Dr Gabriela Da Silva Xavier PhD, SFHEA

Dr Gabriela Da Silva Xavier

Institute of Metabolism and Systems Research
Senior Lecturer in Cellular Metabolism

Contact details

Address
College of Medical and Dental Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
UK

Gaby is Senior Lecturer in Cellular Metabolism and a Senior Fellow of the Higher Education Academy.  She has an interest in energy homeostasis, particularly in fuel sensing mechanisms that may play a role in diabetes and obesity.

Qualifications

2017 PG Diploma in Education (Imperial College London)

2016 PG Certificate in Education (Imperial College London)

2001 PhD in Biochemistry (University of Bristol)

1997 BSc Biochemistry (University of Bristol)

Biography

Gaby completed her BSc in Biochemistry from the University of Bristol in 1997.  She completed her PhD under the supervision of Prof. G.A. Rutter, at the University of Bristol, in 2001. She was awarded a Juvenile Diabetes Research Foundation post-doctoral Fellowship in 2005, to develop her own research on a fuel sensor called PASK. In the same year Gaby was awarded an European Foundation for the Study of Diabetes Albert Renold Travel Fellowship for a sabbatical in the laboratory of Dr. Raphael Scharfmann (INSERM, Paris), where she learned to work with rodent embryonic pancreatic cultures. 

Gaby was awarded the European Association for the Study of Diabetes’ Rising Star Award in 2006.  Gaby moved to the Department of Medicine at Imperial College and was made lecturer in 2009, where she developed projects looking at how genes identified by GWAS as linked to type 2 diabetes may contribute to the manifestation of the disease, using a combination of in vitro and in vivo techniques.  Gaby moved to the Institute of Metabolism and Systems Research at the University of Birmingham in 2018.

Teaching

PGR QA lead (2018-)

Research

My research interest is primarily on glucose sensing mechanisms in pancreatic islets, mainly how fuel sensing protein kinases such as AMP activated protein kinase (AMPK) (1-5) and the distally related, PAS domain containing protein kinase (PASK) (6;7), may be involved in the regulation of pancreatic hormone production and release.  Initially, we were interested in the signaling pathways regulated by these kinases as they may be important in the search for therapeutic targets to improve b cell function and treat diabetes.  It is now apparent that these kinases are important in diabetes and obesity.

We were the first to show that PASK gene expression is lower in pancreatic islets from type 2 diabetic patients vs non-diabetic individuals (7), indicating that loss of PASK may be related to the loss of islet function seen in type 2 diabetes.  We have also shown that PASK is a regulator of insulin gene expression in pancreatic β cells (6), and may be involved in the regulation of glucagon release from pancreatic α cells (7).  We showed that PASK may have a role in the glucose sensing pathway in α cells, and may regulate glucagon secretion through its effects on insulin production in pancreatic β cells (1; 7).  We also showed that the expression of the gene encoding for the AMPK α-2 catalytic subunit is increased in α cells in which Pask gene expression has been silenced (7).  AMPK has been implicated in the regulation of glucagon release (8), raising the possibility that PASK may regulate glucose sensing in the α cell through the modulation of AMPKα-2 content.  Our studies on embryonic pancreatic explants also indicate that PASK may have a role in pancreatic development (7). 

Our current unpublished studies revealed a potential role for PASK in the regulation of food intake and circadian control of glucose homeostasis.  PASK may also be a modulator of the anorectic effects of the gut hormone, glucagon-like peptide 1 (GLP-1).  These effects are only apparent in mice systemically null for Pask- they are absent in the islet-specific Pask null mice, indicating that these responses are mediated by a signal distal from the pancreatic islet.  We suspect that this signal may originate from the brain and hypothesise that this may involved the regulation of AMPKα-2 by PASK (as we have seen in islets of Langerhans).   

My second line of research, funded through an MRC programme grant on which I am a co-investigator, was to study how targets identified by genome wide association studies for type 2 diabetes risk genes, may have a role in pancreatic islet function.  Thus, we showed that the transcription factor, Transcription Factor 7-Like 2 (TCF7L2), a distal component of the Wnt signalling pathway, may be important in the regulation of β cell function and insulin release (9-11).  In collaboration with Dr. Lorna Harries (University of Exeter), we found that an alternative transcript of TCF7L2 may be a dominant negative isoform of TCF7L2 and may contribute to type 2 diabetes susceptibility (10). 

We generated and characterised pancreas and pancreatic β cell specific Tcf7l2 null mice to assess the impact of the loss of Tcf7l2 gene expression on glucose homeostasis (10-11).  Our data indicate that Tcf7l2 may be a regulator of the expression of the glucagon-like peptide 1 (GLP-1) receptor in the islet and required for adequate signalling via the incretin GLP-1.  Our data indicate that mice in which Tcf7l2 gene expression is selectively ablated in pancreatic α cells (12) and adipocytes (Nguyen-Tu, manuscript in preparation) also exhibit glucose dyshomeostasis. 

To conduct the research described above, I utilize techniques which are common in most islet laboratories- biochemical measurements, islet extraction and cell culture, real-time PCR, imaging techniques on live/fixed cells and fixed tissue, physiological measurements in mouse models such as monitoring of glucose and insulin tolerance.  However, my current research on Pask and Tcf7l2 is moving towards the study of the function of these gene products in extra-pancreatic tissues, with a focus on tissue cross-talk in the regulation of energy homeostasis. 

This has led me to use techniques that are not part of the customary repertoire for traditional islet labs- indirect calorimetry (CLAMS), body composition analysis (EchoMRI), analysis of bone (density, structure, fracture, endocrine function), manipulation of circadian rhythm, etc.  Additionally, in collaboration with Dr. Paul Kemp and Dr. Amanda Natanek (Imperial College London), I looked at pharmacological approaches to alter muscle fibre type and/or functional islet cell mass as a potential means to modulate glucose homeostasis.  In this context I have been using imaging techniques to look at muscle fibre type and islet mass (in conjunction with some of the other techniques listed above) in mouse models of diabetes following pharmacological intervention. 

 References

1.         da Silva Xavier, G. et al. Proc.Natl.Acad.Sci.U.S.A 97: 4023-4028 (2000)

2.         da Silva Xavier, G. et al. Biochem.J. 371: 761-774(2003)

3.         Leclerc, I. et al. Am.J.Physiol Endocrinol.Metab 286: E1023-E1031 (2004)

4.         Sun, G. et al. Diabetologia 53: 924-936 (2010)

5.         Tsuboi, T. et al. J.Biol.Chem. 278: 52042-52051 (2003)

6.         da Silva Xavier, G. et al.  Proc.Natl.Acad.Sci.U.S.A 101: 8319-8324 (2004)

7.         da Silva Xavier, G. et al. Diabetologia 54: 819-827 (2011) 

8.         Leclerc, I. et al. Diabetologia 54: 125-134 (2011)

9.         da Silva Xavier, G. et al. Diabetes. 58: 894-905 (2009)

10.       da Silva Xavier, G. et al. Diabetologia 55:2667-76 (2012)

11.       Mitchell, R et alHMG 24:1390-9 (2015)

Other activities

BBSRC Core Committee Member (2018-)

Publications

Kimura T, Obata A, Shimoda M, Shimizu I, Da Silva Xavier G, Okauchi S, Hirukawa H, Kohara K, Mune T, Moriuchi S, Hiraoka A, Tamura K, Chikazawa G, Ishida A, Yoshitaka H, Rutter GA, Kaku K, Kaneto H (2018) Down-regulation of vascular GLP-1 receptor expression in human subjects with obesity. Sci Rep. 2018 Jul 13;8(1):10644. doi: 10.1038/s41598-018-28849-1.

Nguyen-Tu MS, Da Silva Xavier G, Leclerc I, Rutter GA. J Biol (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. Chem. 2018 Jul 2. pii: jbc.RA118.003613. doi: 10.1074/jbc.RA118.003613. [Epub ahead of print]

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 DJ (2018) Neuronatin regulates pancreatic β cell insulin content and secretion. J Clin Invest. 2018 Aug 1;128(8):3369-3381. doi: 10.1172/JCI120115. Epub 2018 Jul 9.

Da Silva Xavier G, Hodson DJ (2018) Mouse models of peripheral metabolic disease. Best Pract Res Clin Endocrinol Metab. 2018 Jun;32(3):299-315. doi: 10.1016/j.beem.2018.03.009. Epub 2018 Mar 31. Review.

Da Silva Xavier G (2018) The Cells of the Islets of Langerhans. J Clin Med. 2018 Mar 12;7(3). pii: E54. doi: 10.3390/jcm7030054. Review.

Fletcher RS, Ratajczak J, Doig CL, Oakey LA, Callingham R, Da Silva Xavier G, Garten A, Elhassan YS, Redpath P, Migaud ME, Philp A, Brenner C, Canto C, Lavery GG (2017) Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells. Mol Metab. 2017 May 29;6(8):819-832. doi: 10.1016/j.molmet.2017.05.011. eCollection 2017 Aug.

Da Silva Xavier G, Mondragon A, Mourougavelou V, Cruciani-Guglielmacci C, Denom J, Herrera PL, Magnan C, Rutter GA (2017) Pancreatic alpha cell-selective deletion of Tcf7l2 impairs glucagon secretion and counter-regulatory responses to hypoglycaemia in mice. Diabetologia. 2017 Jun;60(6):1043-1050. doi: 10.1007/s00125-017-4242-2. Epub 2017 Mar 25.

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, Da Silva Xavier G, Rutter GA (2016) Cell type-specific deletion in mice reveals roles for PAS kinase in insulin and glucagon production. Diabetologia. 2016 Sep;59(9):1938-47. doi: 10.1007/s00125-016-4025-1. Epub 2016 Jun 24.

Sun G, Da Silva Xavier G, Gorman T, Priest C, Solomou A, Hodson DJ, Foretz M, Viollet B, Herrera PL, Parker H, Reimann F, Gribble FM, Migrenne S, Magnan C, Marley A, Rutter GA (2015) LKB1 and AMPKα1 are required in pancreatic alpha cells for the normal regulation of glucagon secretion and responses to hypoglycemia. Mol Metab. 2015 Jan 31;4(4):277-86. doi: 10.1016/j.molmet.2015.01.006. eCollection 2015 Apr.

Mitchell RK, Mondragon A, Chen L, Mcginty JA, French PM, Ferrer J, Thorens B, Hodson DJ, Rutter GA, Da Silva Xavier G (2015) Selective disruption of Tcf7l2 in the pancreatic β cell impairs secretory function and lowers β cell mass. Hum Mol Genet. 2015 Mar 1;24(5):1390-9. doi: 10.1093/hmg/ddu553. Epub 2014 Oct 29.

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