Imperial College London

DrIsabelleLeclerc

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Visiting Professor
 
 
 
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Contact

 

+44 (0)20 7594 3354i.leclerc

 
 
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Location

 

323ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

119 results found

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

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

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

Parks SZ, Rutter GA, Leclerc I, 2022, Effects of whole-body sorcin knockout on body weight and hypothalamic ER-stress in C57BL/6 male mice fed a westernized diet

<jats:title>Abstract</jats:title> <jats:p>Background Soluble Resistance Related Calcium Binding 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.Aim To investigate a potential role of sorcin in hypothalamic ER stress, leptin resistance, hyperphagia and obesity.Methods Whole-body sorcin null mice, backcrossed onto the C57BL/6J genetic background, were used. Body weight, food intake and EchoMRI body composition were measured in vivo whereas qRT-PCR analysis of sorcin and ER stress markers expression were performed on the arcuate nucleus of the hypothalamus. Leptin signalling through STAT3 phosphorylation was measured by Western blots on sorcin-null HEK293 cells, engineered by CRISPR/Cas9, and transfected with leptin receptor (LepRb).Results Sorcin expression was not influenced in the arcuate nucleus (ARC) of the hypothalamus by diet-induced obesity. Whole-body sorcin a

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

Journal article

Jones B, Burade V, Akalestou E, Manchanda Y, Ramchunder Z, Carrat G, Nguyen-Tu M-S, Marchetti P, Piemonti L, Leclerc I, Thennati R, Vilsboll T, Thorens B, Tomas A, Rutter GAet al., 2022, In vivo and in vitro characterization of GL0034, a novel long-acting glucagon-like peptide-1 receptor agonist, Diabetes, Obesity and Metabolism: a journal of pharmacology and therapeutics, Vol: 24, Pages: 2090-2101, ISSN: 1462-8902

AimsTo describe the in vitro characteristics and antidiabetic in vivo efficacy of the novel glucagon-like peptide-1 receptor agonist (GLP-1RA) GL0034.Materials and MethodsGlucagon-like peptide-1 receptor (GLP-1R) kinetic binding parameters, cyclic adenosine monophosphate (cAMP) signalling, endocytosis and recycling were measured using HEK293 and INS-1832/3 cells expressing human GLP-1R. Insulin secretion was measured in vitro using INS-1832/3 cells, mouse islets and human islets. Chronic administration studies to evaluate weight loss and glycaemic effects were performed in db/db and diet-induced obese mice.ResultsCompared to the leading GLP-1RA semaglutide, GL0034 showed increased binding affinity and potency-driven bias in favour of cAMP over GLP-1R endocytosis and β-arrestin-2 recruitment. Insulin secretory responses were similar for both ligands. GL0034 (6 nmol/kg) led to at least as much weight loss and lowering of blood glucose as did semaglutide at a higher dose (14 nmol/kg).ConclusionsGL0034 is a G protein-biased agonist that shows powerful antidiabetic effects in mice, and may serve as a promising new GLP-1RA for obese patients with type 2 diabetes.

Journal article

Cheung R, Pizza G, Chabosseau P, Rolando D, Tomas A, Burgoyne T, Wu Z, Salowka A, Thapa A, Macklin A, Cao Y, Nguyen-Tu M-S, Dickerson MT, Jacobson DA, Marchetti P, Shapiro J, Piemonti L, de Koning E, Leclerc I, Bouzakri K, Sakamoto K, Smith DM, Rutter GA, Martinez-Sanchez Aet al., 2022, Glucose-Dependent miR-125b Is a Negative Regulator of β-Cell Function, DIABETES, Vol: 71, Pages: 1525-1545, ISSN: 0012-1797

Journal article

Nguyen-Tu M-S, Harris J, Martinez-Sanchez A, Chabosseau P, Hu M, Georgiadou E, Pollard A, Otero P, Lopez-Noriega L, Leclerc I, Sakamoto K, Schmoll D, Smith DM, Carling D, Rutter GAet al., 2022, Opposing effects on regulated insulin secretion of acute vs chronic stimulation of AMP-activated protein kinase, DIABETOLOGIA, Vol: 65, Pages: 997-1011, ISSN: 0012-186X

Journal article

Akalestou E, Lopez-Noriega L, Tough IR, Hu M, Leclerc I, Cox HM, Rutter GAet al., 2022, Vertical sleeve gastrectomy lowers SGLT2/Slc5a2 expression in the mouse kidney, Diabetes, Vol: 71, ISSN: 0012-1797

Bariatric surgery improves glucose homeostasis but the underlying mechanisms are not fully elucidated. Here, we show that the expression of sodium glucose cotransporter-2 (SGLT2/Slc5a2) is reduced in the kidney of lean and obese mice following vertical sleeve gastrectomy (VSG). Indicating an important contribution of altered cotransporter expression to the impact of surgery, inactivation of the SGLT2/Slc5a2 gene by CRISPR/Cas9 attenuated the effects of VSG, with glucose excursions following intraperitoneal injection lowered by ∼30% in wild-type mice but by ∼20% in SGLT2 null animals. The effects of the SGLT2 inhibitor dapaglifozin were similarly blunted by surgery. Unexpectedly, effects of dapaglifozin were still observed in SGLT2 null mice, consistent with the existence of metabolically beneficial off-target effects of SGLT2 inhibitors. Thus, we describe a new mechanism involved in mediating the glucose lowering effects of bariatric surgery.

Journal article

Georgiadou E, Muralidharan C, Martinez M, Chabosseau P, Akalestou E, Tomas A, Yong Su Wern F, Stylianides T, Wretlind A, Legido-Quigley C, Jones B, Lopez Noriega L, Xu Y, Gu G, Alsabeeh N, Cruciani-Guglielmacci C, Magnan C, Ibberson M, Leclerc I, Ali Y, Soleimanpour SA, Linnemann AK, Rodriguez TA, Rutter GAet al., 2022, Mitofusins Mfn1 and Mfn2 are required to preserve glucose- but not incretin-stimulated beta cell connectivity and insulin secretion, Diabetes, Vol: 71, Pages: 1472-1489, ISSN: 0012-1797

Mitochondrial glucose metabolism is essential for stimulated insulin release from pancreatic beta cells. Whether mitofusin gene expression, and hence mitochondrial network integrity, is important for glucose or incretin signalling has not previously been explored. Here, we generated mice with beta cell-selective, adult-restricted deletion of the mitofusin genes Mfn1 and Mfn2 (βMfn1/2 dKO). βMfn1/2 dKO mice displayed elevated fed and fasted glycaemia and a >five-fold decrease in plasma insulin. Mitochondrial length, glucose-induced polarisation, ATP synthesis, cytosolic and mitochondrial Ca2+ increases were all reduced in dKO islets. In contrast, oral glucose tolerance was more modestly affected in βMfn1/2 dKO mice and GLP-1 or GIP receptor agonists largely corrected defective GSIS through enhanced EPAC-dependent signalling. Correspondingly, cAMP increases in the cytosol, as measured with an Epac-camps based sensor, were exaggerated in dKO mice. Mitochondrial fusion and fission cycles are thus essential in the beta cell to maintain normal glucose, but not incretin, sensing. These findings broaden our understanding of the roles of mitofusins in beta cells, the potential contributions of altered mitochondrial dynamics to diabetes development and the impact of incretins on this process.

Journal article

Akalestou E, Suba K, Lopez-Noriega L, Georgiadou E, Chabosseau P, Gallie A, Wretlind A, Legido-Quigley C, Leclerc I, Salem V, Rutter GAet al., 2021, Intravital imaging of islet Ca2+ dynamics reveals enhanced beta cell connectivity after bariatric surgery in mice (vol 12, 5165, 2021), Nature Communications, Vol: 12, Pages: 1-1, ISSN: 2041-1723

Journal article

Akalestou E, Suba K, Lopez-Noriega L, Georgiadou E, Chabosseau P, Gallie A, Wretlind A, Quigley C, Leclerc I, Salem V, Rutter GAet al., 2021, Intravital imaging of islet Ca2+ dynamics reveals enhanced beta cell connectivity after bariatric surgery in mice, Nature Communications, Vol: 12, Pages: 1-13, ISSN: 2041-1723

Bariatric surgery improves both insulin sensitivity and secretion and can induce diabetes remission. However, the mechanisms and time courses of these changes, particularly the impact on β cell function, are difficult to monitor directly. In this study, we investigated the effect of Vertical Sleeve Gastrectomy (VSG) on β cell function in vivo by imaging Ca2+ dynamics in islets engrafted into the anterior eye chamber. Mirroring its clinical utility, VSG in mice results in significantly improved glucose tolerance, and enhanced insulin secretion. We reveal that these benefits are underpinned by augmented β cell function and coordinated activity across the islet. These effects involve changes in circulating GLP-1 levels which may act both directly and indirectly on the β cell, in the latter case through changes in body weight. Thus, bariatric surgery leads to time-dependent increases in β cell function and intra-islet connectivity which are likely to contribute to diabetes remission.

Journal article

Parks SZ, Gao T, Awuapura NJ, Ayathamattam J, Chabosseau PL, Kalvakolanu D, Valdivia HH, Rutter GA, Leclerc I, Nakatogawa Het al., 2021, The Ca2+-binding protein sorcin stimulates transcriptional activity of the unfolded protein response mediator ATF6, FEBS Letters, Vol: 595, Pages: 1782-1796, ISSN: 0014-5793

Sorcin is a calcium-binding protein involved in maintaining endoplasmic reticulum (ER) Ca2+ stores. We have previously shown that overexpressing sorcin under the rat insulin promoter was protective against high-fat diet-induced pancreatic beta-cell dysfunction in vivo. Activating transcription factor 6 (ATF6) is a key mediator of the unfolded protein response (UPR) that provides cellular protection during the progression of ER stress. Here, using nonexcitable HEK293 cells, we show that sorcin overexpression increased ATF6 signalling, whereas sorcin knock out caused a reduction in ATF6 transcriptional activity and increased ER stress. Altogether, our data suggest that sorcin downregulation during lipotoxic stress may prevent full ATF6 activation and a normal UPR during the progression of obesity and insulin resistance.

Journal article

Cheung R, Pizza G, Chabosseau P, Rolando D, Salowska A, Burgoyne T, Leclerc I, Tomas A, Rutter GA, Martinez-Sanchez Aet al., 2021, miR-125b impairs beta cell function <i>in vivo</i> by targeting lysosomal and mitochondrial genes, Publisher: WILEY, ISSN: 0742-3071

Conference paper

Mousavy Gharavy SN, Owen BM, Millership SJ, Chabosseau P, Pizza G, Martinez-Sanchez A, Tasoez E, Georgiadou E, Hu M, Fine NHF, Jacobson DA, Dickerson MT, Idevall-Hagren O, Montoya A, Kramer H, Mehta Z, Withers DJ, Ninov N, Gadue PJ, Cardenas-Diaz FL, Cruciani-Guglielmacci C, Magnan C, Ibberson M, Leclerc I, Voz M, Rutter GAet al., 2021, Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis, Diabetologia, Vol: 64, Pages: 850-864, ISSN: 0012-186X

Aims/hypothesisVariants close to the VPS13C/C2CD4A/C2CD4B locus are associated with altered risk of type 2 diabetes in genome-wide association studies. While previous functional work has suggested roles for VPS13C and C2CD4A in disease development, none has explored the role of C2CD4B.MethodsCRISPR/Cas9-induced global C2cd4b-knockout mice and zebrafish larvae with c2cd4a deletion were used to study the role of this gene in glucose homeostasis. C2 calcium dependent domain containing protein (C2CD)4A and C2CD4B constructs tagged with FLAG or green fluorescent protein were generated to investigate subcellular dynamics using confocal or near-field microscopy and to identify interacting partners by mass spectrometry.ResultsSystemic inactivation of C2cd4b in mice led to marked, but highly sexually dimorphic changes in body weight and glucose homeostasis. Female C2cd4b mice displayed unchanged body weight compared with control littermates, but abnormal glucose tolerance (AUC, p = 0.01) and defective in vivo, but not in vitro, insulin secretion (p = 0.02). This was associated with a marked decrease in follicle-stimulating hormone levels as compared with wild-type (WT) littermates (p = 0.003). In sharp contrast, male C2cd4b null mice displayed essentially normal glucose tolerance but an increase in body weight (p < 0.001) and fasting blood glucose (p = 0.003) after maintenance on a high-fat and -sucrose diet vs WT littermates. No metabolic disturbances were observed after global inactivation of C2cd4a in mice, or in pancreatic beta cell function at larval stages in C2cd4a null zebrafish. Fasting blood glucose levels were also unaltered in adult C2cd4a-null fish. C2CD4B and C2CD4A were partially localised to the plasma membrane, with the latter under the control of intracellular Ca2+. Binding partners for both included secretory-granule-localised PTPRN2/phogrin.Conclusions/interpretationOur studies sugge

Journal article

Nguyen-Tu M-S, Martinez-Sanchez A, Leclerc I, Rutter GA, da Silva Xavier Get al., 2021, Adipocyte-specific deletion of <i>Tcf7l2</i> induces dysregulated lipid metabolism and impairs glucose tolerance in mice, DIABETOLOGIA, Vol: 64, Pages: 129-141, ISSN: 0012-186X

Journal article

Carrat GR, Haythorne E, Tomas A, Haataja L, Müller A, Arvan P, Piunti A, Cheng K, Huang M, Pullen TJ, Georgiadou E, Stylianides T, Amirruddin NS, Salem V, Distaso W, Cakebread A, Heesom KJ, Lewis PA, Hodson DJ, Briant LJ, Fung ACH, Sessions RB, Alpy F, Kong APS, Benke PI, Torta F, 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

Callingham RM, Leclerc I, Pullen TJ, Rutter GAet 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

Conference paper

Ali UT, Suba K, Bitsi S, Alonso AM, Patel Y, Leclerc I, Rutter GA, Rothery S, Tomas A, Salem Vet al., 2020, Improving islet transplantation success by increasing expression of the epidermal growth factor receptor (EGFR), Publisher: WILEY, Pages: 36-36, ISSN: 0742-3071

Conference paper

Akalestou E, Lopez-Noriega L, Leclerc I, Rutter GAet 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

Conference paper

Akalestou E, Suba K, Lopez-Noriega L, Georgiadou E, Chabosseau P, Leclerc I, Salem V, Rutter GAet 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

Conference paper

Rutter GA, Georgiadou E, Rodriguez T, Muralidharan C, Martinez M, Chabosseau P, Tomas A, Carrat G, Di Gregorio A, Leclerc I, Linnemann AKet 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

Conference paper

Suba K, Patel Y, Alonso AM, Ukwuoma M, Kalogianni V, Leclerc I, Owen B, Rutter GA, Bloom SR, Salem Vet al., 2020, Clinical care and other categories posters: Hypoglycaemia, Publisher: WILEY, Pages: 25-25, ISSN: 0742-3071

Conference paper

Noriega LL, Sanchez AM, Callingham R, Akalestou E, Chabosseau P, Leclerc I, Marchetti P, Pullen TJ, Rutter GAet al., 2020, The long non-coding RNA PAX6-AS1 modulates human beta cell function, Publisher: WILEY, Pages: 38-39, ISSN: 0742-3071

Conference paper

Suba K, Patel YS, Alonso AM, Scott R, Minnion JS, Leclerc I, Owen B, Distaso W, Tan TM, Murphy K, Bloom S, Rutter GA, Salem Vet 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

Conference paper

Akalestou E, Suba K, Noriega LL, Chabosseau PL, Leclerc I, Salem V, Rutter GAet 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

Conference paper

Akalestou E, Noriega LL, Christakis I, Leclerc I, Rutter GAet 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

Conference paper

Carrat G, Nguyen-Tu M-S, Leclerc I, Thennati R, Jones B, Tomas A, Rutter GAet 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

Conference paper

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