Genetic and functional studies of novel type 2 diabetes susceptibility genes
Lead Research Organisation:
Imperial College London
Department Name: School of Public Health
Abstract
Diabetes is a complex metabolic disease, with both genetic and environmental causes, in which the body?s ability to maintain normal blood glucose levels is compromised. In recent years, diabetes has developed into a global health problem of epidemic proportions, consuming as much as 10 % of the health care budgets of many westernised countries. Increases in blood glucose concentrations have very serious health implications, and can lead to blindness, heart disease, kidney malfunction and nerve damage. There are two main clinical subtypes of diabetes: type 1 diabetes is characterised by the destruction of the insulin-secreting pancreatic cells that regulate blood glucose levels; and type 2 diabetes (T2D) is characterised by insulin resistance and dysfunctional insulin secretion. Of the two subtypes, T2D is by far the predominant form of diabetes, accounting for up to 90% of the total diabetes prevalence.
Our research is focussed on the identification of the genes that predispose an individual to develop T2D and on elucidating the molecular mechanisms by which the products of these T2D ?susceptibility genes? influence an individual?s risk of T2D. We have recently completed the first ever genetic scan of all 46 human chromosomes for T2D susceptibility genes (the results of this research will be published in a top journal, Nature, later in 2007). Our results confirmed a previously known susceptibility gene on chromosome 10 (called TCF7L2) and identified novel T2D susceptibility genes, including a zinc transporter gene called ZnT-8. Zinc is very important for regulating the pancreatic secretion of the hormone insulin that acts to control blood glucose levels.
The proposed project aims to follow up on our genetic scan by: a) carrying out an exhaustive genetic analysis of these novel genetic loci in the European population and b) elucidating the molecular mechanisms by which the key genes, TCF7L2 and ZnT-8, contribute to T2D risk.
Our research is focussed on the identification of the genes that predispose an individual to develop T2D and on elucidating the molecular mechanisms by which the products of these T2D ?susceptibility genes? influence an individual?s risk of T2D. We have recently completed the first ever genetic scan of all 46 human chromosomes for T2D susceptibility genes (the results of this research will be published in a top journal, Nature, later in 2007). Our results confirmed a previously known susceptibility gene on chromosome 10 (called TCF7L2) and identified novel T2D susceptibility genes, including a zinc transporter gene called ZnT-8. Zinc is very important for regulating the pancreatic secretion of the hormone insulin that acts to control blood glucose levels.
The proposed project aims to follow up on our genetic scan by: a) carrying out an exhaustive genetic analysis of these novel genetic loci in the European population and b) elucidating the molecular mechanisms by which the key genes, TCF7L2 and ZnT-8, contribute to T2D risk.
Technical Summary
Type 2 diabetes is a major and growing health problem with both genetic and environmental causes. Together with our collaborators at McGill University, Montreal, Canada, we have performed, in a French population, the first published genome wide association (GWA) scan for T2D genes (Sladek et al., Nature, 2007, in press). Our results replicated the established strong association with the TCF7L2 SNP rs7903146 (p=1.51 x 10-34) and confirmed associations for eight SNPs in four novel T2D susceptibility loci.
This project aims to carry out exhaustive fine mapping of these 4 loci (and additional loci ones likely to appear from ongoing WGA studies) in the European population and to elucidate the molecular mechanisms by which the transcription factor TCF7L2 and the Zinc transporter ZnT-8 contribute to T2D risk.
We have three specific aims:
Aim 1: We will undertake fine mapping of the novel susceptibility loci in order to identify the putative aetiological variants that are responsible for the association signals. We shall genotype the entire catalogue of common SNPs at all four loci in our extensive French case-control samples. T2D-associated SNPs will be subjected to large scale replication and prospective cohort studies.
Aim 2: TCF7L2 is a transcription factor targeted by the Wnt signalling pathway, important for pancreatic development. We seek to determine the following: what is the impact of TCF7L2 silencing on glucose- and other nutrient-stimulated insulin secretion, beta-cell proliferation/survival, and the expression of key beta-cell genes? What is the impact of TCF7L2 over-expression on beta-cell secretory function, proliferation/apoptosis, and beta-cell gene expression? How does the TCF7L2 rs7903146 polymorphism affect mRNA stability, splicing and transcriptional activity? What is the phenotype of knock-in mice bearing the at-risk rs7903146 allele?
Aim 3. Apart from rs7903146 in TCF7L2, the strongest WGA signal was provided by the coding SNP rs13266634, a R325W variant in SLC30A8 (ZnT-8), a beta-cell restricted vesicular zinc transporter. We will firstly examine the importance of ZnT-8 for normal beta cell glucose metabolism, basal and stimulated insulin secretion as well as beta-cell growth and survival. We will then determine the effect of the R325W variant on ZnT-8 activity and function, in terms of protein stability, sub-cellular localisation, and zinc uptake into insulin vesicles.
We believe that this integrated genetic and functional approach to the study of novel T2D susceptibility loci should bring new insights to the molecular determinants of this disease, opening new avenues for predicting and treating diabetes and its complications.
This project aims to carry out exhaustive fine mapping of these 4 loci (and additional loci ones likely to appear from ongoing WGA studies) in the European population and to elucidate the molecular mechanisms by which the transcription factor TCF7L2 and the Zinc transporter ZnT-8 contribute to T2D risk.
We have three specific aims:
Aim 1: We will undertake fine mapping of the novel susceptibility loci in order to identify the putative aetiological variants that are responsible for the association signals. We shall genotype the entire catalogue of common SNPs at all four loci in our extensive French case-control samples. T2D-associated SNPs will be subjected to large scale replication and prospective cohort studies.
Aim 2: TCF7L2 is a transcription factor targeted by the Wnt signalling pathway, important for pancreatic development. We seek to determine the following: what is the impact of TCF7L2 silencing on glucose- and other nutrient-stimulated insulin secretion, beta-cell proliferation/survival, and the expression of key beta-cell genes? What is the impact of TCF7L2 over-expression on beta-cell secretory function, proliferation/apoptosis, and beta-cell gene expression? How does the TCF7L2 rs7903146 polymorphism affect mRNA stability, splicing and transcriptional activity? What is the phenotype of knock-in mice bearing the at-risk rs7903146 allele?
Aim 3. Apart from rs7903146 in TCF7L2, the strongest WGA signal was provided by the coding SNP rs13266634, a R325W variant in SLC30A8 (ZnT-8), a beta-cell restricted vesicular zinc transporter. We will firstly examine the importance of ZnT-8 for normal beta cell glucose metabolism, basal and stimulated insulin secretion as well as beta-cell growth and survival. We will then determine the effect of the R325W variant on ZnT-8 activity and function, in terms of protein stability, sub-cellular localisation, and zinc uptake into insulin vesicles.
We believe that this integrated genetic and functional approach to the study of novel T2D susceptibility loci should bring new insights to the molecular determinants of this disease, opening new avenues for predicting and treating diabetes and its complications.
Organisations
- Imperial College London, United Kingdom (Lead Research Organisation)
- University of Bristol, United Kingdom (Collaboration)
- Yale University (Collaboration)
- University of Geneva, Switzerland (Collaboration)
- University of Toronto (Collaboration)
- Open University of Israel (Collaboration)
- AstraZeneca plc (Collaboration)
- University of Milan, Italy (Collaboration)
- Ben-Gurion University of the Negev (Collaboration)
- University of Pisa, Italy (Collaboration)
- Cochin Institute (Collaboration)
- University of Alberta (Collaboration)
- Institute of Genetics, Molecular and Cellular Biology (IGBMC) (Collaboration)
Publications

Blakemore AI
(2010)
Investigation of Mendelian forms of obesity holds out the prospect of personalized medicine.
in Annals of the New York Academy of Sciences

Bouhaha R
(2010)
TCF7L2 is associated with type 2 diabetes in nonobese individuals from Tunisia.
in Pathologie-biologie

Bousquet J
(2011)
Systems medicine and integrated care to combat chronic noncommunicable diseases.
in Genome medicine

Chambers JC
(2011)
Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma.
in Nature genetics

Da Silva Xavier G
(2012)
Abnormal glucose tolerance and insulin secretion in pancreas-specific Tcf7l2-null mice
in Diabetologia

Duesing K
(2008)
Evaluating the association of common PBX1 variants with type 2 diabetes.
in BMC medical genetics

Gonsorcikova L
(2011)
Familial mild hyperglycemia associated with a novel ABCC8-V84I mutation within three generations.
in Pediatric diabetes

Le Clerc S
(2011)
Screening low-frequency SNPS from genome-wide association study reveals a new risk allele for progression to AIDS.
in Journal of acquired immune deficiency syndromes (1999)

Ma L
(2010)
Evaluation of A2BP1 as an obesity gene.
in Diabetes
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Sector | Academic/University |
PI Contribution | Generation and use of adenoviral constructs |
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Sector | Academic/University |
PI Contribution | Generation of tissue specifi KO mice |
Impact | Publication in Diabetologia, 2010 (Sun et al) |
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Organisation | University of Geneva |
Department | Faculty of Diabetes |
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Sector | Academic/University |
PI Contribution | Experiments for publications |
Collaborator Contribution | Experiments for publications |
Impact | Sorcin links pancreatic ß cell lipotoxicity to ER Ca2+ stores - Marmugi A et al - PMID: 26822088 Hypoxia lowers SLC30A8/ZnT8 expression and free cytosolic Zn2+ in pancreatic beta cells. Gerber PA et al PMID: 24865615 Incretin-modulated beta cell energetics in intact islets of Langerhans. Hodson DJ et al - PMID: 24766140 ADCY5 couples glucose to insulin secretion in human islets. Hodson DJ et al PMID: 24740569 Lipotoxicity disrupts incretin-regulated human ß cell connectivity. Hodson DJ et al - PMID: 24018562 |
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Sector | Academic/University |
PI Contribution | Experiments for publications |
Collaborator Contribution | Experiments for publications |
Impact | manuscript (in press) Denton RM et al Biochem J 2016 |
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Description | Denton |
Organisation | University of Pisa |
Country | Italy |
Sector | Academic/University |
PI Contribution | Experiments for publications |
Collaborator Contribution | Experiments for publications |
Impact | Sorcin links pancreatic ß cell lipotoxicity to ER Ca2+ stores - Marmugi A et al - PMID: 26822088 Hypoxia lowers SLC30A8/ZnT8 expression and free cytosolic Zn2+ in pancreatic beta cells. Gerber PA et al PMID: 24865615 Incretin-modulated beta cell energetics in intact islets of Langerhans. Hodson DJ et al - PMID: 24766140 ADCY5 couples glucose to insulin secretion in human islets. Hodson DJ et al PMID: 24740569 Lipotoxicity disrupts incretin-regulated human ß cell connectivity. Hodson DJ et al - PMID: 24018562 |
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PI Contribution | Experiments for publications |
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Organisation | University of Alberta |
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Sector | Academic/University |
PI Contribution | Experiments for publications |
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Description | Piero Marchetti (Pisa) |
Organisation | University of Pisa |
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Sector | Academic/University |
PI Contribution | experiments for publications |
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Description | Yuval Dor (Israel) |
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PI Contribution | Experiments for publications |
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