Imperial College London

DrGabrielaDa Silva Xavier

Central FacultyEducation Office

Taught Postgraduate
 
 
 
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Contact

 

+44 (0)20 7594 3358g.dasilva-xavier

 
 
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Location

 

326ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

59 results found

Millership SJ, da Silva Xavier G, Choudhury AI, Bertazzo S, Chabosseau P, Pedroni SM, Irvine EE, Montoya A, Faull P, Taylor WR, Kerr-Conte J, Pattou F, Ferrer J, Christian M, John RM, Latreille M, Liu M, Rutter GA, Scott J, Withers DJet al., 2018, Neuronatin regulates pancreatic β cell insulin content and secretion., J Clin Invest

Neuronatin (Nnat) is an imprinted gene implicated in human obesity and widely expressed in neuroendocrine and metabolic tissues in a hormone and nutrient-sensitive manner. However, its molecular and cellular functions and precise role in organismal physiology remain only partly defined. Here we demonstrate that mice lacking Nnat globally or specifically in β cells display impaired glucose-stimulated insulin secretion leading to defective glucose handling under conditions of nutrient-excess. In contrast, we report no evidence for any feeding or body weight phenotypes in global Nnat null mice. At the molecular level neuronatin augments insulin signal peptide cleavage by binding to the signal peptidase complex and facilitates translocation of the nascent preprohormone. Loss of neuronatin expression in β cells therefore reduces insulin content and blunts glucose-stimulated insulin secretion. Nnat expression, in turn, is glucose-regulated. This mechanism therefore represents a novel site of nutrient-sensitive control of β cell function and whole animal glucose homeostasis. These data also suggest a potential wider role for Nnat in the regulation of metabolism through the modulation of peptide processing events.

JOURNAL ARTICLE

Xavier GDS, 2018, The Cells of the Islets of Langerhans, JOURNAL OF CLINICAL MEDICINE, Vol: 7, ISSN: 2077-0383

JOURNAL ARTICLE

Xavier GDS, Hodson DJ, 2018, Mouse models of peripheral metabolic disease, BEST PRACTICE & RESEARCH CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 32, Pages: 299-315, ISSN: 1521-690X

JOURNAL ARTICLE

Fletcher RS, Ratajczak J, Doig CL, Oakey LA, Callingham R, Xavier GDS, Garten A, Elhassan YS, Redpath P, Migaud ME, Philp A, Brenner C, Canto C, Lavery GGet al., 2017, Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells, MOLECULAR METABOLISM, Vol: 6, Pages: 819-832, ISSN: 2212-8778

JOURNAL ARTICLE

Xavier GDS, Mondragon A, Mourougavelou V, Cruciani-Guglielmacci C, Denom J, Herrera PL, Magnan C, Rutter GAet al., 2017, Pancreatic alpha cell-selective deletion of Tcf7l2 impairs glucagon secretion and counter-regulatory responses to hypoglycaemia in mice, DIABETOLOGIA, Vol: 60, Pages: 1043-1050, ISSN: 0012-186X

JOURNAL ARTICLE

Nguyen-Tu M-S, Leclerc I, da Silva-Xavier G, Rutter GAet al., 2016, Role of the type 2 diabetes GWAS gene TCF7L2 in LKB1-mediated regulation of insulin secretion in the murine beta cell, 52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S169-S169, ISSN: 0012-186X

CONFERENCE PAPER

Semplici F, Mondragon A, Macintyre B, Madeyski-Bengston K, Persson-Kry A, Barr S, Ramne A, Marley A, McGinty J, French P, Soedling H, Yokosuka R, Gaitan J, Lang J, Migrenne-Li S, Philippe E, Herrera PL, Magnan C, Xavier GDS, Rutter GAet al., 2016, Cell type-specific deletion in mice reveals roles for PAS kinase in insulin and glucagon production, DIABETOLOGIA, Vol: 59, Pages: 1938-1947, ISSN: 0012-186X

JOURNAL ARTICLE

Mitchell RK, Mondragon A, Chen L, Mcginty JA, French PM, Ferrer J, Thorens B, Hodson DJ, Rutter GA, Xavier GDSet al., 2015, Selective disruption of Tcf7l2 in the pancreatic beta cell impairs secretory function and lowers beta cell mass, HUMAN MOLECULAR GENETICS, Vol: 24, Pages: 1390-1399, ISSN: 0964-6906

JOURNAL ARTICLE

Sun G, Da Silva Xavier G, Gorman T, Priest C, Solomou A, Hodson DJ, Foretz M, Viollet B, Herrera PL, Parker HE, Reimann FM, Gribble FM, Migrenne S, Magnan CN, Marley AE, Rutter GAet al., 2015, LKB1 and AMPKα1 are required in pancreatic alpha cells for the normal regulation of glucagon secretion and responses to hypoglycemia, Molecular Metabolism, Vol: 4, Pages: 277-286, ISSN: 2212-8778

Aims/Hypothesis: Glucagon release from pancreatic alpha cells is required for normal glucose homoeostasis and is dysregulated in both Type 1 and Type 2 diabetes. The tumour suppressor LKB1 (STK11) and the downstream kinase AMP-activated protein kinase (AMPK), modulate cellular metabolism and growth, and AMPK is an important target of the anti-hyperglycaemic agent metformin. While LKB1 and AMPK have emerged recently as regulators of beta cell mass and insulin secretion, the role of these enzymes in the control of glucagon production invivo is unclear. Methods: Here, we ablated LKB1 (αLKB1KO), or the catalytic alpha subunits of AMPK (αAMPKdKO, -α1KO, -α2KO), selectively in ~45% of alpha cells in mice by deleting the corresponding flox'd alleles with a preproglucagon promoter (. PPG) Cre. Results: Blood glucose levels in male αLKB1KO mice were lower during intraperitoneal glucose, aminoimidazole carboxamide ribonucleotide (AICAR) or arginine tolerance tests, and glucose infusion rates were increased in hypoglycemic clamps (p<0.01). αLKB1KO mice also displayed impaired hypoglycemia-induced glucagon release. Glucose infusion rates were also elevated (p<0.001) in αAMPKα1 null mice, and hypoglycemia-induced plasma glucagon increases tended to be lower (p=0.06). Glucagon secretion from isolated islets was sensitized to the inhibitory action of glucose in αLKB1KO, αAMPKdKO, and -α1KO, but not -α2KO islets. Conclusions/Interpretation: An LKB1-dependent signalling cassette, involving but not restricted to AMPKα1, is required in pancreatic alpha cells for the control of glucagon release by glucose.

JOURNAL ARTICLE

Zatyka M, Xavier GDS, Bellomo EA, Leadbeater W, Astuti D, Smith J, Michelangeli F, Rutter GA, Barrett TGet al., 2015, Sarco(endo)plasmic reticulum ATPase is a molecular partner of Wolfram syndrome 1 protein, which negatively regulates its expression, HUMAN MOLECULAR GENETICS, Vol: 24, Pages: 814-827, ISSN: 0964-6906

JOURNAL ARTICLE

Locke JM, Xavier GDS, Dawe HR, Rutter GA, Harries LWet al., 2014, Increased expression of miR-187 in human islets from individuals with type 2 diabetes is associated with reduced glucose-stimulated insulin secretion, DIABETOLOGIA, Vol: 57, Pages: 122-128, ISSN: 0012-186X

JOURNAL ARTICLE

Mondragon A, Davidsson D, Kyriakoudi S, Bertling A, Gomes-Faria R, Cohen P, Rothery S, Chabosseau P, Rutter GA, Xavier GDSet al., 2014, Divergent Effects of Liraglutide, Exendin-4, and Sitagliptin on Beta-Cell Mass and Indicators of Pancreatitis in a Mouse Model of Hyperglycaemia, PLOS ONE, Vol: 9, ISSN: 1932-6203

JOURNAL ARTICLE

Xavier GDS, Bellomo EA, McGinty JA, French PM, Rutter GAet al., 2013, Animal Models of GWAS-Identified Type 2 Diabetes Genes, JOURNAL OF DIABETES RESEARCH, ISSN: 2314-6745

JOURNAL ARTICLE

Xavier GDS, Mondragon A, Sun G, Chen L, McGinty JA, French PM, Rutter GAet al., 2012, Abnormal glucose tolerance and insulin secretion in pancreas-specific Tcf7l2-null mice, DIABETOLOGIA, Vol: 55, Pages: 2667-2676, ISSN: 0012-186X

JOURNAL ARTICLE

da Silva Xavier G, 2012, Protein kinases and pancreatic islet function, Protein kinases, Editors: da Silva Xavier, Publisher: Intech, ISBN: 978-953-51-0640-1

BOOK CHAPTER

da Silva Xavier G, Others M, 2012, Protein Kinases, Online, Publisher: InTech, ISBN: 978-953-51-0640-1

Proteins are the work horses of the cell. As regulators of protein function, protein kinases are involved in the control of cellular functions via intricate signalling pathways, allowing for fine tuning of physiological functions. This book is a collaborative effort, with contribution from experts in their respective fields, reflecting the spirit of collaboration - across disciplines and borders - that exists in modern science. Here, we review the existing literature and, on occasions, provide novel data on the function of protein kinases in various systems. We also discuss the implications of these findings in the context of disease, treatment, and drug development.

BOOK

Dominguez V, Raimondi C, Somanath S, Bugliani M, Loder MK, Edling CE, Divecha N, da Silva-Xavier G, Marselli L, Persaud SJ, Turner MD, Rutter GA, Marchetti P, Falasca M, Maffucci Tet al., 2011, Class II Phosphoinositide 3-Kinase Regulates Exocytosis of Insulin Granules in Pancreatic beta Cells, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 286, Pages: 4216-4225, ISSN: 0021-9258

JOURNAL ARTICLE

Locke JM, Xavier GDS, Rutter GA, Harries LWet al., 2011, An alternative polyadenylation signal in TCF7L2 generates isoforms that inhibit T cell factor/lymphoid-enhancer factor (TCF/LEF)-dependent target genes, DIABETOLOGIA, Vol: 54, Pages: 3078-3082, ISSN: 0012-186X

JOURNAL ARTICLE

Meur G, Qian Q, Xavier GDS, Pullen TJ, Tsuboi T, McKinnon C, Fletcher L, Tavare JM, Hughes S, Johnson P, Rutter GAet al., 2011, Nucleo-cytosolic Shuttling of FoxO1 Directly Regulates Mouse Ins2 but Not Ins1 Gene Expression in Pancreatic Beta Cells (MIN6), JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 286, Pages: 13647-13656, ISSN: 0021-9258

JOURNAL ARTICLE

Pullen TJ, Xavier GDS, Kelsey G, Rutter GAet al., 2011, miR-29a and miR-29b Contribute to Pancreatic beta-Cell-Specific Silencing of Monocarboxylate Transporter 1 (Mct1), MOLECULAR AND CELLULAR BIOLOGY, Vol: 31, Pages: 3182-3194, ISSN: 0270-7306

JOURNAL ARTICLE

Xavier GDS, Farhan H, Kim H, Caxaria S, Johnson P, Hughes S, Bugliani M, Marselli L, Marchetti P, Birzele F, Sun G, Scharfmann R, Rutter J, Siniakowicz K, Weir G, Parker H, Reimann F, Gribble FM, Rutter GAet al., 2011, Per-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion, DIABETOLOGIA, Vol: 54, Pages: 819-827, ISSN: 0012-186X

JOURNAL ARTICLE

An R, Xavier GDS, Semplici F, Vakhshouri S, Hao H-X, Rutter J, Pagano MA, Meggio F, Pinna LA, Rutter GAet al., 2010, Pancreatic and duodenal homeobox 1 (PDX1) phosphorylation at serine-269 is HIPK2-dependent and affects PDX1 subnuclear localization, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol: 399, Pages: 155-161, ISSN: 0006-291X

JOURNAL ARTICLE

Noordeen NA, Khera TK, Sun G, Longbottom ER, Pullen TJ, Xavier GDS, Rutter GA, Leclerc Iet al., 2010, Carbohydrate-Responsive Element-Binding Protein (ChREBP) Is a Negative Regulator of ARNT/HIF-1 beta Gene Expression in Pancreatic Islet beta-Cells, DIABETES, Vol: 59, Pages: 153-160, ISSN: 0012-1797

JOURNAL ARTICLE

Rutter GA, Pullen TJ, 2010, miR-29a, miR-29b and miR-124 contribute to pancreatic beta cell specific silencing of monocarboxylate transporter 1 (Mct1/Slc16a1), 46th Annual Meeting of the European-Association-for-the- Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S35-S36, ISSN: 0012-186X

CONFERENCE PAPER

Sun G, Tarasov AI, McGinty J, McDonald A, Xavier GDS, Gorman T, Marley A, French PM, Parker H, Gribble F, Reimann F, Prendiville O, Carzaniga R, Viollet B, Leclerc I, Rutter GAet al., 2010, Ablation of AMP-activated protein kinase alpha 1 and alpha 2 from mouse pancreatic beta cells and RIP2.Cre neurons suppresses insulin release in vivo, DIABETOLOGIA, Vol: 53, Pages: 924-936, ISSN: 0012-186X

JOURNAL ARTICLE

Voronina SG, Barrow SL, Simpson AWM, Gerasimenko OV, Xavier GDS, Rutter GA, Petersen OH, Tepikin AVet al., 2010, Dynamic Changes in Cytosolic and Mitochondrial ATP Levels in Pancreatic Acinar Cells, GASTROENTEROLOGY, Vol: 138, Pages: 1976-U111, ISSN: 0016-5085

JOURNAL ARTICLE

Xavier GDS, Sun G, Qian Q, Rutter GA, Leclerc Iet al., 2010, ChREBP regulates Pdx-1 and other glucose-sensitive genes in pancreatic beta-cells, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol: 402, Pages: 252-257, ISSN: 0006-291X

JOURNAL ARTICLE

Nicolson TJ, Bellomo EA, Wijesekara N, Loder MK, Baldwin JM, Gyulkhandanyan AV, Koshkin V, Tarasov AI, Carzaniga R, Kronenberger K, Taneja TK, Xavier GDS, Libert S, Froguel P, Scharfmann R, Stetsyuk V, Ravassard P, Parker H, Gribble FM, Reimann F, Sladek R, Hughes SJ, Johnson PRV, Masseboeuf M, Burcelin R, Baldwin SA, Liu M, Lara-Lemus R, Arvan P, Schuit FC, Wheeler MB, Chimienti F, Rutter GAet al., 2009, Insulin Storage and Glucose Homeostasis in Mice Null for the Granule Zinc Transporter ZnT8 and Studies of the Type 2 Diabetes-Associated Variants, DIABETES, Vol: 58, Pages: 2070-2083, ISSN: 0012-1797

JOURNAL ARTICLE

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