Gaby Da Silva Xavier
Colleges, School and Institutes
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 Our current unpublished studies revealed a potential role for PASK in the regulation of food intake and circadian control of glucose homeostasis.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.
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 al. HMG 24:1390-9 (2015)
12. da Silva Xavier et al. Diabetologia 60:1043-1050 (2017)
1997 B.Sc. Biochemistry (University of Bristol
2001 Ph.D. in Biochemistry (University of Bristol)
2016 PG Certificate in Education (Imperial College London)
2017 PG Diploma in Education (Imperial College London)