Imperial College London

ProfessorGuyRutter

Faculty of MedicineDepartment of Medicine

Visiting Professor
 
 
 
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Contact

 

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

 
 
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Location

 

ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

674 results found

Slieker RC, Münch M, Donnelly LA, Bouland GA, Dragan I, Kuznetsov D, Elders PJM, Rutter GA, Ibberson M, Pearson ER, 't Hart LM, van de Wiel MA, Beulens JWJet al., 2024, An omics-based machine learning approach to predict diabetes progression: a RHAPSODY study., Diabetologia, Vol: 67, Pages: 885-894

AIMS/HYPOTHESIS: People with type 2 diabetes are heterogeneous in their disease trajectory, with some progressing more quickly to insulin initiation than others. Although classical biomarkers such as age, HbA1c and diabetes duration are associated with glycaemic progression, it is unclear how well such variables predict insulin initiation or requirement and whether newly identified markers have added predictive value. METHODS: In two prospective cohort studies as part of IMI-RHAPSODY, we investigated whether clinical variables and three types of molecular markers (metabolites, lipids, proteins) can predict time to insulin requirement using different machine learning approaches (lasso, ridge, GRridge, random forest). Clinical variables included age, sex, HbA1c, HDL-cholesterol and C-peptide. Models were run with unpenalised clinical variables (i.e. always included in the model without weights) or penalised clinical variables, or without clinical variables. Model development was performed in one cohort and the model was applied in a second cohort. Model performance was evaluated using Harrel's C statistic. RESULTS: Of the 585 individuals from the Hoorn Diabetes Care System (DCS) cohort, 69 required insulin during follow-up (1.0-11.4 years); of the 571 individuals in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) cohort, 175 required insulin during follow-up (0.3-11.8 years). Overall, the clinical variables and proteins were selected in the different models most often, followed by the metabolites. The most frequently selected clinical variables were HbA1c (18 of the 36 models, 50%), age (15 models, 41.2%) and C-peptide (15 models, 41.2%). Base models (age, sex, BMI, HbA1c) including only clinical variables performed moderately in both the DCS discovery cohort (C statistic 0.71 [95% CI 0.64, 0.79]) and the GoDARTS replication cohort (C 0.71 [95% CI 0.69, 0.75]). A more extensive model including HDL-cholesterol and C-peptide performed better in

Journal article

Cuozzo F, Viloria K, Shilleh AH, Nasteska D, Frazer-Morris C, Tong J, Jiao Z, Boufersaoui A, Marzullo B, Rosoff DB, Smith HR, Bonner C, Kerr-Conte J, Pattou F, Nano R, Piemonti L, Johnson PRV, Spiers R, Roberts J, Lavery GG, Clark A, Ceresa CDL, Ray DW, Hodson L, Davies AP, Rutter GA, Oshima M, Scharfmann R, Merrins MJ, Akerman I, Tennant DA, Ludwig C, Hodson DJet al., 2024, LDHB contributes to the regulation of lactate levels and basal insulin secretion in human pancreatic β cells., Cell Rep, Vol: 43

Using 13C6 glucose labeling coupled to gas chromatography-mass spectrometry and 2D 1H-13C heteronuclear single quantum coherence NMR spectroscopy, we have obtained a comparative high-resolution map of glucose fate underpinning β cell function. In both mouse and human islets, the contribution of glucose to the tricarboxylic acid (TCA) cycle is similar. Pyruvate fueling of the TCA cycle is primarily mediated by the activity of pyruvate dehydrogenase, with lower flux through pyruvate carboxylase. While the conversion of pyruvate to lactate by lactate dehydrogenase (LDH) can be detected in islets of both species, lactate accumulation is 6-fold higher in human islets. Human islets express LDH, with low-moderate LDHA expression and β cell-specific LDHB expression. LDHB inhibition amplifies LDHA-dependent lactate generation in mouse and human β cells and increases basal insulin release. Lastly, cis-instrument Mendelian randomization shows that low LDHB expression levels correlate with elevated fasting insulin in humans. Thus, LDHB limits lactate generation in β cells to maintain appropriate insulin release.

Journal article

Yu V, Yong F, Marta A, Khadayate S, Osakwe A, Bhattacharya S, Varghese S, Chabosseau P, Tabibi S, Chen K, Georgiadou E, Parveen N, Suleiman M, Stamoulis Z, Marselli L, De Luca C, Tesi M, Ostinelli G, Delgadillo-Silva L, Wu X, Hatanaka Y, Montoya A, Elliott J, Bhavik P, Demchenko N, Whilding C, Hajkova P, Shliaha P, Kramer H, Ali Y, Marchetti P, Sladek R, Dhawan S, Withers D, Rutter G, Millership Set al., 2024, Differential CpG methylation at Nnat in the early establishment of beta cell heterogeneity, Diabetologia, ISSN: 0012-186X

Aims/hypothesis: Beta cells within the pancreatic islet represent a heterogenous population wherein individual sub-groups of cells make distinct contributions to the overall control of insulin secretion. These include a subpopulation of highly-connected ‘hub’ cells, important for the propagation of intercellular Ca2+ waves. Functional subpopulations have also been demonstrated in human beta cells, with an altered subtype distribution apparent in type 2 diabetes. At present, the molecular mechanisms through which beta cell hierarchy is established are poorly understood. Changes at the level of the epigenome provide one such possibility which we explore here by focussing on the imprinted gene neuronatin (Nnat), which is required for normal insulin synthesis and secretion.Methods: Single cell RNA-seq datasets were examined using Seurat 4.0 and ClusterProfiler running under R. Transgenic mice expressing eGFP under the control of the Nnat enhancer/promoter regions were generated for fluorescence-activated cell (FAC) sorting of beta cells and downstream analysis of CpG methylation by bisulphite and RNA sequencing, respectively. Animals deleted for the de novo methyltransferase, DNMT3A from the pancreatic progenitor stage were used to explore control of promoter methylation. Proteomics was performed using affinity purification mass spectrometry and Ca2+ dynamics explored by rapid confocal imaging of Cal-520 and Cal-590. Insulin secretion was measured using Homogeneous Time Resolved Fluorescence Imaging.Results: Nnat mRNA was differentially expressed in a discrete beta cell population in a developmental stage- and DNA methylation (DNMT3A)-dependent manner. Thus, pseudo-time analysis of embryonic data sets demonstrated the early establishment of Nnat-positive and negative subpopulations during embryogenesis. NNAT expression is also restricted to a subset of beta cells across the human islet that is maintained throughout adult life. NNAT+ beta cells also displayed

Journal article

Li S, Dragan J, Tran VDT, Fung CH, Kuznetsov D, Hansen MK, Beulens JWJ, Hart LMT, Slieker RC, Donnelly LA, Gerl MJ, Klose C, Mehl F, Simons K, Elders PJM, Pearson ER, Rutter G, Ibberson Met al., 2024, Multi-omics subgroups associated with glycaemic deterioration in type 2 diabetes: an IMI-RHAPSODY study, Frontiers in Endocrinology, Vol: 15, ISSN: 1664-2392

Introduction: Type 2 diabetes (T2D) onset, progression and outcomes differ substantially between individuals. Multi-omics analyses may allow a deeper understanding of these differences and ultimately facilitate personalised treatments. Here, in an unsupervised “bottom-up” approach, we attempt to group T2D patients based solely on -omics data generated from plasma.Methods: Circulating plasma lipidomic and proteomic data from two independent clinical cohorts, Hoorn Diabetes Care System (DCS) and Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS), were analysed using Similarity Network Fusion. The resulting patient network was analysed with Logistic and Cox regression modelling to explore relationships between plasma -omic profiles and clinical characteristics.Results: From a total of 1,134 subjects in the two cohorts, levels of 180 circulating plasma lipids and 1195 proteins were used to separate patients into two subgroups. These differed in terms of glycaemic deterioration (Hazard Ratio=0.56;0.73), insulin sensitivity and secretion (C-peptide, p=3.7e-11;2.5e-06, DCS and GoDARTS, respectively; Homeostatic model assessment 2 (HOMA2)-B; -IR; -S, p=0.0008;4.2e-11;1.1e-09, only in DCS). The main molecular signatures separating the two groups included triacylglycerols, sphingomyelin, testican-1 and interleukin 18 receptor.Conclusions: Using an unsupervised network-based fusion method on plasma lipidomics and proteomics data from two independent cohorts, we were able to identify two subgroups of T2D patients differing in terms of disease severity. The molecular signatures identified within these subgroups provide insights into disease mechanisms and possibly new prognostic markers for T2D.

Journal article

Rutter G, Ghiasi S, 2024, Proinflammatory Cytokines Suppress Nonsense-Mediated RNA Decay to Impair Regulated Transcript Isoform Processing in Pancreatic β-Cells, Frontiers in Endocrinology, ISSN: 1664-2392

Journal article

Ghiasi SM, Marchetti P, Piemonti L, Nielsen JH, Porse BT, Mandrup-Poulsen T, Rutter GAet al., 2024, Proinflammatory Cytokines Suppress Nonsense-Mediated RNA Decay to Impair Regulated Transcript Isoform Processing in Pancreatic β-Cells., bioRxiv

Proinflammatory cytokines are implicated in pancreatic β-cell failure in type 1 and type 2 diabetes and are known to stimulate alternative RNA splicing and the expression of Nonsense-Mediated RNA Decay (NMD) components. Here, we investigate whether cytokines regulate NMD activity and identify transcript isoforms targeted in β-cells. A luciferase-based NMD reporter transiently expressed in rat INS1(832/13), human-derived EndoC-βH3 or dispersed human islet cells is used to examine the effect of proinflammatory cytokines (Cyt) on NMD activity. Gain- or loss-of function of two key NMD components UPF3B and UPF2 is used to reveal the effect of cytokines on cell viability and function. RNA-sequencing and siRNA-mediated silencing are deployed using standard techniques. Cyt attenuate NMD activity in insulin-producing cell lines and primary human β-cells. These effects are found to involve ER stress and are associated with downregulation of UPF3B. Increases or decreases in NMD activity achieved by UPF3B overexpression (OE) or UPF2 silencing, raises or lowers Cyt-induced cell death, respectively, in EndoC-βH3 cells, and are associated with decreased or increased insulin content, respectively. No effects of these manipulations are observed on glucose-stimulated insulin secretion. Transcriptomic analysis reveals that Cyt increase alternative splicing (AS)-induced exon skipping in the transcript isoforms, and this is potentiated by UPF2 silencing. Gene enrichment analysis identifies transcripts regulated by UPF2 silencing whose proteins are localized and/or functional in extracellular matrix (ECM) including the serine protease inhibitor SERPINA1/α-1-antitrypsin, whose silencing sensitises β-cells to Cyt cytotoxicity. Cytokines suppress NMD activity via UPR signalling, potentially serving as a protective response against Cyt-induced NMD component expression. Our findings highlight the central importance of RNA turnover in β-cell responses t

Journal article

Cherkaoui I, Du Q, Elgi D, Misra S, Rutter Get al., 2024, Optimized protocol for generating functional pancreatic insulin-secreting cells from human pluripotent stem cells, Journal of Visualized Experiments, Vol: 204, ISSN: 1940-087X

Human pluripotent stem cells (hPSCs) can differentiate into any kind of cell, making them an excellent alternative source of human pancreatic β-cells. hPSCs can either be embryonic stem cells (hESCs) derived from the blastocyst or induced pluripotent cells (hiPSCs) generated directly from somatic cells using a reprogramming process. Here a video-based protocol is presented to outline the optimal culture and passage conditions for hPSCs, prior to their differentiation and subsequent generation of insulin-producing pancreatic cells. This methodology follows the six-stage process for β-cell directed differentiation, wherein hPSCs differentiate into definitive endoderm (DE), primitive gut tube, posterior foregut fate, pancreatic progenitors, pancreatic endocrine progenitors, and ultimately pancreatic β-cells. It is noteworthy that this differentiation methodology takes a period of 27 days to generate human pancreatic β-cells. The potential of insulin secretion was evaluated through three experiments, which included immunostaining and glucose-stimulated insulin secretion.

Journal article

He S, Silva LD, Rutter GA, Lim GEet al., 2023, A high-throughput screening approach to discover potential colorectal cancer chemotherapeutics: Repurposing drugs to disrupt 14-3-3 protein-BAD interactions., bioRxiv

Inducing apoptosis in different types of cancer cells is an effective therapeutic strategy. However, the success of existing chemotherapeutics can be compromised by tumor cell resistance and systemic off-target effects. Therefore, the discovery of pro-apoptotic compounds with minimal systemic side-effects is crucial. 14-3-3 proteins are molecular scaffolds that serve as important regulators of cell survival. Our previous study demonstrated that 14-3-3ζ can sequester BAD, a pro-apoptotic member of the BCL-2 protein family, in the cytoplasm and prevent its translocation to mitochondria to inhibit the induction of apoptosis. Despite being a critical mechanism of cell survival, it is unclear whether disrupting 14-3-3 protein:BAD interactions could be harnessed as a chemotherapeutic approach. Herein, we established a BRET-based high-throughput drug screening approach (Z'-score= 0.52) capable of identifying molecules that can disrupt 14-3-3ζ:BAD interactions. An FDA-approved drug library containing 1971 compounds was used for screening, and the capacity of identified hits to induce cell death was examined in NIH3T3-fibroblasts and colorectal cancer cell lines, HT-29 and Caco-2. Our in vitro results suggest that terfenadine, penfluridol, and lomitapide could be potentially repurposed for treating colorectal cancer. Moreover, our screening method demonstrates the feasibility of identifying pro-apoptotic agents that can be applied towards conditions where aberrant cell growth or function are key determinants of disease pathogenesis.

Journal article

So WY, Liao Y, Liu WN, Rutter GA, Han Wet al., 2023, Paired box 6 gene delivery preserves beta cells and improves islet transplantation efficacy, EMBO Molecular Medicine, Vol: 15, ISSN: 1757-4676

Loss of pancreatic beta cells is the central feature of all forms of diabetes. Current therapies fail to halt the declined beta cell mass. Thus, strategies to preserve beta cells are imperatively needed. In this study, we identified paired box 6 (PAX6) as a critical regulator of beta cell survival. Under diabetic conditions, the human beta cell line EndoC-βH1, db/db mouse and human islets displayed dampened insulin and incretin signalings and reduced beta cell survival, which were alleviated by PAX6 overexpression. Adeno-associated virus (AAV)-mediated PAX6 overexpression in beta cells of streptozotocin-induced diabetic mice and db/db mice led to a sustained maintenance of glucose homeostasis. AAV-PAX6 transduction in human islets reduced islet graft loss and improved glycemic control after transplantation into immunodeficient diabetic mice. Our study highlights a previously unappreciated role for PAX6 in beta cell survival and raises the possibility that ex vivo PAX6 gene transfer into islets prior to transplantation might enhance islet graft function and transplantation outcome.

Journal article

Li S, Rutter G, Ibberson M, Tran V, Hansen M, Hart LT, Slieker R, Donnelly L, Gerl M, Mehl Fet al., 2023, AN UNSUPERVISED APPROACH TO SYSTEMATICALLY ANALYSIS THE MULTI-OMICS PROFILES ASSOCIATED WITH T2D INSULIN RESISTANCE AND BETA-CELL FUNCTION: AN EU-RHAPSODY STUDY, Canadian Journal of Diabetes, Vol: 47, Pages: S142-S142, ISSN: 1499-2671

Journal article

Thompson PJ, Pipella J, Rutter G, Gaisano HY, Santamaria Pet al., 2023, Islet autoimmunity in human type 1 diabetes: initiation and progression from the perspective of the beta cell, Diabetologia, Vol: 66, Pages: 1971-1982, ISSN: 0012-186X

Type 1 diabetes results from the poorly understood process of islet autoimmunity, which ultimately leads to the loss of functional pancreatic beta cells. Mounting evidence supports the notion that the activation and evolution of islet autoimmunity in genetically susceptible people is contingent upon early life exposures affecting the islets, especially beta cells. Here, we review some of the recent advances and studies that highlight the roles of these changes as well asantigen presentation and stress response pathways in beta cells in the onset and propagation of the autoimmune process in type 1 diabetes. Future progress in this area holds promise for advancing islet- and beta cell-directed therapies that could be implemented in the early stages ofthe disease and could be combined with immunotherapies.

Journal article

Hu M, Kim I, Morán I, Peng W, Sun O, Bonnefond A, Khamis A, Bonas-Guarch S, Froguel P, Rutter GAet al., 2023, Multiple genetic variants at the SLC30A8 locus affect local super-enhancer activity and influence pancreatic β-cell survival and function., bioRxiv

Variants at the SLC30A8 locus are associated with type 2 diabetes (T2D) risk. The lead variant, rs13266634, encodes an amino acid change, Arg325Trp (R325W), at the C-terminus of the secretory granule-enriched zinc transporter, ZnT8. Although this protein-coding variant was previously thought to be the sole driver of T2D risk at this locus, recent studies have provided evidence for lowered expression of SLC30A8 mRNA in protective allele carriers. In the present study, combined allele-specific expression (cASE) analysis in human islets revealed multiple variants that influence SLC30A8 expression. Epigenomic mapping identified an islet-selective enhancer cluster at the SLC30A8 locus, hosting multiple T2D risk and cASE associations, which is spatially associated with the SLC30A8 promoter and additional neighbouring genes. Deletions of variant-bearing enhancer regions using CRISPR-Cas9 in human-derived EndoC-βH3 cells lowered the expression of SLC30A8 and several neighbouring genes, and improved insulin secretion. Whilst down-regulation of SLC30A8 had no effect on beta cell survival, loss of UTP23, RAD21 or MED30 markedly reduced cell viability. Although eQTL or cASE analyses in human islets did not support the association between these additional genes and diabetes risk, the transcriptional regulator JQ1 lowered the expression of multiple genes at the SLC30A8 locus and enhanced stimulated insulin secretion.

Journal article

Millership SJ, Yu V, Yong F, Marta A, Chen K, Georgiadou E, Bhattacharya S, Parveen N, Khadayate S, Stamoulis Z, Ali Y, Dhawan S, Withers DJ, Rutter GAet al., 2023, Establishment of beta cell heterogeneity via differential CpG methylation at Nnat, 59th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S206-S206, ISSN: 0012-186X

Conference paper

Xiao J, El Eid L, Buenaventura T, Boutry R, Bonnefond A, Jones B, Rutter GA, Froguel P, Tomas Aet al., 2023, Control of human pancreatic beta cell kinome by glucagon-like peptide-1 receptor biased agonism, Diabetes, Obesity and Metabolism, Vol: 25, Pages: 2105-2119, ISSN: 1462-8902

AimTo determine the kinase activity profiles of human pancreatic beta cells downstream of glucagon-like peptide-1 receptor (GLP-1R) balanced versus biased agonist stimulations.Materials and MethodsThis study analysed the kinomic profiles of human EndoC-βh1 cells following vehicle and GLP-1R stimulation with the pharmacological agonist exendin-4, as well as exendin-4–based biased derivatives exendin-phe1 and exendin-asp3 for acute (10-minute) versus sustained (120-minute) responses, using PamChip protein tyrosine kinase and serine/threonine kinase assays. The raw data were filtered and normalized using BioNavigator. The kinase analyses were conducted with R, mainly including kinase-substrate mapping and Kyoto Encyclopedia of Genes and Genomes pathway analysis.ResultsThe present analysis reveals that kinomic responses are distinct for acute versus sustained GLP-1R agonist exposure, with individual responses associated with agonists presenting specific bias profiles. According to pathway analysis, several kinases, including JNKs, PKCs, INSR and LKB1, are important GLP-1R signalling mediators, constituting potential targets for further research on biased GLP-1R downstream signalling.ConclusionThe results from this study suggest that differentially biased exendin-phe1 and exendin-asp3 can modulate distinct kinase interaction networks. Further understanding of these mechanisms will have important implications for the selection of appropriate anti-type 2 diabetes therapies with optimized downstream kinomic profiles.

Journal article

Firth G, Georgiadou E, Griffiths A, Amrahli M, Kim J, Yu Z, Hu M, Stewart TJ, Leclerc I, Okamoto H, Gomez D, Blower PJ, Rutter Get al., 2023, Impact of an SLC30A8 loss-of-function variant on the pancreatic distribution of zinc and manganese: laser ablation-ICP-MS and positron emission tomography studies in mice, Frontiers in Endocrinology, Vol: 14, Pages: 1-12, ISSN: 1664-2392

Common variants in the SLC30A8 gene, encoding the secretory granule zinc transporter ZnT8 (expressed largely in pancreatic islet alpha and beta cells), are associated with altered risk of type 2 diabetes. Unexpectedly, rare loss-of-function (LoF) variants in the gene, described in heterozygous individuals only, are protective against the disease, even though knockout of the homologous SLC30A8 gene in mice leads to unchanged or impaired glucose tolerance. Here, we aimed to determine how one or two copies of the mutant R138X allele in the mouse SLC30A8 gene impacts the homeostasis of zinc at a whole-body (using non-invasive 62Zn PET imaging to assess the acute dynamics of zinc handling) and tissue/cell level (using LA-ICP-MS to map the long-term distribution of zinc and manganese in the pancreas). Following intravenous administration of [62Zn]Zn-citrate (~7 MBq, 150 μL) in wild-type (WT), heterozygous (R138X+/-) and homozygous (R138X+/+) mutant mice (14-15 weeks old, n = 4 per genotype), zinc dynamics were measured over 60 minutes using PET. Histological, islet hormone immunohistochemistry and elemental analysis with LA-ICP-MS (Zn, Mn, P) were performed on sequential pancreas sections. Bulk Zn and Mn concentration in the pancreas was determined by solution ICP-MS. Our findings reveal that whereas uptake into organs, assessed using PET imaging of 62Zn, is largely unaffected by the R138X variant, mice homozygous of the mutant allele show a substantial lowering (to 40% of WT) of total islet zinc, as anticipated. In contrast, mice heterozygous for this allele, thus mimicking human carriers of LoF alleles, show markedly increased endocrine and exocrine zinc content (1.6-fold increase for both compared to WT), as measured by LA-ICP-MS. Both endocrine and exocrine manganese content were also sharply increased in R138X+/- mice, with smaller increases observed in R138X+/+ mice. These data challenge the view that zinc depletion from the beta cell is the likely underlying dri

Journal article

Rutter GA, Sidarala V, Kaufman BA, Soleimanpour SAet al., 2023, Mitochondrial metabolism and dynamics in pancreatic beta cell glucose sensing, BIOCHEMICAL JOURNAL, Vol: 480, Pages: 773-789, ISSN: 0264-6021

Journal article

Cherkaoui I, Du Q, Dion C, Leitch H, Chabosseau PL, Egli DM, Sachedina D, Wastin J, Misra S, Rutter GAet al., 2023, Differential Impacts of Two Novel HNF1A Variants Associated with Familial Young-Onset Diabetes on Protein Function and Insulin Secretion In Vitro, 83rd Annual Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797

Conference paper

Silva LFD, Rutter GA, Chabosseau PL, Provencher-Girard A, Prat A, Noriega LLet al., 2023, "Leader" β-Cells within the Pancreatic Islet Are a Functionally Stable Subpopulation In Vitro and In Vivo, 83rd Annual Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797

Conference paper

Slieker R, Donnellly L, Akalestou E, Lopez-Noriega L, Melhem R, Gunes A, Abou Azar F, Efanov A, Georgiadou E, Muniangi-Muhitu H, Shiekh M, Giordano G, Åkerlund M, Ahlqvist E, Ashfaq A, Banasik K, Brunak S, Barovic M, Bouland G, Burdet F, Canouil M, Dragan I, Elders P, Fernandez C, Festa A, Fitipaldi H, Froguel P, Gudmundsdottir V, Gudnason V, Gerl M, van der Heijden A, Jennings L, Hansen M, Kim M, Leclerc I, Klose C, Kuznetsov D, Mansour Aly D, Mehl F, Marek D, Melander O, Niknejad A, Ottosson F, Pavo I, Duffin K, Syed S, Shaw J, Cabrera O, Pullen T, Simons K, Solimena M, Suvitaival T, Wretlind A, Rossing P, Lyssenko V, Legido Quigley C, Groop L, Thorens B, Franks P, Lim G, Estall J, Ibberson M, Beulens J, t Hart L, Pearson E, Rutter Get al., 2023, Identification of biomarkers for glycaemic deterioration in type 2 diabetes, Nature Communications, Vol: 14, Pages: 1-18, ISSN: 2041-1723

We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.

Journal article

Tomas Catala A, Bitsi S, Manchanda Y, El Eid L, Oqua A, Mohamed N, Hansen B, Suba K, Rutter G, Jones B, Salem Vet al., 2023, Divergent acute versus prolonged pharmacological GLP-1R responses in adult beta cell-specific β-arrestin 2 knockout mice, Science Advances, Vol: 9, Pages: 1-23, ISSN: 2375-2548

The glucagon-like peptide-1 receptor (GLP-1R) is a major type 2 diabetes therapeutic target. Stimulated GLP-1Rs are rapidly desensitized by β-arrestins, scaffolding proteins that not only terminate G protein interactions but also act as independent signaling mediators. Here, we have assessed in vivo glycemic responses to the pharmacological GLP-1R agonist exendin-4 in adult β cell–specific β-arrestin 2 knockout (KO) mice. KOs displayed a sex-dimorphic phenotype consisting of weaker acute responses that improved 6 hours after agonist injection. Similar effects were observed for semaglutide and tirzepatide but not with biased agonist exendin-phe1. Acute cyclic adenosine 5′-monophosphate increases were impaired, but desensitization reduced in KO islets. The former defect was attributed to enhanced β-arrestin 1 and phosphodiesterase 4 activities, while reduced desensitization co-occurred with impaired GLP-1R recycling and lysosomal targeting, increased trans-Golgi network signaling, and reduced GLP-1R ubiquitination. This study has unveiled fundamental aspects of GLP-1R response regulation with direct application to the rational design of GLP-1R–targeting therapeutics.

Journal article

Millership SJ, Yu V, Yong F, Georgiadou E, Marchetti P, Dhawan S, Withers DJ, Rutter GAet al., 2023, Epigenetic beta cell functional heterogeneity during postnatal islet development via the imprinted gene neuronatin, Publisher: WILEY, ISSN: 0742-3071

Conference paper

Cherkaoui I, Du Q, Egli DM, Sachedina D, Dion C, Leitch HG, Chabosseau P, Wastin J, Misra S, Rutter GAet al., 2023, Impact on insulin secretion and CA<SUP>2+</SUP> dynamics of the homozygous P.A251T HNF1A variant in beta-like cells differentiated from patient-derived induced pluripotent cells, Publisher: WILEY, ISSN: 0742-3071

Conference paper

Surekha MV, Suneetha N, Balakrishna N, Putcha UK, Satyanarayana K, Geddam JJB, Sreenu P, Tulja B, Mamidi RS, Rutter GA, Meur Get al., 2023, Impact of COVID-19 during pregnancy on placental pathology, maternal and neonatal outcome – a cross-sectional study on anemic term pregnant women from a tertiary care hospital in southern India, Frontiers in Endocrinology, Vol: 14, Pages: 1-16, ISSN: 1664-2392

BACKGROUND: SARS-CoV-2 infection during pregnancy may cause adverse maternal, neonatal and placental outcomes. While tissue hypoxia is often reported in COVID-19 patients, pregnant women with anemia are suspected to be more prone to placental hypoxia-related injuries. METHODS: This hospital-based cross-sectional study was conducted between August-November 2021, during COVID-19 second wave in India. Term pregnant women (N=212) admitted to hospital for delivery were enrolled consecutively. Since hospital admission mandated negative RT-PCR test for SARS-CoV-2 virus, none had active infection. Data on socio-demography, COVID-19 history, maternal, obstetric, and neonatal outcomes were recorded. Pre-delivery maternal and post-delivery cord blood samples were tested for hematological parameters and SARS-CoV-2 IgG. Placentae were studied for histology. RESULTS: Of 212 women, 122 (58%) were seropositive for SARS-CoV-2 IgG, but none reported COVID-19 history; 134 (63.2%) were anemic. In seropositive women, hemoglobin (p=0.04), total WBC (p=0.009), lymphocytes (p=0.005) and neutrophils (p=0.02) were significantly higher, while ferritin was high, but not significant and neutrophils to lymphocytes (p=0.12) and platelets to lymphocytes ratios (p=0.03) were lower. Neonatal outcomes were similar. All RBC parameters and serum ferritin were significantly lower in anemic mothers but not in cord blood, except RDW that was significantly higher in both, maternal (p=0.007) and cord (p=0.008) blood from seropositive anemic group compared to other groups. Placental histology showed significant increase in villous hypervascularity (p=0.000), dilated villous capillaries (p=0.000), and syncytiotrophoblasts (p=0.02) in seropositive group, typically suggesting placental hypoxia. Maternal anemia was not associated with any histological parameters. Univariate and multivariate logistic regression analyses of placental histopathological adverse outcomes showed strong association with SARS-CoV-2 sero

Journal article

Chabosseau P, Yong F, Delgadillo-Silva LF, Lee EY, Melhem R, Li S, Gandhi N, Wastin J, Noriega LL, Leclerc I, Ali Y, Hughes JW, Sladek R, Martinez-Sanchez A, Rutter GAet al., 2023, Molecular phenotyping of single pancreatic islet leader beta cells by "Flash-Seq", Life Sciences, Vol: 316, ISSN: 0024-3205

AIMS: Spatially-organized increases in cytosolic Ca2+ within pancreatic beta cells in the pancreatic islet underlie the stimulation of insulin secretion by high glucose. Recent data have revealed the existence of subpopulations of beta cells including "leaders" which initiate Ca2+ waves. Whether leader cells possess unique molecular features, or localisation, is unknown. MAIN METHODS: High speed confocal Ca2+ imaging was used to identify leader cells and connectivity analysis, running under MATLAB and Python, to identify highly connected "hub" cells. To explore transcriptomic differences between beta cell sub-groups, individual leaders or followers were labelled by photo-activation of the cryptic fluorescent protein PA-mCherry and subjected to single cell RNA sequencing ("Flash-Seq"). KEY FINDINGS: Distinct Ca2+ wave types were identified in individual islets, with leader cells present in 73 % (28 of 38 islets imaged). Scale-free, power law-adherent behaviour was also observed in 29 % of islets, though "hub" cells in these islets did not overlap with leaders. Transcripts differentially expressed (295; padj < 0.05) between leader and follower cells included genes involved in cilium biogenesis and transcriptional regulation. Providing some support for these findings, ADCY6 immunoreactivity tended to be higher in leader than follower cells, whereas cilia number and length tended to be lower in the former. Finally, leader cells were located significantly closer to delta, but not alpha, cells in Euclidian space than were follower cells. SIGNIFICANCE: The existence of both a discrete transcriptome and unique localisation implies a role for these features in defining the specialized function of leaders. These data also raise the possibility that localised signalling between delta and leader cells contributes to the initiation and propagation of islet Ca2+ waves.

Journal article

Avari P, Eng PC, Hu M, Chen R, Popovic N, Polychronakos C, Spalding D, Rutter GA, Oliver N, Wernig Fet al., 2023, A novel somatic mutation implicates ATP6V0D1 in proinsulin processing, Journal of the Endocrine Society, Vol: 7, Pages: 1-5, ISSN: 2472-1972

ContextProhormone convertase 1/3 (PC1/3), encoded by protein convertase subtilisin kexin type 1 (PCSK1), converts inactive prohormones into biologically active peptides. Somatic mutations of insulinomas are associated with genetic defects interfering with control of insulin secretion from pancreatic beta cells. However, somatic mutations in proinsulinomas have not been described.ObjectiveWe report a case of a proinsulinoma, with suppressed insulin and C-peptide levels.MethodsA 70-year-old woman presented with a 20-year history of “blackouts.” During a 72-hour fast, blood glucose level dropped to 1.9 mmol/L with suppressed plasma insulin and C-peptide levels, but proinsulin levels were raised at 37 pmol/L (<10 pmol/L).ResultsImaging revealed 3 distinct DOTATATE-avid pancreatic lesions. Laparoscopic spleen-preserving distal pancreatomy was performed. In view of discordant insulin, C-peptide, and proinsulin levels, whole exome sequencing analysis was performed on the tumor. In the somatic exome of the tumor, we found mutations in PCSK expression regulators, as well as a novel truncating somatic mutation in ATP6V0D1, a subunit of the ion pump that acidifies the β-cell compartments where the PCSKs act.ConclusionAppropriately suppressed insulin levels in the context of hypoglycemia do not always indicate the absence of a neuroendocrine islet cell tumor and proinsulin levels may be indicated to solidify the diagnosis. In the context of elevated proinsulin levels, low insulin and C-peptide levels might be explained by somatic mutations that likely implicate proinsulin processing within the tumor. Furthermore, we propose several mechanistic candidates, including ATP6V0D1. Experimental validation using cellular approaches may in future confirm pathomechanisms involved in this rare condition.

Journal article

Sui L, Du Q, Romer A, Su Q, Chabosseau PL, Xin Y, Kim J, Kleiner S, Rutter GA, Egli Det al., 2023, ZnT8 Loss of Function Mutation Increases Resistance of Human Embryonic Stem Cell-Derived Beta Cells to Apoptosis in Low Zinc Condition, CELLS, Vol: 12

Journal article

Anindya R, Rutter GA, Meur G, 2023, New-onset type 1 diabetes and severe acute respiratory syndrome coronavirus 2 infection, IMMUNOLOGY AND CELL BIOLOGY, Vol: 101, Pages: 191-203, ISSN: 0818-9641

Journal article

Bosi E, Marchetti P, Rutter GA, Eizirik DLet al., 2022, Human alpha cell transcriptomic signatures of types 1 and 2 diabetes highlight disease-specific dysfunction pathways, iScience, Vol: 25, ISSN: 2589-0042

Although glucagon secretion is perturbed in both T1D and T2D, the pathophysiological changes in individual pancreatic alpha cells are still obscure. Using recently curated single-cell RNASeq data from T1D or T2D donors and their controls, we identified alpha cell transcriptomic alterations consistent with both common and discrete pathways. Although alterations in alpha cell identity gene (ARX, MAFB) expression were conserved, cytokine-regulated genes and genes involved in glucagon biosynthesis and processing were up-regulated in T1D. Conversely, mitochondrial genes associated with ROS (COX7B, NQO2) were dysregulated in T2D. Additionally, T1D alpha cells displayed altered expression of autoimmune-induced ER stress genes (ERLEC1, HSP90), whilst those from T2D subjects showed modified glycolytic and citrate cycle gene (LDHA?, PDHB, PDK4) expression. Thus, despite conserved alterations related to loss of function, alpha cells display disease-specific gene signatures which may be secondary to the main pathogenic events in each disease, namely immune- or metabolism-mediated-stress, in T1D and T2D, respectively.

Journal article

Akalestou E, Lopez-Noriega L, Christakis I, Hu M, Miras A, Leclerc I, Rutter Get al., 2022, Vertical Sleeve Gastrectomy normalizes circulating glucocorticoid levels and lowers glucocorticoid action tissue-selectively in mice, Frontiers in Endocrinology, Vol: 13, Pages: 1-16, ISSN: 1664-2392

Objectives: Glucocorticoids produced by the adrenal cortex are essential for the maintenance of metabolic homeostasis.Glucocorticoid activation is catalysed by 11β‐hydroxysteroid dehydrogenase 1 (11β‐HSD1). Excess glucocorticoids are associatedwith insulin resistance and hyperglycaemia. A small number of studies have demonstrated effects on glucocorticoid metabolism ofbariatric surgery, a group of gastrointestinal procedures known to improve insulin sensitivity and secretion, which were assumedto result from weight loss. In this study, we hypothesize that a reduction in glucocorticoid action following bariatric surgerycontributes to the widely observed euglycemic effects of the treatment. Methods: Glucose and insulin tolerance tests wereperformed at ten weeks post operatively and circulating corticosterone was measured. Liver and adipose tissues were harvestedfrom fed mice and 11β‐HSD1 levels were measured by quantitative RT‐PCR or Western (immuno‐) blotting, respectively. 11β‐HSD1null mice (Hsd11b1-/-) were generated using CRISPR/ Cas9 genome editing. Wild type (WT) and littermate Hsd11b1-/- miceunderwent Vertical Sleeve Gastrectomy (VSG) or sham surgery. Results: WT VSG-treated mice displayed significantly improvedglucose tolerance versus sham controls, and this effect was observed in both regular chow- and HFD-fed animals. VSG lowered bodyweight in HFD but not regular chow-fed mice. Remarkably, VSG restored physiological corticosterone production in HFD mice andreduced 11β‐HSD1 expression in liver and adipose tissue post‐surgery. Elimination of the 11β‐HSD1/Hsd11b1 gene mimicked theeffects of VSG on body weight and tolerance to 1g/kg glucose challenge. However, at 3 g/kg glucose, the impact of VSG on glucoseexcursion was indistinguishable between WT and Hsd11b1-/- mice, suggesting that the euglycemic effect of VSG was superior toHsd11b1 elimination. Conclusions: Bariatric surgery improves insulin sensitivity and reduces glucocorticoi

Journal article

Parks SZ, Rutter GA, Leclerc I, 2022, Whole-body sorcin invalidation does not cause hypothalamic ER stress nor worsens obesity in C57BL/6 male mice fed a westernized diet

<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Background</jats:title><jats:p><jats:underline>So</jats:underline>luble <jats:underline>R</jats:underline>esistance Related <jats:underline>C</jats:underline>alcium B<jats:underline>in</jats:underline>ding Protein (sorcin) is a calcium (Ca<jats:sup>2+</jats:sup>) binding protein which has been shown to play a role in maintaining intracellular endoplasmic reticulum (ER) Ca<jats:sup>2+</jats:sup> stores and lowering ER stress. Recently, our lab has demonstrated that sorcin expression was downregulated in the islets of Langerhans of mice fed a high-fat diet or in human islets incubated with the saturated fatty acid palmitate. We also showed that overexpression of sorcin under control of the rat insulin promoter (RIP7) in C57BL/6J mice, or whole body sorcin deletion in 129S1/SvImJ mice, improves or impairs insulin secretion and pancreatic β-cell function respectively. The mechanisms behind this beneficial role of sorcin in the pancreatic β-cell might depend on protection against lipotoxic endoplasmic reticulum (ER) stress through improved ER Ca<jats:sup>2+</jats:sup> dynamics and activation of the Activating Transcription Factor 6 (ATF6) branch of the unfolded protein response (UPR). Whether sorcin is also implicated in hypothalamic ER stress during the progression of obesity is unknown. This could potentially contribute to the diminished satiety typically observed in overweight individuals.</jats:p></jats:sec><jats:sec><jats:title>Aim</jats:title><jats:p>To investigate a potential role of sorcin in hypothalamic ER stress, leptin resistance, hyperphagia and obesity.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Whole-body sorcin null mice, backcrossed onto the C57BL/6J genetic background, were u

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