X
Caton PW, Beavil R, Hodson DJ, et al., 2018, Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) induces beta cell dysfunction via p38 and STAT3 signalling, 54th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S262-S263, ISSN: 0012-186X
Nasteska D, Rutter GA, Zhou Q, et al., 2018, Loss of beta cell heterogeneity disrupts normal islet function, 54th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S17-S17, ISSN: 0012-186X
Benninger RKP, Dorrell C, Hodson DJ, et al., 2018, The Impact of Pancreatic Beta Cell Heterogeneity on Type 1 Diabetes Pathogenesis, CURRENT DIABETES REPORTS, Vol: 18, ISSN: 1534-4827
Nasteska D, Hodson DJ, 2018, The role of beta cell heterogeneity in islet function and insulin release, JOURNAL OF MOLECULAR ENDOCRINOLOGY, Vol: 61, Pages: R43-R60, ISSN: 0952-5041
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- Citations: 46
Xavier GDS, Hodson DJ, 2018, Mouse models of peripheral metabolic disease, BEST PRACTICE & RESEARCH CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 32, Pages: 299-315, ISSN: 1521-690X
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- Citations: 11
Janjuha S, Singh SP, Tsakmaki A, et 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.
Salem V, Suba K, Martin Alonso A, et al., 2018, Real-Time In Vivo Imaging of Whole Islet Ca2+ Dynamics Reveals Glucose-Induced Changes in Beta-Cell Connectivity in Mouse and Human Islets, American Diabetes Association, 78th Scientific Sessions, Publisher: American Diabetes Association, ISSN: 0012-1797
Benninger RKP, Hodson DJ, 2018, New Understanding of β-Cell Heterogeneity and In Situ Islet Function, DIABETES, Vol: 67, Pages: 537-547, ISSN: 0012-1797
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- Citations: 94
Rutter GA, Hodson DJ, 2018, Beta cell connectivity in pancreatic islets: a type 2 diabetes target? (vol 72, pg 453, 2015), CELLULAR AND MOLECULAR LIFE SCIENCES, Vol: 75, Pages: 1303-1305, ISSN: 1420-682X
Hollinshead KER, Munford H, Eales KL, et al., 2018, Oncogenic IDH1 Mutations Promote Enhanced Proline Synthesis through PYCR1 to Support the Maintenance of Mitochondrial Redox Homeostasis, CELL REPORTS, Vol: 22, Pages: 3107-3114, ISSN: 2211-1247
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- Citations: 52
Carrat GR, Haythorne E, Chabosseau P, et al., 2018, The Type 2 diabetes genome-wide association study (GWAS) gene STARD10 controls beta cell granule morphogenesis and proinsulin release, Diabetes UK, Publisher: WILEY, Pages: 46-46, ISSN: 0742-3071
Pullen TJ, Groen N, van Oudenaarden A, et al., 2018, Identification of potential hub beta cells using single-cell RNA-Seq, Publisher: WILEY, Pages: 51-51, ISSN: 0742-3071
Sayers SR, Beavil R, Hodson DJ, et al., 2018, Monomeric and dimeric forms of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) have contrasting roles in the regulation of insulin secretion, Publisher: WILEY, Pages: 48-48, ISSN: 0742-3071
Podewin T, Ast J, Broichhagen J, et al., 2018, Conditional and reversible activation of class A and B G protein-coupled receptors using tethered pharmacology, ACS Central Science, Vol: 4, Pages: 166-179, ISSN: 2374-7943
Understanding the activation and internalization of G protein-coupled receptors (GPCRs) using conditional approaches is paramount to developing new therapeutic strategies. Here, we describe the design, synthesis, and testing of ExONatide, a benzylguanine-linked peptide agonist of the glucagon-like peptide-1 receptor (GLP-1R), a class B GPCR required for maintenance of glucose levels in humans. ExONatide covalently binds to SNAP-tagged GLP-1R-expressing cells, leading to prolonged cAMP generation, Ca2+ rises, and intracellular retention of the receptor. These effects were readily switched OFF following cleavage of the introduced disulfide bridge using the cell-permeable reducing agent beta-mercaptoethanol (BME). A similar approach could be extended to a class A GPCR using GhrelON, a benzylguanine-linked peptide agonist of the growth hormone secretagogue receptor 1a (GHS-R1a), which is involved in food intake and growth. Thus, ExONatide and GhrelON allow SNAP-tag-directed activation of class A and B GPCRs involved in gut hormone signaling in a reversible manner. This tactic, termed reductively cleavable agONist (RECON), may be useful for understanding GLP-1R and GHS-R1a function both in vitro and in vivo, with applicability across GPCRs.
Fine NHF, Doig CL, Elhassan YS, et al., 2017, Glucocorticoids reprogram beta cell signaling to preserve insulin secretion, Diabetes, Vol: 67, Pages: 278-290, ISSN: 0012-1797
Excessive glucocorticoid exposure has been shown to be deleterious for pancreatic beta cell function and insulin release. However, glucocorticoids at physiological levels are essential for many homeostatic processes, including glycemic control. Here, we show that corticosterone and cortisol and their less active precursors, 11-dehydrocorticosterone (11-DHC) and cortisone, suppress voltage-dependent Ca2+ channel function and Ca2+ fluxes in rodent as well as human beta cells. However, insulin secretion, maximal ATP/ADP responses to glucose and beta cell identity were all unaffected. Further examination revealed the upregulation of parallel amplifying cAMP signals, and an increase in the number of membrane-docked insulin secretory granules. Effects of 11-DHC could be prevented by lipotoxicity and were associated with paracrine regulation of glucocorticoid activity, since global deletion of 11β-hydroxysteroid dehydrogenase type 1 normalized Ca2+ and cAMP responses. Thus, we have identified an enzymatically-amplified feedback loop whereby glucocorticoids boost cAMP to maintain insulin secretion in the face of perturbed ionic signals. Failure of this protective mechanism may contribute to diabetes in states of glucocorticoid excess such as Cushing's syndrome, which are associated with frank dyslipidemia.
Frank JA, Yushchenko DA, Fine NHF, et al., 2017, Optical control of GPR40 signalling in pancreatic β-cells, CHEMICAL SCIENCE, Vol: 8, Pages: 7604-7610, ISSN: 2041-6520
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- Citations: 32
Carrat G, Haythorne E, Chabosseau P, et al., 2017, Role of StarD10 in beta cell physiology, 53rd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S190-S191, ISSN: 0012-186X
Rutter GA, Hodson DJ, Chabosseau P, et al., 2017, Local and regional control of calcium dynamics in the pancreatic islet, Diabetes, Obesity and Metabolism, Vol: 19, Pages: 30-41, ISSN: 1462-8902
Ca2+ is the key intracellular regulator of insulin secretion, acting in the β-cell as the ultimate trigger for exocytosis. In response to high glucose, ATP-sensitive K+ channel closure and plasma membrane depolarization engage a sophisticated machinery to drive pulsatile cytosolic Ca2+ changes. Voltage-gated Ca2+ channels, Ca2+-activated K+ channels and Na+/Ca2+ exchange all play important roles. The use of targeted Ca2+ probes has revealed that during each cytosolic Ca2+ pulse, uptake of Ca2+ by mitochondria, endoplasmic reticulum (ER), secretory granules and lysosomes fine-tune cytosolic Ca2+ dynamics and control organellar function. For example, changes in the expression of the Ca2+-binding protein Sorcin appear to provide a link between ER Ca2+ levels and ER stress, affecting β-cell function and survival. Across the islet, intercellular communication between highly interconnected “hubs,” which act as pacemaker β-cells, and subservient “followers,” ensures efficient insulin secretion. Loss of connectivity is seen after the deletion of genes associated with type 2 diabetes (T2D) and follows metabolic and inflammatory insults that characterize this disease. Hubs, which typically comprise ~1%-10% of total β-cells, are repurposed for their specialized role by expression of high glucokinase (Gck) but lower Pdx1 and Nkx6.1 levels. Single cell-omics are poised to provide a deeper understanding of the nature of these cells and of the networks through which they communicate. New insights into the control of both the intra- and intercellular Ca2+ dynamics may thus shed light on T2D pathology and provide novel opportunities for therapy.
Nasteska D, Fine NHF, Rutter GA, et al., 2017, β cell diversity is required for normal islet function, Publisher: WILEY, Pages: 12-14, ISSN: 1748-1708
Fine NHF, Doig CL, Elhassan Y, et al., 2017, Glucocorticoids re-programme the beta cell signalling cassette to preserve functional identity and insulin secretion, 53rd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S83-S83, ISSN: 0012-186X
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- Citations: 1
Hodson DJ, Nasteska D, Fine NHF, et al., 2017, Forced maturity in pancreatic beta cells impairs islet function, 53rd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S183-S183, ISSN: 0012-186X
Botfield HF, Uldall MS, Westgate CSJ, et al., 2017, A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus, SCIENCE TRANSLATIONAL MEDICINE, Vol: 9, ISSN: 1946-6234
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- Citations: 55
Cegla J, Jones BJ, Gardiner JV, et al., 2017, RAMP2 influences glucagon receptor pharmacology via trafficking and signaling, Endocrinology, Vol: 158, Pages: 2680-2693, ISSN: 0013-7227
Endogenous satiety hormones provide an attractive target for obesity drugs. Glucagon causes weight loss by reducing food intake and increasing energy expenditure. To further understand the cellular mechanisms by which glucagon and related ligands activate the glucagon receptor (GCGR), we investigated the interaction of the GCGR with receptor activity modifying protein (RAMP)2, a member of the family of receptor activity modifying proteins. We used a combination of competition binding experiments, cell surface enzyme-linked immunosorbent assay, functional assays assessing the Gαs and Gαq pathways and β-arrestin recruitment, and small interfering RNA knockdown to examine the effect of RAMP2 on the GCGR. Ligands tested were glucagon; glucagonlike peptide-1 (GLP-1); oxyntomodulin; and analog G(X), a GLP-1/glucagon coagonist developed in-house. Confocal microscopy was used to assess whether RAMP2 affects the subcellular distribution of GCGR. Here we demonstrate that coexpression of RAMP2 and the GCGR results in reduced cell surface expression of the GCGR. This was confirmed by confocal microscopy, which demonstrated that RAMP2 colocalizes with the GCGR and causes significant GCGR cellular redistribution. Furthermore, the presence of RAMP2 influences signaling through the Gαs and Gαq pathways, as well as recruitment of β-arrestin. This work suggests that RAMP2 may modify the agonist activity and trafficking of the GCGR, with potential relevance to production of new peptide analogs with selective agonist activities.
Jones BJ, Scopelliti R, Tomas A, et al., 2017, Potent prearranged positive allosteric modulators of the glucagon-like peptide-1 receptor, ChemistryOpen, Vol: 6, Pages: 501-505, ISSN: 2191-1363
Drugs that allosterically modulate G protein-coupled receptor (GPCR) activity display higher specificity and may improve disease treatment. However, the rational design of compounds that target the allosteric site is difficult, as conformations required for receptor activation are poorly understood. Guided by photopharmacology, a set of prearranged positive allosteric modulators (PAMs) with restricted degrees of freedom was designed and tested against the glucagon-like peptide-1 receptor (GLP-1R), a GPCR involved in glucose homeostasis. Compounds incorporating a trans-stilbene comprehensively outperformed those with a cis-stilbene, as well as the benchmark BETP, as GLP-1R PAMs. We also identified major effects of ligand conformation on GLP-1R binding kinetics and signal bias. Thus, we describe a photopharmacology-directed approach for rational drug design, and introduce a new class of stilbene-containing PAM for the specific regulation of GPCR activity.
Podewin T, Broichhagen J, Frost C, et al., 2017, Optical control of a receptor-linked guanylyl cyclase using a photoswitchable peptidic hormone, CHEMICAL SCIENCE, Vol: 8, Pages: 4644-4653, ISSN: 2041-6520
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- Citations: 18
Mitchell RK, Nguyen-Tu MS, Chabosseau P, et al., 2017, The transcription factor Pax6 is required for pancreatic β cell identity, glucose-regulated ATP synthesis and Ca2+ dynamics in adult mice., Journal of Biological Chemistry, Vol: 292, Pages: 8892-8906, ISSN: 1083-351X
Heterozygous mutations in the human paired box gene PAX6 lead to impaired glucose tolerance. Although embryonic deletion of the Pax6 gene in mice leads to the loss of most pancreatic islet cell types, the functional consequences of Pax6 loss in adults are poorly defined. Here, we developed a mouse line in which Pax6 was selectively inactivated in β cells by crossing animals with floxed Pax6 alleles to mice expressing the inducible Pdx1CreERT transgene. Pax6 deficiency, achieved by tamoxifen injection, caused progressive hyperglycemia. While β-cell mass was preserved 8 days post injection, total insulin content and insulin:chromogranin A immunoreactivity were reduced by ~60%, and glucose-stimulated insulin secretion was eliminated. RNAseq and qRT-PCR analyses revealed that whereas the expression of key β cell genes including Ins2, Slc30a8, MafA, Slc2a2, G6pc2 and Glp1r was reduced after Pax6 deletion, that of several genes which are usually selectively repressed ("disallowed") in β-cells, including Slc16a1, was increased. Assessed in intact islets, glucose-induced ATP:ADP increases were significantly reduced (p<0.05) in βPax6KO versus control β cells, and the former displayed attenuated increases in cytosolic Ca2+. Unexpectedly, glucose-induced increases in intercellular connectivity were enhanced after Pax6 deletion, consistent with increases in the expression of the glucose sensor glucokinase, but decreases in that of two transcription factors usually expressed in fully differentiated β-cells, Pdx1 and Nkx6.1, as observed in islet "hub" cells. These results indicate that Pax6 is required for the functional identity of adult β cells. Furthermore, deficiencies in β cell glucose-sensing are likely to contribute to defective insulin secretion in human carriers of PAX6 mutations.
Mehta ZB, Johnston NR, Nguyen-Tu M-S, et al., 2017, Remote control of glucose homeostasis in vivo using photopharmacology, Scientific Reports, Vol: 7, ISSN: 2045-2322
Photopharmacology describes the use of light to precisely deliver drug activity in space and time. Such approaches promise to improve drug specificity by reducing off-target effects. As a proof-of-concept, we have subjected the fourth generation photoswitchable sulfonylurea JB253 to comprehensive toxicology assessment, including mutagenicity and maximum/repeated tolerated dose studies, as well as in vivo testing in rodents. Here, we show that JB253 is well-tolerated with minimal mutagenicity and can be used to optically-control glucose homeostasis in anesthetized mice following delivery of blue light to the pancreas. These studies provide the first demonstration that photopharmacology may one day be applicable to the light-guided treatment of type 2 diabetes and other metabolic disease states in vivo in humans.
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