Imperial College London

DrIsabelleLeclerc

Faculty of MedicineDepartment of Medicine

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

108 results found

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

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

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 in vivo 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

Journal article

Nguyen-Tu M-S, Martinez-Sanchez A, Leclerc I, Rutter GA, da Silva Xavier Get al., 2020, Adipocyte-specific deletion of Tcf7l2 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

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

Callingham RM, Leclerc I, Pullen TJ, Rutter GAet al., 2020, The impact of a long non-coding RNA at the Pax6 locus on beta cell identity and function, Publisher: WILEY, Pages: 38-38, ISSN: 0742-3071

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

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

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

Akalestou E, Suba K, Lopez-Noriega L, Georgiadou E, Chabosseau P, Leclerc I, Salem V, Rutter GAet al., 2020, Metabolic surgery recovers Ca(2+)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

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

Salem V, Ali U, Suba K, Bitsi S, Lopes T, Alonso AM, Patel YS, Leclerc I, Owen B, Rutter GA, Rothery SM, Tomas Aet al., 2020, Upregulation of Pancreatic Islet EGF Receptor Improves Beta-Cell Identity and In Vivo Vascularisation in a Directly Observed Transplant Model, 80th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797

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

Georgiadou E, Chabosseau PL, Tomas A, Leclerc I, Rutter GAet al., 2020, Deletion of the Mitofusins 1 and 2 (Mfn1 and Mfn2) in the Pancreatic Beta Cell Disrupts Mitochondrial Structure and Function In Vitro and Strongly Impairs Glucose-Stimulated Insulin Secretion In Vivo, 80th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797

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

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

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

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: an international journal of inorganic chemistry, Vol: 49, Pages: 4732-4740, ISSN: 1477-9226

Global rates of diabetes mellitus are increasing, and treatment of the disease consumes a growing proportion of healthcare spending across the world. Pancreatic β-cells, responsible for insulin production, decline in mass in type 1 and, to a more limited degree, in type 2 diabetes. However, the extent and rate of loss in both diseases differs between patients resulting in the need for the development of novel diagnostic tools, which could quantitatively assess changes in mass of β-cells over time and potentially lead to earlier diagnosis and improved treatments. Exendin-4, a potent analogue of glucagon-like-peptide 1 (GLP-1), binds to the receptor GLP-1R, whose expression is enriched in β-cells. GLP-1R has thus been used in the past as a means of targeting probes for a wide variety of imaging modalities to the endocrine pancreas. However, exendin-4 conjugates designed specifically for MRI contrast agents are an under-explored area. In the present work, the synthesis and characterization of an exendin-4-dota(ga)-Gd(III) complex, GdEx, is reported, along with its in vivo behaviour in healthy and in β-cell-depleted C57BL/6J mice. Compared to the ubiquitous probe, [Gd(dota)]−, GdEx shows selective uptake by the pancreas with a marked decrease in accumulation observed after the loss of β-cells elicited by deleting the microRNA processing enzyme, DICER. These results open up pathways towards the development of other targeted MRI contrast agents based on similar chemistry methodology.

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, Teo AKK, 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, Publisher: Cold Spring Harbor Laboratory

<jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>Risk alleles for type 2 diabetes at the<jats:italic>STARD10</jats:italic>locus are associated with lowered<jats:italic>STARD10</jats:italic>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 its effect on proinsulin processing and insulin granule biogenesis and maturation.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We used isolated islets from mice deleted selectively in the β-cell for<jats:italic>Stard10</jats:italic>(β<jats:italic>StarD10</jats:italic>KO) and performed electron microscopy, pulse-chase, RNA sequencing and lipidomic analyses. Proteomic analysis of STARD10 binding partners was executed in INS1 (832/13) cell line. X-ray crystallography followed by molecular docking and lipid overlay assay were performed on purified STARD10 protein.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>β<jats:italic>StarD10</jats:italic>KO 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. Amongst the differentially expressed genes in β<jats:italic>StarD10</jats:italic>KO islets, expression of the phosphoinositide binding proteins<jats:italic>Pirt</jats:italic>and<jats:italic>Synaptotagmin 1</jats:

Working 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

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

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 G, Georgiadou Eet 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

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

Nguyen-Tu M-S, da Silva Xavier G, Leclerc I, Rutter GAet al., 2018, Transcription factor-7-like 2 (TCF7L2) gene acts downstream of the Lkb1/Stk11 kinase to control mTOR signaling, β cell growth, and insulin secretion, Journal of Biological Chemistry, Vol: 293, Pages: 14178-14189, ISSN: 0021-9258

Variants in the transcription factor-7-like 2 (TCF7L2/TCF4) gene, involved in Wnt signalling, are associated with type 2 diabetes. Loss of Tcf7l2 selectively from the β cell in mice has previously been shown to cause glucose intolerance and to lower β cell mass. Deletion of the tumour suppressor liver kinase B1 (LKB1/STK11) leads to β cell hyperplasia and enhanced glucose-stimulated insulin secretion, providing a convenient genetic model for increased β cell growth and function. The aim of this study was to explore the possibility that Tcf7l2 may be required for the effects of Lkb1 deletion on insulin secretion in the mouse β cell. Mice bearing floxed Lkb1 and/or Tcf7l2 alleles were bred with knock-in mice bearing Cre recombinase inserted at the Ins1 locus (Ins1Cre), allowing highly β cell-selective deletion of either or both genes. Oral glucose tolerance was unchanged by the further deletion of a single Tcf7l2 allele in these cells. By contrast, mice lacking both Tcf7l2 alleles on this background showed improved oral glucose tolerance and insulin secretion in vivo and in vitro compared to mice lacking a single Tcf7l2 allele. Bi-allelic Tcf7l2 deletion also enhanced β cell proliferation, increased β cell mass and caused changes in polarity as revealed by the "rosette-like" arrangement of β cells. Tcf7l2 deletion also increased signalling by Target of Rapamycin (mTOR), augmenting phospho-ribosomal S6 levels. We identified a novel signalling mechanism through which a modifier gene, Tcf7l2, lies on a pathway through which LKB1 acts in the β cell to restrict insulin secretion.

Journal article

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