Publications
674 results found
Hu M, Cebola I, Carrat G, et al., 2020, Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a new regulator of insulin secretion, Publisher: SPRINGER
Pickford P, Lucey M, Fang Z, et al., 2020, Signalling, trafficking and glucoregulatory properties of glucagon-like peptide-1 receptor agonists exendin-4 and lixisenatide., British Journal of Pharmacology, Vol: 177, Pages: 3905-3923, ISSN: 0007-1188
BACKGROUND AND PURPOSE: Amino acid substitutions at the N-termini of glucagon-like peptide-1 receptor agonist (GLP-1RA) peptides result in distinct patterns of intracellular signalling, sub-cellular trafficking and efficacy in vivo. Here we aimed to determine whether sequence differences at the ligand C-termini of clinically approved GLP-1RAs exendin-4 and lixisenatide lead to similar phenomena. EXPERIMENTAL APPROACH: Exendin-4, lixisenatide, and N-terminally substituted analogues with biased signalling characteristics were compared across a range of in vitro trafficking and signalling assays in different cell types. Fluorescent ligands and new time-resolved FRET approaches were developed to study agonist behaviours at the cellular and sub-cellular level. Anti-hyperglycaemic and anorectic effects of each parent ligand, and their biased derivatives, were assessed in mice. KEY RESULTS: Lixisenatide and exendin-4 showed equal binding affinity, but lixisenatide was 5-fold less potent for cAMP signalling. Both peptides induced extensive GLP-1R clustering in the plasma membrane and were rapidly endocytosed, but the GLP-1R recycled more slowly to the cell surface after lixisenatide treatment. These combined deficits resulted in reduced maximal sustained insulin secretion and reduced anti-hyperglycaemic and anorectic effects in mice with lixisenatide. N-terminal substitution of His1 by Phe1 to both ligands had favourable effects on their pharmacology, resulting in improved insulin release and lowering of blood glucose. CONCLUSION AND IMPLICATIONS: Changes to the C-terminus of exendin-4 affect signalling potency and GLP-1R trafficking via mechanisms unrelated to GLP-1R occupancy. These differences were associated with changes in their ability to control blood glucose and therefore may be therapeutically relevant.
Ali UT, Suba K, Bitsi S, et al., 2020, Improving islet transplantation success by increasing expression of the epidermal growth factor receptor (EGFR), Publisher: WILEY, Pages: 36-36, ISSN: 0742-3071
Suba K, Patel Y, Alonso AM, et al., 2020, Clinical care and other categories posters: Hypoglycaemia, Publisher: WILEY, Pages: 25-25, ISSN: 0742-3071
Akalestou E, Lopez-Noriega L, Leclerc I, et al., 2020, Metabolic surgery inhibits sodium glucose co-transporter 2 (SGLT2) expression in the kidney of lean mice, Publisher: WILEY, Pages: 43-43, ISSN: 0742-3071
Carrat G, Haataja L, Arvan P, et al., 2020, The type 2 diabetes-associated lipid-binding protein STARD10 could bind phosphatidylinositides and affect islet lipid composition, Publisher: WILEY, Pages: 39-39, ISSN: 0742-3071
Noriega LL, Sanchez AM, Callingham R, et al., 2020, The long non-coding RNA PAX6-AS1 modulates human beta cell function, Publisher: WILEY, Pages: 38-39, ISSN: 0742-3071
Callingham RM, Leclerc I, Pullen TJ, et al., 2020, The impact of a long non-coding RNA at the <i>Pax6</i> locus on beta cell identity and function, Publisher: WILEY, Pages: 38-38, ISSN: 0742-3071
Rutter GA, Georgiadou E, Rodriguez T, et al., 2020, Pancreatic beta cell-selective deletion of themitofusins 1 and 2 (Mfn1 and Mfn2) impairs glucose-stimulated insulin secretion in vitro and in vivo, 56th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S6-S7, ISSN: 0012-186X
Akalestou E, Suba K, Lopez-Noriega L, et al., 2020, Metabolic surgery recovers Ca<SUP>2+</SUP>dynamics across pancreatic islets in obese mice, 56th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S114-S114, ISSN: 0012-186X
Rutter GA, Ninov N, Salem V, et 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
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- Citations: 11
Mostafa D, Yanagiya A, Georgiadou E, et al., 2020, Loss of β-cell identity and diabetic phenotype in mice caused by disruption of CNOT3-dependent mRNA deadenylation, COMMUNICATIONS BIOLOGY, Vol: 3
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- Citations: 11
Ralston JC, Nguyen-Tu M-S, Lyons CL, et al., 2020, Dietary substitution of SFA with MUFA within high-fat diets attenuates hyperinsulinaemia and pancreatic islet dysfunction, BRITISH JOURNAL OF NUTRITION, Vol: 124, Pages: 247-255, ISSN: 0007-1145
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- Citations: 10
Amouyal C, Castel J, Guay C, et al., 2020, A surrogate of Roux-en-Y gastric bypass (the enterogastro anastomosis surgery) regulates multiple beta-cell pathways during resolution of diabetes in ob/ob mice, EBioMedicine, Vol: 58, ISSN: 2352-3964
BACKGROUND: Bariatric surgery is an effective treatment for type 2 diabetes. Early post-surgical enhancement of insulin secretion is key for diabetes remission. The full complement of mechanisms responsible for improved pancreatic beta cell functionality after bariatric surgery is still unclear. Our aim was to identify pathways, evident in the islet transcriptome, that characterize the adaptive response to bariatric surgery independently of body weight changes. METHODS: We performed entero-gastro-anastomosis (EGA) with pyloric ligature in leptin-deficient ob/ob mice as a surrogate of Roux-en-Y gastric bypass (RYGB) in humans. Multiple approaches such as determination of glucose tolerance, GLP-1 and insulin secretion, whole body insulin sensitivity, ex vivo glucose-stimulated insulin secretion (GSIS) and functional multicellular Ca2+-imaging, profiling of mRNA and of miRNA expression were utilized to identify significant biological processes involved in pancreatic islet recovery. FINDINGS: EGA resolved diabetes, increased pancreatic insulin content and GSIS despite a persistent increase in fat mass, systemic and intra-islet inflammation, and lipotoxicity. Surgery differentially regulated 193 genes in the islet, most of which were involved in the regulation of glucose metabolism, insulin secretion, calcium signaling or beta cell viability, and these were normalized alongside changes in glucose metabolism, intracellular Ca2+ dynamics and the threshold for GSIS. Furthermore, 27 islet miRNAs were differentially regulated, four of them hubs in a miRNA-gene interaction network and four others part of a blood signature of diabetes resolution in ob/ob mice and in humans. INTERPRETATION: Taken together, our data highlight novel miRNA-gene interactions in the pancreatic islet during the resolution of diabetes after bariatric surgery that form part of a blood signature of diabetes reversal. FUNDING: European Union's Horizon 2020 research and innovation programme via the Innovat
Rutter GA, McCormack JG, Halestrap AP, et al., 2020, The roles of cytosolic and intramitochondrial Ca<SUP>2+</SUP> and the mitochondrial Ca<SUP>2+</SUP>-uniporter (MCU) in the stimulation of mammalian oxidative phosphorylation, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 295, Pages: 10506-10506, ISSN: 0021-9258
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- Citations: 3
Lopez-Noriega L, Callingham R, Martinez-Sánchez A, et al., 2020, Roles for the long non-coding RNA<i>Pax6os1</i>/<i>PAX6-AS1</i>in pancreatic beta cell identity and function
<jats:title>Abstract</jats:title><jats:sec><jats:title>Aim/Hypothesis</jats:title><jats:p>Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of beta cell development and function. Here, we investigate roles for an antisense lncRNA expressed from the<jats:italic>Pax6</jats:italic>locus (annotated as<jats:italic>Pax6os1</jats:italic>in mice and<jats:italic>PAX6-AS1</jats:italic>in humans) in beta cell identity and functionality.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p><jats:italic>Pax6os1</jats:italic>expression was silenced in MIN6 cells using siRNAs and changes in gene expression were determined by RNA sequencing or qRT-PCR. Mice inactivated for<jats:italic>Pax6os1</jats:italic>and human<jats:italic>PAX6-AS1</jats:italic>-null EndoC-βH1 cells, were generated using CRISPR/Cas9 technology. Human islets were infected with lentiviral vectors bearing a targeted shRNA or<jats:italic>PAX6-AS1</jats:italic>, which were used to silence or overexpress, respectively, the lncRNA. RNA sequencing or RT-qPCR were used to measure transcriptomic changes and RNA pulldown in mice and human cells followed by mass spectrometry/western blot were performed to explore RNA protein interactions.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p><jats:italic>Pax6os1/PAX6-AS1</jats:italic>expression was upregulated at high glucose concentrations in derived beta cell lines as well as in mouse and human islets, and in pancreatic islets isolated from mice fed a high fat diet (n=6, p=0.003) and patients with type 2 diabetes (n=11-5, p<0.01). Silencing or deletion of<jats:italic>Pax6os1</jats:italic>/<jats:italic>PAX6-AS1</jats:italic>in MIN6 or EndoC-βH1cells increased the expression of several
Georgiadou E, Rutter GA, 2020, Age matters: Grading granule secretion in beta cells, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 295, Pages: 8912-8913, ISSN: 0021-9258
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- Citations: 1
Georgiadou E, Rutter GA, 2020, Age matters: Grading granule secretion in beta cells., J Biol Chem, Vol: 295, Pages: 8912-8913
Insulin is stored in secretory granules to facilitate rapid release in response to rising glucose levels, but the mechanisms by which these granules are identified and prioritized for secretion remains unclear. Using a fluorescent timer and flow cytometry-assisted organelle sorting, Yau et al. develop an elegant approach to assess insulin secretion as a function of granule age in pancreatic islet beta cells. Their findings supply quantitative evidence supporting the age-dependent release of different granule pools and confirm earlier models of preferential release of younger granules.
Jones B, Pickford P, Lucey M, et al., 2020, Disconnect between signalling potency and in vivo efficacy of pharmacokinetically optimised biased glucagon-like peptide-1 receptor agonists, Molecular Metabolism, Vol: 37, ISSN: 2212-8778
ObjectiveThe objective of this study was to determine how pharmacokinetically advantageous acylation impacts on glucagon-like peptide-1 receptor (GLP-1R) signal bias, trafficking, anti-hyperglycaemic efficacy, and appetite suppression.MethodsIn vitro signalling responses were measured using biochemical and biosensor assays. GLP-1R trafficking was determined by confocal microscopy and diffusion-enhanced resonance energy transfer. Pharmacokinetics, glucoregulatory effects, and appetite suppression were measured in acute, sub-chronic, and chronic settings in mice.ResultsA C-terminally acylated ligand, [F1,K⁴⁰.C16 diacid]exendin-4, was identified that showed undetectable β-arrestin recruitment and GLP-1R internalisation. Depending on the cellular system used, this molecule was up to 1000-fold less potent than the comparator [D3,K⁴⁰.C16 diacid]exendin-4 for cyclic AMP signalling, yet was considerably more effective in vivo, particularly for glucose regulation.ConclusionsC-terminal acylation of biased GLP-1R agonists increases their degree of signal bias in favour of cAMP production and improves their therapeutic potential.
Akalestou E, Suba K, Noriega LL, et al., 2020, Bariatric Surgery Improves Ca2+Dynamics across Pancreatic Islets In Vivo, 80th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797
Suba K, Patel YS, Alonso AM, et al., 2020, Chronic Administration of a Long-Acting Glucagon Analogue Results in Enhanced Insulin Secretory Activity in a Directly-Observed Murine Model, 80th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797
Georgiadou E, Chabosseau PL, Tomas A, et al., 2020, Deletion of the Mitofusins 1 and 2 (Mfn1 and Mfn2) in the Pancreatic Beta Cell Disrupts Mitochondrial Structure and Function In Vitro and Strongly Impairs Glucose-Stimulated Insulin Secretion In Vivo, 80th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797
Carrat G, Nguyen-Tu M-S, Leclerc I, et al., 2020, Binding Kinetics, GLP-1 Receptor Internalization, and Effects on Insulin Secretion for GL0034 and Related GLP-1R Agonists, 80th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797
Salem V, Ali U, Suba K, et al., 2020, Upregulation of Pancreatic Islet EGF Receptor Improves Beta-Cell Identity and In Vivo Vascularisation in a Directly Observed Transplant Model, 80th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797
Akalestou E, Noriega LL, Christakis I, et al., 2020, Bariatric Surgery Downregulates Glucocorticoid Signaling in Mice, 80th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797
Nguyen-Tu M-S, Martinez-Sanchez A, Leclerc I, et al., 2020, Reduced expression of TCF7L2 in adipocyte impairs glucose tolerance associated with decreased insulin secretion, incretins levels and lipid metabolism dysregulation in male mice
<jats:title>Abstract</jats:title><jats:p>Transcription factor 7-like 2 (TCF7L2) is a downstream effector of the Wnt/beta-catenin signalling pathway and its expression is critical for adipocyte development. The precise role of TCF7L2 in glucose and lipid metabolism in adult adipocytes remains to be defined. Here, we aim to investigate how changes in TCF7L2 expression in mature adipocytes affect glucose homeostasis. <jats:italic>Tcf7l2</jats:italic> was selectively ablated from mature adipocytes in C57BL/6J mice using an adiponectin promoter-driven <jats:italic>Cre</jats:italic> recombinase to recombine alleles floxed at exon 1 of the <jats:italic>Tcf7l2</jats:italic> gene. Mice lacking <jats:italic>Tcf7l2</jats:italic> in mature adipocytes displayed normal body weight. Male mice exhibited normal glucose homeostasis at eight weeks of age. Male heterozygote knockout mice (aTCF7L2het) exhibited impaired glucose tolerance (AUC increased 1.14 ± 0.04 -fold, p=0.03), as assessed by intraperitoneal glucose tolerance test, and changes in fat mass at 16 weeks (increased by 1.4 ± 0.09-fold, p=0.007). Homozygote knockout mice exhibited impaired oral glucose tolerance at 16 weeks of age (AUC increased 2.15 ± 0.15-fold, p=0.0001). Islets of Langerhans exhibited impaired glucose-stimulated insulin secretion <jats:italic>in vitro</jats:italic> (decreased 0.54 ± 0.13-fold aTCF7L2KO vs control, p=0.02), but no changes in <jats:italic>in vivo</jats:italic> glucose-stimulated insulin secretion. Female mice in which one or two alleles of the <jats:italic>Tcf7l2</jats:italic> gene was knocked out in adipocytes displayed no changes in glucose tolerance, insulin sensitivity or insulin secretion. Plasma levels of glucagon-like peptide-1 and gastric inhibitory polypeptide were lowered in knockout mice (decreased 0.57 ± 0.03-fold and 0.41 ± 0.12-fold
Georgiadou E, Haythorne E, Dickerson MT, et al., 2020, The pore-forming subunit MCU of the mitochondrial Ca2+ uniporter is required for normal glucose-stimulated insulin secretion in vitro and in vivo in mice, Diabetologia, Vol: 63, Pages: 1368-1381, ISSN: 0012-186X
Aims/hypothesisMitochondrial oxidative metabolism is central to glucose-stimulated insulin secretion (GSIS). Whether Ca2+ uptake into pancreatic beta cell mitochondria potentiates or antagonises this process is still a matter of debate. Although the mitochondrial Ca2+ importer (MCU) complex is thought to represent the main route for Ca2+ transport across the inner mitochondrial membrane, its role in beta cells has not previously been examined in vivo.MethodsHere, we inactivated the pore-forming subunit of the MCU, encoded by Mcu, selectively in mouse beta cells using Ins1Cre-mediated recombination. Whole or dissociated pancreatic islets were isolated and used for live beta cell fluorescence imaging of cytosolic or mitochondrial Ca2+ concentration and ATP production in response to increasing glucose concentrations. Electrophysiological recordings were also performed on whole islets. Serum and blood samples were collected to examine oral and i.p. glucose tolerance.ResultsGlucose-stimulated mitochondrial Ca2+ accumulation (p< 0.05), ATP production (p< 0.05) and insulin secretion (p< 0.01) were strongly inhibited in beta cell-specific Mcu-null (βMcu-KO) animals, in vitro, as compared with wild-type (WT) mice. Interestingly, cytosolic Ca2+ concentrations increased (p< 0.001), whereas mitochondrial membrane depolarisation improved in βMcu-KO animals. βMcu-KO mice displayed impaired in vivo insulin secretion at 5 min (p< 0.001) but not 15 min post-i.p. injection of glucose, whilst the opposite phenomenon was observed following an oral gavage at 5 min. Unexpectedly, glucose tolerance was improved (p< 0.05) in young βMcu-KO (<12 weeks), but not in older animals vs WT mice.Conclusions/interpretationMCU is crucial for mitochondrial Ca2+ uptake in pancreatic beta cells and is required for normal GSIS. The apparent compensatory mechanisms that maintain glucose tolerance in βMcu-KO mice remain
Ma Y, Ratnasabapathy R, De Backer I, et al., 2020, Glucose in the hypothalamic paraventricular nucleus regulates GLP-1 release, JCI insight, Vol: 5, ISSN: 2379-3708
Glucokinase (GK) is highly expressed in the hypothalamic paraventricular nucleus (PVN); however, its role is currently unknown. We found that GK in the PVN acts as part of a glucose-sensing mechanism within the PVN that regulates glucose homeostasis by controlling glucagon-like peptide 1 (GLP-1) release. GLP-1 is released from enteroendocrine L cells in response to oral glucose. Here we identify a brain mechanism critical to the release of GLP-1 in response to oral glucose. We show that increasing expression of GK or injection of glucose into the PVN increases GLP-1 release in response to oral glucose. On the contrary, decreasing expression of GK or injection of nonmetabolizable glucose into the PVN prevents GLP-1 release. Our results demonstrate that gluco-sensitive GK neurons in the PVN are critical to the response to oral glucose and subsequent release of GLP-1.
Clough TJ, Baxan N, Coakley EJ, et al., 2020, Synthesis and in vivo behaviour of an exendin-4-based MRI probe capable of beta-cell-dependent contrast enhancement in the pancreas, Dalton Transactions: an international journal of inorganic chemistry, Vol: 49, Pages: 4732-4740, ISSN: 1477-9226
Global rates of diabetes mellitus are increasing, and treatment of the disease consumes a growing proportion of healthcare spending across the world. Pancreatic β-cells, responsible for insulin production, decline in mass in type 1 and, to a more limited degree, in type 2 diabetes. However, the extent and rate of loss in both diseases differs between patients resulting in the need for the development of novel diagnostic tools, which could quantitatively assess changes in mass of β-cells over time and potentially lead to earlier diagnosis and improved treatments. Exendin-4, a potent analogue of glucagon-like-peptide 1 (GLP-1), binds to the receptor GLP-1R, whose expression is enriched in β-cells. GLP-1R has thus been used in the past as a means of targeting probes for a wide variety of imaging modalities to the endocrine pancreas. However, exendin-4 conjugates designed specifically for MRI contrast agents are an under-explored area. In the present work, the synthesis and characterization of an exendin-4-dota(ga)-Gd(III) complex, GdEx, is reported, along with its in vivo behaviour in healthy and in β-cell-depleted C57BL/6J mice. Compared to the ubiquitous probe, [Gd(dota)]−, GdEx shows selective uptake by the pancreas with a marked decrease in accumulation observed after the loss of β-cells elicited by deleting the microRNA processing enzyme, DICER. These results open up pathways towards the development of other targeted MRI contrast agents based on similar chemistry methodology.
Fang Z, Chen S, Pickford P, et 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.
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