Imperial College London

ProfessorGuyRutter

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Chair in Cell Biology and Head of Cell Biology
 
 
 
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Contact

 

+44 (0)20 7594 3340g.rutter Website

 
 
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Assistant

 

Ms Shazi Singh +44 (0)20 7594 3391

 
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Location

 

327ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

545 results found

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, Keong Teo AK, 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, Molecular Metabolism, Vol: 40, ISSN: 2212-8778

OBJECTIVE: Risk alleles for type 2 diabetes at the STARD10 locus are associated with lowered STARD10 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 the role of the protein in controlling proinsulin processing and insulin granule biogenesis and maturation. METHODS: We used isolated islets from mice deleted selectively in the β-cell for Stard10 (βStard10KO) and performed electron microscopy, pulse-chase, RNA sequencing, and lipidomic analyses. Proteomic analysis of STARD10 binding partners was executed in the INS1 (832/13) cell line. X-ray crystallography followed by molecular docking and lipid overlay assay was performed on purified STARD10 protein. RESULTS: βStard10KO 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 versus wild-type islets. The solution of the crystal structure of STARD10 to 2.3 Å resolution revealed a binding pocket capable of accommodating polyphosphoinositides, and STARD10 was shown to bind to inositides phosphorylated at the 3' position. Lipidomic analysis of âStard10KO islets demonstrated changes in phosphatidylinositol levels, and the inositol lipid kinase PIP4K2C was identified as a STARD10 binding partner. Also consistent with roles for STARD10 in phosphoinositide signalling, the phosphoinositide-binding proteins Pirt and Synaptotagmin 1 were amongst the differentially expressed genes in βStard10KO islets. CONCLUSION: Our data indicate that STARD10 binds to, and may transp

Journal article

Ralston JC, Nguyen-Tu M-S, Lyons CL, Cooke AA, Murphy AM, Falvey A, Finucane OM, McGillicuddy FC, Rutter GA, Roche HMet 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

Journal article

Amouyal C, Castel J, Guay C, Lacombe A, Denom J, Migrenne-Li S, Rouault C, Marquet F, Georgiadou E, Stylianides T, Luquet S, Le Stunff H, Scharfmann R, Clément K, Rutter GA, Taboureau O, Magnan C, Regazzi R, Andreelli Fet 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

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

Journal article

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

Journal article

Jones B, Pickford P, Lucey M, Tomas-Catala A, Minnion J, Bitsi S, Ungewiss J, Schoeneberg K, Rutter G, Bloom Set 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.

Journal article

Mao D, Tian XY, Mao D, Hung SW, Wang CC, Lau CBS, Lee HM, Wong CK, Chow E, Xing M, Cao H, Ma RC, Chan PKS, Kong APS, Li JJX, Rutter GA, Tam WH, Chan JCNet al., 2020, A polysaccharide extract from the medicinal plant Maidong inhibits the IKK-NF-κB pathway and IL-1β-induced islet inflammation and increases insulin secretion., J Biol Chem

The herb dwarf lilyturf tube (Maidong, Ophiopogonis Radix) is widely used in Chinese Traditional Medicine to manage diabetes and its complications. However, the role of Maidong polysaccharide extract (MPE) in pancreatic β-cell function is unclear. Here, we investigated whether MPE protects β-cell function and studied the underlying mechanisms. We treated db/db and high-fat diet (HFD)-induced obese mice with 800 or 400 mg/kg MPE or water for 4 weeks, followed by an oral glucose tolerance test. Pancreas and blood were collected for molecular analyses, and clonal MIN6 β cells and primary islets from HFD-induced obese mice and normal chow diet (NCD)-fed mice were used in additional analyses. In vivo, MPE both increased insulin secretion and reduced blood glucose in the db/db mice, but increased only insulin secretion in the HFD-induced obese mice. MPE substantially increased the β-cell area in both models (3-fold and 2-fold, p < 0.01, for db/db and HFD mice, respectively). We observed reduced nuclear translocation of the p65 subunit of NFκB in islets of MPE-treated db/db mice, coinciding with enhanced glucose-stimulated insulin secretion (GSIS). In vitro, MPE potentiated GSIS and decreased interleukin 1β (IL-1β) secretion in MIN6 β cells. Incubation of MIN6 cells with tumor necrosis factor α (TNF-α), IFN-γ, and IL-1β amplified IL-1β secretion and inhibited GSIS. These effects were partially reversed with MPE or the I-k-B-kinase β (IKK) inhibitor PS1145, coinciding with reduced activation of p65 and p-IκB in the NF-κB pathway. We conclude that MPE may have potential for therapeutic development for β-cell protection.

Journal article

Pickford P, Lucey M, Fang Z, Bitsi S, de la Serna JB, Broichhagen J, Hodson DJ, Minnion J, Rutter GA, Bloom SR, Tomas A, Jones Bet al., 2020, Signalling, trafficking and glucoregulatory properties of glucagon-like peptide-1 receptor agonists exendin-4 and lixisenatide., British Journal of Pharmacology, 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.

Journal article

Georgiadou E, Haythorne E, Dickerson MT, Lopez-Noriega L, Pullen TJ, da Silva Xavier G, Davis SPX, Martinez-Sanchez A, Semplici F, Rizzuto R, McGinty JA, French PM, Cane MC, Jacobson DA, Leclerc I, Rutter GAet 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

Journal article

Ma Y, Ratnasabapathy R, De Backer I, Izzi-Engbeaya C, Nguyen-Tu M-S, Cuenco J, Jones B, John C, Lam B, Rutter G, Yeo G, Dhillo W, Gardiner Jet 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.

Journal article

Clough TJ, Baxan N, Coakley EJ, Rivas C, Zhao L, Leclerc I, Martinez-Sanchez A, Rutter GA, Long NJet 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, Vol: 49, Pages: 4732-4740, ISSN: 1477-9226

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

Xavier GDS, Rutter GA, 2020, Metabolic and Functional Heterogeneity in Pancreatic beta Cells, JOURNAL OF MOLECULAR BIOLOGY, Vol: 432, Pages: 1395-1406, ISSN: 0022-2836

Journal article

Khan R, Tomas A, Rutter GA, 2020, Effects on pancreatic Beta and other Islet cells of the glucose-dependent insulinotropic polypeptide, PEPTIDES, Vol: 125, ISSN: 0196-9781

Journal article

Akalestou E, Genser L, Rutter GA, 2020, Glucocorticoid metabolism in obesity and following weight loss, Frontiers in Endocrinology, Vol: 11, ISSN: 1664-2392

Glucocorticoids are steroid hormones produced by the adrenal cortex and are essential for the maintenance of various metabolicand homeostatic functions. Their function is regulated at the tissue level by 11β‐hydroxysteroid dehydrogenases and they signalthrough the glucocorticoid receptor, a ligand-dependent transcription factor. Clinical observations have linked excess glucocorticoidlevels with profound metabolic disturbances of intermediate metabolism resulting in abdominal obesity, insulin resistance anddyslipidaemia. In this review, we discuss the physiological mechanisms of glucocorticoid secretion, regulation and function, andsurvey the metabolic consequences of excess glucocorticoid action resulting from elevated release and activation or up-regulatedsignalling. Finally, we summarise the reported impact of weight loss by diet, exercise or bariatric surgery on circulating andtissue-specific glucocorticoid levels and examine the therapeutic possibility of reversing glucocorticoid-associated metabolicdisorders.

Journal article

Davis SPX, Kumar S, Alexandrov Y, Bhargava A, da Silva Xavier G, Rutter GA, Frankel P, Sahai E, Flaxman S, French PMW, McGinty Jet al., 2019, Convolutional neural networks for reconstruction of undersampled optical projection tomography data applied to in vivo imaging of zebrafish., Journal of Biophotonics, Vol: 12, ISSN: 1864-063X

Optical projection tomography (OPT) is a 3D mesoscopic imaging modality that can utilize absorption or fluorescence contrast. 3D images can be rapidly reconstructed from tomographic data sets sampled with sufficient numbers of projection angles using the Radon transform, as is typically implemented with optically cleared samples of the mm-to-cm scale. For in vivo imaging, considerations of phototoxicity and the need to maintain animals under anesthesia typically preclude the acquisition of OPT data at a sufficient number of angles to avoid artifacts in the reconstructed images. For sparse samples, this can be addressed with iterative algorithms to reconstruct 3D images from undersampled OPT data, but the data processing times present a significant challenge for studies imaging multiple animals. We show here that convolutional neural networks (CNN) can be used in place of iterative algorithms to remove artifacts - reducing processing time for an undersampled in vivo zebrafish dataset from 77 to 15 minutes. We also show that using CNN produces reconstructions of equivalent quality to CS with 40% fewer projections. We further show that diverse training data classes, for example ex vivo mouse tissue data, can be used for CNN-based reconstructions of OPT data of other species including live zebrafish.

Journal article

Rutter GA, 2019, DIABETES pancreatic islet secretion: gabbling via GABA, Nature Metabolism, Vol: 1, Pages: 1032-1033, ISSN: 2522-5812

Journal article

Dwivedi OP, Lehtovirta M, Hastoy B, Chandra V, Krentz NAJ, Kleiner S, Jain D, Richard A-M, Abaitua F, Beer NL, Grotz A, Prasad RB, Hansson O, Ahlqvist E, Krus U, Artner I, Suoranta A, Gomez D, Baras A, Champon B, Payne AJ, Moralli D, Thomsen SK, Kramer P, Spiliotis I, Ramracheya R, Chabosseau P, Theodoulou A, Cheung R, van de Bunt M, Flannick J, Trombetta M, Bonora E, Wolheim CB, Sarelin L, Bonadonna RC, Rorsman P, Davies B, Brosnan J, McCarthy MI, Otonkoski T, Lagerstedt JO, Rutter GA, Gromada J, Gloyn AL, Tuomi T, Groop Let al., 2019, Loss of ZnT8 function protects against diabetes by enhanced insulin secretion., Nature Genetics, Vol: 51, Pages: 1596-1606, ISSN: 1061-4036

A rare loss-of-function allele p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is enriched in Western Finland, protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with individuals matched for the genotype of a common T2D-risk allele in SLC30A8, p.Arg325. In genome-edited human induced pluripotent stem cell (iPSC)-derived β-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human β cells, loss of SLC30A8 leads to increased glucose responsiveness and reduced KATP channel function similar to isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aimed at maintaining insulin secretion capacity in T2D.

Journal article

Marselli L, Suleiman M, Colli ML, Pocai A, Burdet F, Turatsinze J-V, Steinmeyer K, Thorens B, Schulte AM, Ibberson M, Rutter GA, Norquay L, Eizirik DL, Cnop M, Marchetti Pet al., 2019, The transcriptome of persistent or transient human beta cell dysfunction caused by lipo-glucotoxicity correlates with the gene expression signature of type 2 diabetic islets, 55th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S167-S167, ISSN: 0012-186X

Conference paper

Bitsi S, Buenaventura T, Laughlin WE, Burgoyne T, Lyu Z, Grimes J, Koszegi Z, Calebiro D, Rutter GA, Bloom SR, Jones B, Tomas Aet al., 2019, GLP-1R translocation to plasma membrane nanodomains and downstream signalling are modulated by agonist-dependent receptor palmitoylation, 55th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S215-S215, ISSN: 0012-186X

Conference paper

Noriega LL, Sanchez AM, Callingham R, Akalestou E, Nguyen-Tu M-S, Leclerc I, Cardenas L, Gadue PJ, Marchetti P, Pullen TJ, Rutter GAet al., 2019, The long non-coding RNA PAX6-AS1 controls human beta cell identity, 55th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S205-S206, ISSN: 0012-186X

Conference paper

Jaafar R, Tran S, Shah A, Sun G, Valdearcos M, Marchetti P, Masini M, Swisa A, Giacometti S, Bernal-Mizrachi E, Matveyenko A, Hebrok M, Dor Y, Rutter GA, Koliwad SK, Bhushan Aet al., 2019, mTORC1 to AMPK switching underlies β-cell metabolic plasticity during maturation and diabetes., Journal of Clinical Investigation, Vol: 130, Pages: 4124-4137, ISSN: 0021-9738

Pancreatic beta cells (β-cells) differentiate during fetal life, but only postnatally acquire the capacity for glucose-stimulated insulin secretion (GSIS). How this happens is not clear. In exploring what molecular mechanisms drive the maturation of β-cell function, we found that the control of cellular signaling in β-cells fundamentally switched from the nutrient sensor target of rapamycin (mTORC1) to the energy sensor 5'-adenosine monophosphate-activated protein kinase (AMPK), and that this was critical for functional maturation. Moreover, AMPK was activated by the dietary transition taking place during weaning, and this in turn inhibited mTORC1 activity to drive the adult β-cell phenotype. While forcing constitutive mTORC1 signaling in adult β-cells relegated them to a functionally immature phenotype with characteristic transcriptional and metabolic profiles, engineering the switch from mTORC1 to AMPK signaling was sufficient to promote β-cell mitochondrial biogenesis, a shift to oxidative metabolism, and functional maturation. We also found that type 2 diabetes, a condition marked by both mitochondrial degeneration and dysregulated GSIS, was associated with a remarkable reversion of the normal AMPK-dependent adult β-cell signature to a more neonatal one characterized by mTORC1 activation. Manipulating the way in which cellular nutrient signaling pathways regulate β-cell metabolism may thus offer new targets to improve β-cell function in diabetes.

Journal article

Buenaventura T, Bitsi S, Laughlin WE, Burgoyne T, Lyu Z, Oqua AI, Norman H, McGlone ER, Klymchenko AS, Corrêa IR, Walker A, Inoue A, Hanyaloglu A, Grimes J, Koszegi Z, Calebiro D, Rutter GA, Bloom SR, Jones B, Tomas A, Buenaventura T, Bitsi S, Laughlin W, Burgoyne T, Lyu Z, Oqua A, Norman H, McGlone E, Klymchenko A, Corrêa Jr I, Walker A, Inoue A, Hanyaloglu A, Grimes J, Koszegi Z, Calebiro D, Rutter G, Bloom S, Jones B, Tomas Catala Aet al., 2019, Agonist-induced membrane nanodomain clustering drives GLP-1 receptor responses in pancreatic beta cells., PLoS Biology, Vol: 17, Pages: 1-40, ISSN: 1544-9173

The glucagon-like peptide-1 receptor (GLP-1R), a key pharmacological target in type 2 diabetes (T2D) and obesity, undergoes rapid endocytosis after stimulation by endogenous and therapeutic agonists. We have previously highlighted the relevance of this process in fine-tuning GLP-1R responses in pancreatic beta cells to control insulin secretion. In the present study, we demonstrate an important role for the translocation of active GLP-1Rs into liquid-ordered plasma membrane nanodomains, which act as hotspots for optimal coordination of intracellular signaling and clathrin-mediated endocytosis. This process is dynamically regulated by agonist binding through palmitoylation of the GLP-1R at its carboxyl-terminal tail. Biased GLP-1R agonists and small molecule allosteric modulation both influence GLP-1R palmitoylation, clustering, nanodomain signaling, and internalization. Downstream effects on insulin secretion from pancreatic beta cells indicate that these processes are relevant to GLP-1R physiological actions and might be therapeutically targetable.

Journal article

Sposito T, Tu M-SN, Rutter GA, Novelli M, Thirlwell C, Salomoni Pet al., 2019, The PanNET-related histone H3.3 chaperone Daxx regulates lineage specification and tissue homeostasis in the pancreas, Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472

Conference paper

Salem V, Delgadillo Silva L, Suba K, Mousavy Gharavy SN, Akhtar N, Martin-Alonso A, Gaboriau DCA, Rothery SM, Styliandes T, Carrat G, Pullen TJ, Pal Singh S, Hodson DJ, Leclerc I, Shapiro AMJ, Marchetti P, Briant LB, Distaso W, Ninov N, Rutter Get al., 2019, Leader β cells coordinate Ca2+ dynamics across pancreatic islets in vivo, Nature Metabolism, Vol: 1, Pages: 615-629, ISSN: 2522-5812

Pancreatic β-cells form highly connected networks within isolated islets. Whether this behaviour pertains to the situation in vivo, after innervation and during continuous perfusion with blood, is unclear. In the present study, we used the recombinant Ca2+ sensor GCaMP6 to assess glucose-regulated connectivity in living zebrafish Danio rerio, and in murine or human islets transplanted into the anterior eye chamber. In each setting, Ca2+ waves emanated from temporally defined leader β-cells, and three-dimensional connectivity across the islet increased with glucose stimulation. Photoablation of zebrafish leader cells disrupted pan-islet signalling, identifying these as likely pacemakers. Correspondingly, in engrafted mouse islets, connectivity was sustained during prolonged glucose exposure, and super-connected ‘hub’ cells were identified. Granger causality analysis revealed a controlling role for temporally defined leaders, and transcriptomic analyses revealed a discrete hub cell fingerprint. We thus define a population of regulatory β-cells within coordinated islet networks in vivo. This population may drive Ca2+ dynamics and pulsatile insulin secretion.

Journal article

Akalestou E, Noriega LL, Chabosseau PL, Leclerc I, Rutter GAet al., 2019, Inhibition of Kidney SGLT2 Expression following Bariatric Surgery in Mice, 79th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797

Conference paper

Cheung R, Pizza G, Rolando DM, Chabosseau PL, Nguyen-Tu M-S, Leclerc I, Rutter GA, Martinez-Sanchez Aet al., 2019, miR-125b Is Regulated by Glucose via AMPK and Impairs beta-Cell Function, 79th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797

Conference paper

Salem V, Suba K, Alonso AM, Chabosseau PL, Georgiadou E, Stylianides T, Briant L, Hodson D, Carrat G, Leclerc I, Gaboriau DC, Rothery SM, Rutter GAet al., 2019, Real-Time In Vivo Imaging of Whole Islet Ca2+Dynamics Reveals Glucose -Induced Changes in Beta-Cell Connectivity in Mouse and Human Islets, 79th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797

Conference paper

Gharavy SNM, Hu M, Gadue P, Leclerc I, Martinez-Sanchez A, Rutter GAet al., 2019, Roles for the Type 2 diabetes-associated genes C2CD4A and C2CD4B in the control of glucose homeostasis and insulin secretion, Publisher: WILEY, Pages: 43-43, ISSN: 0742-3071

Conference paper

Hu M, Rutter GA, 2019, Impact of Type 2 diabetes-associated variants at the STARD10 locus on chromatin conformation and human beta cell function, Publisher: WILEY, Pages: 21-21, ISSN: 0742-3071

Conference paper

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