Table of Contents Author Guidelines Submit a Manuscript
Journal of Diabetes Research
Volume 2013, Article ID 906590, 12 pages
http://dx.doi.org/10.1155/2013/906590
Review Article

Animal Models of GWAS-Identified Type 2 Diabetes Genes

1Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London SW7 2AZ, UK
2Biophotonics Section, Department of Physics, Imperial College London, London SW7 2AZ, UK

Received 4 February 2013; Accepted 18 March 2013

Academic Editor: Daisuke Koya

Copyright © 2013 Gabriela da Silva Xavier et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. Diabetes UK, “Diabetes in the UK 2012: key statistics on diabetes,” 2013.
  2. F. B. Hu, “Globalization of diabetes: the role of diet, lifestyle, and genes,” Diabetes Care, vol. 34, pp. 1249–1257, 2011. View at Google Scholar
  3. F. B. Hu, T. Y. Li, G. A. Colditz, W. C. Willett, and J. E. Manson, “Television watching and other sedentary behaviors in relation to risk of obesity and type 2 diabetes mellitus in women,” Journal of the American Medical Association, vol. 289, no. 14, pp. 1785–1791, 2003. View at Publisher · View at Google Scholar · View at Scopus
  4. W. C. Knowler, E. Barrett-Connor, S. E. Fowler et al., “Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin,” New England Journal of Medicine, vol. 346, no. 6, pp. 393–403, 2002. View at Publisher · View at Google Scholar · View at Scopus
  5. A. Ramachandran, C. Snehalatha, S. Mary, B. Mukesh, A. D. Bhaskar, and V. Vijay, “The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1),” Diabetologia, vol. 49, no. 2, pp. 289–297, 2006. View at Publisher · View at Google Scholar · View at Scopus
  6. J. Salas-Salvadó, M. Bulló, N. Babio et al., “Reduction in the incidence of type 2 diabetes with the mediterranean diet: results of the PREDIMED-Reus nutrition intervention randomized trial,” Diabetes Care, vol. 34, no. 1, pp. 14–19, 2011. View at Publisher · View at Google Scholar · View at Scopus
  7. J. Tuomilehto, J. Lindström, J. G. Eriksson et al., “Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance,” New England Journal of Medicine, vol. 344, no. 18, pp. 1343–1350, 2001. View at Publisher · View at Google Scholar · View at Scopus
  8. R. M. Van Dam, “The epidemiology of lifestyle and risk for type 2 diabetes,” European Journal of Epidemiology, vol. 18, no. 12, pp. 1115–1125, 2003. View at Publisher · View at Google Scholar · View at Scopus
  9. D. Yach, D. Stuckler, and K. D. Brownell, “Epidemiologic and economic consequences of the global epidemics of obesity and diabetes,” Nature Medicine, vol. 12, pp. 62–66, 2006. View at Publisher · View at Google Scholar · View at Scopus
  10. P. W. F. Wilson, J. B. Meigs, L. Sullivan, C. S. Fox, D. M. Nathan, and R. B. D'Agostino Sr., “Prediction of incident diabetes mellitus in middle-aged adults: the framingham offspring study,” Archives of Internal Medicine, vol. 167, no. 10, pp. 1068–1074, 2007. View at Publisher · View at Google Scholar · View at Scopus
  11. J. S. Rana, T. Y. Li, J. E. Manson, and F. B. Hu, “Adiposity compared with physical inactivity and risk of type 2 diabetes in women,” Diabetes Care, vol. 30, no. 1, pp. 53–58, 2007. View at Publisher · View at Google Scholar · View at Scopus
  12. V. S. Malik, B. M. Popkin, G. A. Bray, J. P. Després, W. C. Willett, and F. B. Hu, “Sugar-sweetened beverages and risk of metabolic syndrome and type 2 diabetes: a meta-analysis,” Diabetes Care, vol. 33, no. 11, pp. 2477–2483, 2010. View at Publisher · View at Google Scholar · View at Scopus
  13. U. Risérus, W. C. Willett, and F. B. Hu, “Dietary fats and prevention of type 2 diabetes,” Progress in Lipid Research, vol. 48, no. 1, pp. 44–51, 2009. View at Publisher · View at Google Scholar · View at Scopus
  14. A. W. Barclay, P. Petocz, J. McMillan-Price et al., “Glycemic index, glycemic load, and chronic disease risk—a metaanalysis of observational studies,” American Journal of Clinical Nutrition, vol. 87, no. 3, pp. 627–637, 2008. View at Google Scholar · View at Scopus
  15. N. A. Christakis and J. H. Fowler, “The spread of obesity in a large social network over 32 years,” New England Journal of Medicine, vol. 357, no. 4, pp. 370–379, 2007. View at Publisher · View at Google Scholar · View at Scopus
  16. C. Willi, P. Bodenmann, W. A. Ghali, P. D. Faris, and J. Cornuz, “Active smoking and the risk of type 2 diabetes: a systematic review and meta-analysis,” Journal of the American Medical Association, vol. 298, no. 22, pp. 2654–2664, 2007. View at Publisher · View at Google Scholar · View at Scopus
  17. G. C. Burdge and K. A. Lillycrop, “Nutrition, epigenetics, and developmental plasticity: implications for understanding human disease,” Annual Review of Nutrition, vol. 30, pp. 315–339, 2010. View at Publisher · View at Google Scholar · View at Scopus
  18. P. Poulsen, K. Ohm Kyvik, A. Vaag, and H. Beck-Nielsen, “Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance—a population-based twin study,” Diabetologia, vol. 42, no. 2, pp. 139–145, 1999. View at Publisher · View at Google Scholar · View at Scopus
  19. K. Owen and A. T. Hattersley, “Maturity-onset diabetes of the young: from clinical description to molecular genetic characterization,” Best Practice and Research, vol. 15, no. 3, pp. 309–323, 2001. View at Publisher · View at Google Scholar · View at Scopus
  20. I. S. Farooqi and S. O'Rahilly, “Genetics of obesity in humans,” Endocrine Reviews, vol. 27, no. 7, pp. 710–718, 2006. View at Publisher · View at Google Scholar · View at Scopus
  21. N. Risch and K. Merikangas, “The future of genetic studies of complex human diseases,” Science, vol. 273, no. 5281, pp. 1516–1517, 1996. View at Google Scholar · View at Scopus
  22. D. Altshuler, J. N. Hirschhorn, M. Klannemark et al., “The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes,” Nature Genetics, vol. 26, no. 1, pp. 76–80, 2000. View at Publisher · View at Google Scholar · View at Scopus
  23. J. M. Lehmann, L. B. Moore, T. A. Smith-Oliver, W. O. Wilkison, T. M. Willson, and S. A. Kliewer, “An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ),” Journal of Biological Chemistry, vol. 270, no. 22, pp. 12953–12956, 1995. View at Publisher · View at Google Scholar · View at Scopus
  24. A. L. Gloyn, M. N. Weedon, K. R. Owen et al., “Large-scale association studies of variants in genes encoding the pancreatic β-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes,” Diabetes, vol. 52, no. 2, pp. 568–572, 2003. View at Publisher · View at Google Scholar · View at Scopus
  25. S. F. A. Grant, G. Thorleifsson, I. Reynisdottir et al., “Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes,” Nature Genetics, vol. 38, no. 3, pp. 320–323, 2006. View at Publisher · View at Google Scholar · View at Scopus
  26. R. Saxena, B. F. Voight, V. Lyssenko et al., “Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels,” Science, vol. 316, no. 5829, pp. 1331–1336, 2007. View at Publisher · View at Google Scholar · View at Scopus
  27. L. J. Scott, K. L. Mohlke, L. L. Bonnycastle et al., “A genome-wide association study of type 2 diabetes in finns detects multiple susceptibility variants,” Science, vol. 316, no. 5829, pp. 1341–1345, 2007. View at Publisher · View at Google Scholar · View at Scopus
  28. R. Sladek, G. Rocheleau, J. Rung et al., “A genome-wide association study identifies novel risk loci for type 2 diabetes,” Nature, vol. 445, no. 7130, pp. 881–885, 2007. View at Publisher · View at Google Scholar · View at Scopus
  29. E. Zeggini, M. N. Weedon, C. M. Lindgren et al., “Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes,” Science, vol. 316, pp. 1336–1341, 2007. View at Google Scholar
  30. Y. S. Cho, C. H. Chen, C. Hu et al., “Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians,” Nature Genetics, vol. 44, pp. 67–72, 2012. View at Google Scholar
  31. J. Dupuis, C. Langenberg, I. Prokopenko et al., “New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk,” Nature Genetics, vol. 42, pp. 105–116, 2010. View at Google Scholar
  32. J. S. Kooner, D. Saleheen, X. Sim et al., “Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci,” Nature Genetics, vol. 43, pp. 984–989, 2011. View at Google Scholar
  33. N. D. Palmer, C. W. McDonough, P. J. Hicks et al., “A genome-wide association search for type 2 diabetes genes in African Americans,” PLoS ONE, vol. 7, Article ID e29202, 2012. View at Google Scholar
  34. B. F. Voight, L. J. Scott, V. Steinthorsdottir et al., “Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis,” Nature Genetics, vol. 42, pp. 579–589, 2010. View at Google Scholar
  35. A. P. Morris, B. F. Voight, T. M. Teslovich et al., “Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes,” Nature Genetics, vol. 44, pp. 981–990, 2012. View at Google Scholar
  36. M. C. Cornelis, L. Qi, C. Zhang et al., “Joint effects of common genetic variants on the risk for type 2 diabetes in U.S. men and women of European ancestry,” Annals of Internal Medicine, vol. 150, no. 8, pp. 541–550, 2009. View at Google Scholar · View at Scopus
  37. J. M. De Miguel-Yanes, P. Shrader, M. J. Pencina et al., “Genetic risk reclassification for type 2 diabetes by age below or above 50 years using 40 type 2 diabetes risk single nucleotide polymorphisms,” Diabetes Care, vol. 34, no. 1, pp. 121–125, 2011. View at Publisher · View at Google Scholar · View at Scopus
  38. J. C. Florez, “Newly identified loci highlight beta cell dysfunction as a key cause of type 2 diabetes: where are the insulin resistance genes?” Diabetologia, vol. 51, no. 7, pp. 1100–1110, 2008. View at Publisher · View at Google Scholar · View at Scopus
  39. S. Cauchi, D. Meyre, C. Dina et al., “Transcription factor TCF7L2 genetic study in the French population: expression in human β-cells and adipose tissue and strong association with type 2 diabetes,” Diabetes, vol. 55, no. 10, pp. 2903–2908, 2006. View at Publisher · View at Google Scholar · View at Scopus
  40. S. Maeda, N. Osawa, T. Hayashi, S. Tsukada, M. Kobayashi, and R. Kikkawa, “Genetic variations associated with diabetic nephropathy and type II diabetes in a Japanese population,” Kidney International, vol. 72, no. 106, supplement, pp. S43–S48, 2007. View at Publisher · View at Google Scholar · View at Scopus
  41. J. B. Meigs, M. K. Rutter, L. M. Sullivan, C. S. Fox, R. B. D'Agostino, and P. W. F. Wilson, “Impact of insulin resistance on risk of type 2 diabetes and cardiovascular disease in people with metabolic syndrome,” Diabetes Care, vol. 30, no. 5, pp. 1219–1225, 2007. View at Publisher · View at Google Scholar · View at Scopus
  42. C. Herder, W. Rathmann, K. Strassburger et al., “Variants of the PPARG, IGF2BP2, CDKAL1, HHEX, and TCF7L2 genes confer risk of type 2 diabetes independently of BMI in the German KORA studies,” Hormone and Metabolic Research, vol. 40, no. 10, pp. 722–726, 2008. View at Publisher · View at Google Scholar · View at Scopus
  43. D. K. Sanghera, L. Ortega, S. Han et al., “Impact of nine common type 2 diabetes risk polymorphisms in Asian Indian Sikhs: PPARG2 (Pro12Ala), IGF2BP2, TCF7L2 and FTO variants confer a significant risk,” BMC Medical Genetics, vol. 9, article 59, 2008. View at Publisher · View at Google Scholar · View at Scopus
  44. Y. M. Cho, T. H. Kim, S. Lim et al., “Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population,” Diabetologia, vol. 52, no. 2, pp. 253–261, 2009. View at Publisher · View at Google Scholar · View at Scopus
  45. Y. Tabara, H. Osawa, R. Kawamoto et al., “Replication study of candidate genes associated with type 2 diabetes based on genome-wide screening,” Diabetes, vol. 58, no. 2, pp. 493–498, 2009. View at Publisher · View at Google Scholar · View at Scopus
  46. G. F. Marquezine, A. C. Pereira, A. G. P. Sousa, J. G. Mill, W. A. Hueb, and J. E. Krieger, “TCF7L2 variant genotypes and type 2 diabetes risk in Brazil: significant association, but not a significant tool for risk stratification in the general population,” BMC Medical Genetics, vol. 9, article 106, 2008. View at Publisher · View at Google Scholar · View at Scopus
  47. I. Ezzidi, N. Mtiraoui, S. Cauchi et al., “Contribution of type 2 diabetes associated loci in the Arabic population from Tunisia: a case-control study,” BMC Medical Genetics, vol. 10, article 33, 2009. View at Publisher · View at Google Scholar · View at Scopus
  48. F. Takeuchi, M. Serizawa, K. Yamamoto et al., “Confirmation of multiple risk loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population,” Diabetes, vol. 58, no. 7, pp. 1690–1699, 2009. View at Publisher · View at Google Scholar · View at Scopus
  49. S. Ereqat, A. Nasereddin, S. Cauchi, K. Azmi, Z. Abdeen, and R. Amin, “Association of a common variant in TCF7L2 gene with type 2 diabetes mellitus in the Palestinian population,” Acta Diabetologica, vol. 47, no. 1, supplement, pp. S195–S198, 2010. View at Publisher · View at Google Scholar · View at Scopus
  50. J. Wen, T. Rönn, A. Olsson et al., “Investigation of type 2 diabetes risk alleles support CDKN2A/B, CDKAL1, and TCF7L2 as susceptibility genes in a Han Chinese cohort,” PLoS ONE, vol. 5, no. 2, Article ID e9153, 2010. View at Publisher · View at Google Scholar · View at Scopus
  51. G. Chauhan, C. J. Spurgeon, R. Tabassum et al., “Impact of common variants of PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 on the risk of type 2 diabetes in 5,164 Indians,” Diabetes, vol. 59, no. 8, pp. 2068–2074, 2010. View at Publisher · View at Google Scholar · View at Scopus
  52. R. Karns, G. Zhang, N. Jeran et al., “Replication of genetic variants from genome-wide association studies with metabolic traits in an island population of the Adriatic coast of Croatia,” European Journal of Human Genetics, vol. 19, no. 3, pp. 341–346, 2011. View at Publisher · View at Google Scholar · View at Scopus
  53. E. Ramos, G. Chen, D. Shriner et al., “Replication of genome-wide association studies (GWAS) loci for fasting plasma glucose in African-Americans,” Diabetologia, vol. 54, no. 4, pp. 783–788, 2011. View at Publisher · View at Google Scholar · View at Scopus
  54. S. D. Rees, M. Z. Hydrie, A. S. Shera et al., “Replication of 13 genome-wide association (GWA)-validated risk variants for type 2 diabetes in Pakistani populations,” Diabetologia, vol. 54, pp. 1368–1374, 2011. View at Google Scholar
  55. R. Saxena, C. C. Elbers, Y. Guo et al., “Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci,” American Journal of Human Genetics, vol. 90, pp. 410–425, 2012. View at Google Scholar
  56. S. Cauchi, I. Ezzidi, A. Y. El et al., “European genetic variants associated with type 2 diabetes in North African Arabs,” Diabetes & Metabolism, vol. 38, pp. 316–323, 2012. View at Google Scholar
  57. N. Mtiraoui, A. Turki, R. Nemr et al., “Contribution of common variants of ENPP1, IGF2BP2, KCNJ11, MLXIPL, PPARgamma, SLC30A8 and TCF7L2 to the risk of type 2 diabetes in Lebanese and Tunisian Arabs,” Diabetes & Metabolism, vol. 38, pp. 444–449, 2012. View at Google Scholar
  58. A. Turki, G. S. Al-Zaben, N. Mtiraoui, H. Marmmuoch, T. Mahjoub, and W. Y. Almawi, “Transcription factor-7-like 2 gene variants are strongly associated with type 2 diabetes in Tunisian Arab subjects,” Gene, vol. 513, pp. 244–248, 2013. View at Google Scholar
  59. J. Long, T. Edwards, L. B. Signorello et al., “Evaluation of genome-wide association study-identified type 2 diabetes loci in African Americans,” American Journal of Epidemiology, vol. 176, pp. 995–1001, 2012. View at Google Scholar
  60. A. Helgason, S. Pálsson, G. Thorleifsson et al., “Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution,” Nature Genetics, vol. 39, no. 2, pp. 218–225, 2007. View at Publisher · View at Google Scholar · View at Scopus
  61. J. C. Florez, K. A. Jablonski, N. Bayley et al., “TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program,” New England Journal of Medicine, vol. 355, no. 3, pp. 241–250, 2006. View at Publisher · View at Google Scholar · View at Scopus
  62. J. Wang, J. Kuusisto, M. Vänttinen et al., “Variants of transcription factor 7-like 2 (TCF7L2) gene predict conversion to type 2 diabetes in the Finnish Diabetes Prevention Study and are associated with impaired glucose regulation and impaired insulin secretion,” Diabetologia, vol. 50, no. 6, pp. 1192–1200, 2007. View at Publisher · View at Google Scholar · View at Scopus
  63. D. Dabelea, L. M. Dolan, R. D'Agostino et al., “Association testing of TCF7L2 polymorphisms with type 2 diabetes in multi-ethnic youth,” Diabetologia, vol. 54, no. 3, pp. 535–539, 2011. View at Publisher · View at Google Scholar · View at Scopus
  64. O. T. Raitakari, T. Rönnemaa, R. Huupponen et al., “Variation of the transcription factor 7-like 2 (TCF7L2) gene predicts impaired fasting glucose in healthy young adults. The Cardiovascular Risk in Young Finns Study,” Diabetes Care, vol. 30, pp. 2299–2301, 2007. View at Publisher · View at Google Scholar · View at Scopus
  65. T. Jin and L. Liu, “The Wnt signaling pathway effector TCF7L2 and type 2 diabetes mellitus,” Molecular Endocrinology, vol. 22, no. 11, pp. 2383–2392, 2008. View at Publisher · View at Google Scholar · View at Scopus
  66. T. Reya and H. Clevers, “Wnt signalling in stem cells and cancer,” Nature, vol. 434, no. 7035, pp. 843–850, 2005. View at Publisher · View at Google Scholar · View at Scopus
  67. I. C. Rulifson, S. K. Karnik, P. W. Heiser et al., “Wnt signaling regulates pancreatic β cell proliferation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 15, pp. 6247–6252, 2007. View at Publisher · View at Google Scholar · View at Scopus
  68. S. Papadopoulou and H. Edlund, “Attenuated Wnt signaling perturbs pancreatic growth but not pancreatic function,” Diabetes, vol. 54, no. 10, pp. 2844–2851, 2005. View at Publisher · View at Google Scholar · View at Scopus
  69. J. M. Wells, F. Esni, G. P. Boivin et al., “Wnt/β-catenin signaling is required for development of the exocrine pancreas,” BMC Developmental Biology, vol. 7, article 4, 2007. View at Publisher · View at Google Scholar · View at Scopus
  70. P. W. Heiser, J. Lau, M. M. Taketo, P. L. Herrera, and M. Hebrok, “Stabilization of β-catenin impacts pancreas growth,” Development, vol. 133, no. 10, pp. 2023–2032, 2006. View at Publisher · View at Google Scholar · View at Scopus
  71. R. J. F. Loos, P. W. Franks, R. W. Francis et al., “TCF7L2 polymorphisms modulate proinsulin levels and β-cell function in a British europid population,” Diabetes, vol. 56, no. 7, pp. 1943–1947, 2007. View at Publisher · View at Google Scholar · View at Scopus
  72. V. Lyssenko, R. Lupi, P. Marchetti et al., “Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes,” Journal of Clinical Investigation, vol. 117, no. 8, pp. 2155–2163, 2007. View at Publisher · View at Google Scholar · View at Scopus
  73. D. T. Villareal, H. Robertson, G. I. Bell et al., “TCF7L2 variant rs7903146 affects the risk of type 2 diabetes by modulating incretin action,” Diabetes, vol. 59, no. 2, pp. 479–485, 2010. View at Publisher · View at Google Scholar · View at Scopus
  74. L. Shu, A. V. Matveyenko, J. Kerr-Conte, J. H. Cho, C. H. S. McIntosh, and K. Maedler, “Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP- and GLP-1 receptors and impaired beta-cell function,” Human Molecular Genetics, vol. 18, no. 13, pp. 2388–2399, 2009. View at Publisher · View at Google Scholar · View at Scopus
  75. L. Shu, N. S. Sauter, F. T. Schulthess, A. V. Matveyenko, J. Oberholzer, and K. Maedler, “Transcription factor 7-like 2 regulates β-cell survival and function in human pancreatic islets,” Diabetes, vol. 57, no. 3, pp. 645–653, 2008. View at Publisher · View at Google Scholar · View at Scopus
  76. G. Da Silva Xavier, M. K. Loder, A. McDonald et al., “TCF7L2 regulates late events in insulin secretion from pancreatic islet β-cells,” Diabetes, vol. 58, no. 4, pp. 894–905, 2009. View at Publisher · View at Google Scholar · View at Scopus
  77. G. da Silva Xavier, A. Mondragon, G. Sun et al., “Abnormal glucose tolerance and insulin secretion in pancreas-specific Tcf7l2-null mice,” Diabetologia, vol. 55, pp. 2667–2676, 2012. View at Google Scholar
  78. L. Prokunina-Olsson, C. Welch, O. Hansson et al., “Tissue-specific alternative splicing of TCF7L2,” Human Molecular Genetics, vol. 18, no. 20, pp. 3795–3804, 2009. View at Publisher · View at Google Scholar · View at Scopus
  79. Z. Liu and J. F. Habener, “Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic beta cell proliferation,” Journal of Biological Chemistry, vol. 283, no. 13, pp. 8723–8735, 2008. View at Publisher · View at Google Scholar · View at Scopus
  80. M. L. Slattery, A. R. Folsom, R. Wolff, J. Herrick, B. J. Caan, and J. D. Potter, “Transcription factor 7-like 2 polymorphism and colon cancer,” Cancer Epidemiology Biomarkers and Prevention, vol. 17, no. 4, pp. 978–982, 2008. View at Publisher · View at Google Scholar · View at Scopus
  81. A. Saadeddin, R. Babaei-Jadidi, B. Spencer-Dene, and A. S. Nateri, “The links between transcription, β-catenin/JNK signaling, and carcinogenesis,” Molecular Cancer Research, vol. 7, no. 8, pp. 1189–1196, 2009. View at Publisher · View at Google Scholar · View at Scopus
  82. J. Roose and H. Clevers, “TCF transcription factors: molecular switches in carcinogenesis,” Biochimica et Biophysica Acta, vol. 1424, no. 2-3, pp. M23–M37, 1999. View at Publisher · View at Google Scholar · View at Scopus
  83. V. Korinek, N. Barker, P. Moerer et al., “Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4,” Nature Genetics, vol. 19, no. 4, pp. 379–383, 1998. View at Publisher · View at Google Scholar · View at Scopus
  84. S. F. Boj, J. H. van Es, M. Huch et al., “Diabetes risk gene and Wnt effector Tcf7l2/TCF4 controls hepatic response to perinatal and adult metabolic demand,” Cell, vol. 151, no. 7, pp. 1595–1607, 2012. View at Google Scholar
  85. D. Savic, H. Ye, I. Aneas, S. Y. Park, G. I. Bell, and M. A. Nobrega, “Alterations in TCF7L2 expression define its role as a key regulator of glucose metabolism,” Genome Research, vol. 21, pp. 1417–1425, 2011. View at Google Scholar
  86. H. Yang, Q. Li, J. H. Lee, and Y. Shu, “Reduction in Tcf7l2 expression decreases diabetic susceptibility in mice,” International Journal of Biological Sciences, vol. 8, pp. 791–801, 2012. View at Google Scholar
  87. N. Barker, G. Huls, V. Korinek, and H. Clevers, “Restricted high level expression of Tcf-4 protein in intestinal and mammary gland epithelium,” American Journal of Pathology, vol. 154, no. 1, pp. 29–35, 1999. View at Google Scholar · View at Scopus
  88. M. Horikoshi, K. Hara, C. Ito, R. Nagai, P. Froguel, and T. Kadowaki, “A genetic variation of the transcription factor 7-like 2 gene is associated with risk of type 2 diabetes in the Japanese population,” Diabetologia, vol. 50, no. 4, pp. 747–751, 2007. View at Publisher · View at Google Scholar · View at Scopus
  89. S. A. Schäfer, O. Tschritter, F. Machicao et al., “Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms,” Diabetologia, vol. 50, no. 12, pp. 2443–2450, 2007. View at Publisher · View at Google Scholar · View at Scopus
  90. G. Gu, J. Dubauskaite, and D. A. Melton, “Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors,” Development, vol. 129, no. 10, pp. 2447–2457, 2002. View at Google Scholar · View at Scopus
  91. K. Hisadome, M. A. Smith, A. I. Choudhury, M. Claret, D. J. Withers, and M. L. J. Ashford, “5-HT inhibition of rat insulin 2 promoter Cre recombinase transgene and proopiomelanocortin neuron excitability in the mouse arcuate nucleus,” Neuroscience, vol. 159, no. 1, pp. 83–93, 2009. View at Publisher · View at Google Scholar · View at Scopus
  92. G. Sun, A. I. Tarasov, J. A. McGinty et al., “LKB1 deletion with the RIP2.Cre transgene modifies pancreatic β-cell morphology and enhances insulin secretion in vivo,” American Journal of Physiology: Endocrinology and Metabolism, vol. 298, no. 6, pp. E1261–E1273, 2010. View at Publisher · View at Google Scholar · View at Scopus
  93. G. Sun, R. Reynolds, I. Leclerc, and G. A. Rutter, “RIP2-mediated LKB1 deletion causes axon degeneration in the spinal cord and hind-limb paralysis,” DMM Disease Models and Mechanisms, vol. 4, no. 2, pp. 193–202, 2011. View at Publisher · View at Google Scholar · View at Scopus
  94. L. Shu, K. Zien, G. Gutjahr et al., “TCF7L2 promotes beta cell regeneration in human and mouse pancreas,” Diabetologia, vol. 55, pp. 3296–3307, 2012. View at Google Scholar
  95. B. Wicksteed, M. Brissova, W. Yan et al., “Conditional gene targeting in mouse pancreatic β-cells: analysis of ectopic cre transgene expression in the brain,” Diabetes, vol. 59, no. 12, pp. 3090–3098, 2010. View at Publisher · View at Google Scholar · View at Scopus
  96. Y. Dor, J. Brown, O. I. Martinez, and D. A. Melton, “Adult pancreatic β-cells are formed by self-duplication rather than stem-cell differentiation,” Nature, vol. 429, no. 6987, pp. 41–46, 2004. View at Publisher · View at Google Scholar · View at Scopus
  97. T. J. Nicolson, E. A. Bellomo, N. Wijesekara et al., “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, no. 9, pp. 2070–2083, 2009. View at Publisher · View at Google Scholar · View at Scopus
  98. A. B. Hardy, N. Wijesekara, I. Genkin et al., “Effects of high-fat diet feeding on Znt8-null mice: differences between beta-cell and global knockout of Znt8,” American Journal of Physiology: Endocrinology and Metabolism, vol. 302, pp. E1084–E1096, 2012. View at Google Scholar
  99. K. Lemaire, M. A. Ravier, A. Schraenen et al., “Insulin crystallization depends on zinc transporter ZnT8 expression, but is not required for normal glucose homeostasis in mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 35, pp. 14872–14877, 2009. View at Publisher · View at Google Scholar · View at Scopus
  100. L. D. Pound, S. A. Sarkar, R. K. P. Benninger et al., “Deletion of the mouse Slc30a8 gene encoding zinc transporter-8 results in impaired insulin secretion,” Biochemical Journal, vol. 421, no. 3, pp. 371–376, 2009. View at Publisher · View at Google Scholar · View at Scopus
  101. L. D. Pound, S. A. Sarkar, A. Ustione et al., “The physiological effects of deleting the mouse SLC30A8 gene encoding zinc transporter-8 are influenced by gender and genetic background,” PLoS ONE, vol. 7, Article ID e40972, 2012. View at Google Scholar
  102. N. Wijesekara, F. F. Dai, A. B. Hardy et al., “Beta cell-specific Znt8 deletion in mice causes marked defects in insulin processing, crystallisation and secretion,” Diabetologia, vol. 53, no. 8, pp. 1656–1668, 2010. View at Publisher · View at Google Scholar · View at Scopus
  103. K. J. Gaulton, T. Nammo, L. Pasquali et al., “A map of open chromatin in human pancreatic islets,” Nature Genetics, vol. 42, no. 3, pp. 255–259, 2010. View at Publisher · View at Google Scholar · View at Scopus
  104. A. Duval, S. Rolland, E. Tubacher, H. Bui, G. Thomas, and R. Hamelin, “The human T-cell transcription factor-4 gene: structure, extensive characterization of alternative splicings, and mutational analysis in colorectal cancer cell lines,” Cancer Research, vol. 60, no. 14, pp. 3872–3879, 2000. View at Google Scholar · View at Scopus
  105. O. Le Bacquer, L. Shu, M. Marchand et al., “TCF7L2 splice variants have distinct effects on β-cell turnover and function,” Human Molecular Genetics, vol. 20, no. 10, pp. 1906–1915, 2011. View at Publisher · View at Google Scholar · View at Scopus
  106. A. K. Mondal, S. K. Das, G. Baldini et al., “Genotype and tissue-specific effects on alternative splicing of the transcription factor 7-like 2 gene in humans,” Journal of Clinical Endocrinology and Metabolism, vol. 95, no. 3, pp. 1450–1457, 2010. View at Publisher · View at Google Scholar · View at Scopus
  107. A. Weise, K. Bruser, S. Elfert et al., “Alternative splicing of Tcf7l2 transcripts generates protein variants with differential promoter-binding and transcriptional activation properties at Wnt/β-catenin targets,” Nucleic Acids Research, vol. 38, no. 6, pp. 1964–1981, 2009. View at Publisher · View at Google Scholar · View at Scopus
  108. L. A. Lichten and R. J. Cousins, “Mammalian zinc transporters: nutritional and physiologic regulation,” Annual Review of Nutrition, vol. 29, pp. 153–176, 2009. View at Publisher · View at Google Scholar
  109. F. Chimienti, S. Devergnas, A. Favier, and M. Seve, “Identification and cloning of a β-cell-specific zinc transporter, ZnT-8, localized into insulin secretory granules,” Diabetes, vol. 53, no. 9, pp. 2330–2337, 2004. View at Publisher · View at Google Scholar · View at Scopus
  110. F. Chimienti, A. Favier, and M. Seve, “ZnT-8, a pancreatic beta-cell-specific zinc transporter,” BioMetals, vol. 18, no. 4, pp. 313–317, 2005. View at Publisher · View at Google Scholar · View at Scopus
  111. S. O. Emdin, G. G. Dodson, J. M. Cutfield, and S. M. Cutfield, “Role of zinc in insulin biosynthesis. Some possible zinc-insulin interactions in the pancreatic B-cell,” Diabetologia, vol. 19, no. 3, pp. 174–182, 1980. View at Google Scholar · View at Scopus
  112. G. A. Rutter, “Think zinc: new roles for zinc in the control of insulin secretion,” Islets, vol. 2, no. 1, pp. 49–50, 2010. View at Google Scholar · View at Scopus
  113. E. D. Berglund, C. Y. Li, G. Poffenberger et al., “Glucose metabolism in vivo in four commonly used inbred mouse strains,” Diabetes, vol. 57, no. 7, pp. 1790–1799, 2008. View at Publisher · View at Google Scholar · View at Scopus
  114. A. T. Hattersley, “Unlocking the secrets of the pancreatic β cell: man and mouse provide the key,” Journal of Clinical Investigation, vol. 114, no. 3, pp. 314–316, 2004. View at Publisher · View at Google Scholar · View at Scopus
  115. D. Reyon, S. Q. Tsai, C. Khayter, J. A. Foden, J. D. Sander, and J. K. Joung, “FLASH assembly of TALENs for high-throughput genome editing,” Nature Biotechnology, vol. 30, pp. 460–465, 2012. View at Google Scholar
  116. C. Mussolino and T. Cathomen, “TALE nucleases: tailored genome engineering made easy,” Current Opinion in Biotechnology, vol. 23, pp. 644–650, 2012. View at Google Scholar
  117. D. Hockemeyer, H. Wang, S. Kiani et al., “Genetic engineering of human pluripotent cells using TALE nucleases,” Nature Biotechnology, vol. 29, no. 8, pp. 731–734, 2011. View at Publisher · View at Google Scholar · View at Scopus
  118. J. B. Meigs, P. Shrader, L. M. Sullivan et al., “Genotype score in addition to common risk factors for prediction of type 2 diabetes,” New England Journal of Medicine, vol. 359, no. 21, pp. 2208–2219, 2008. View at Publisher · View at Google Scholar · View at Scopus
  119. V. Lyssenko, A. Jonsson, P. Almgren et al., “Clinical risk factors, DNA variants, and the development of type 2 diabetes,” New England Journal of Medicine, vol. 359, no. 21, pp. 2220–2232, 2008. View at Publisher · View at Google Scholar · View at Scopus
  120. P. J. Talmud, A. D. Hingorani, J. A. Cooper et al., “Utility of genetic and non-genetic risk factors in prediction of type 2 diabetes: whitehall II prospective cohort study,” British Medical Journal, vol. 340, article b4838, 2010. View at Publisher · View at Google Scholar · View at Scopus
  121. H. Langothe, C. N. A. Palmer, A. D. Morris et al., “Assessing the combined impact of 18 common genetic variants of modest effect sizes on type 2 diabetes risk,” Diabetes, vol. 57, no. 11, pp. 3129–3135, 2008. View at Publisher · View at Google Scholar · View at Scopus
  122. R. K. Simmons, A. H. Harding, N. J. Wareham, and S. J. Griffin, “Do simple questions about diet and physical activity help to identify those at risk of Type 2 diabetes?” Diabetic Medicine, vol. 24, no. 8, pp. 830–835, 2007. View at Publisher · View at Google Scholar · View at Scopus
  123. J. Lindström and J. Tuomilehto, “The diabetes risk score: a practical tool to predict type 2 diabetes risk,” Diabetes Care, vol. 26, no. 3, pp. 725–731, 2003. View at Publisher · View at Google Scholar · View at Scopus
  124. M. C. Cornelis, L. Qi, P. Kraft, and F. B. Hu, “TCF7L2, dietary carbohydrate, and risk of type 2 diabetes in US women,” American Journal of Clinical Nutrition, vol. 89, no. 4, pp. 1256–1262, 2009. View at Publisher · View at Google Scholar · View at Scopus
  125. E. Fisher, H. Boeing, A. Fritsche, F. Doering, H. G. Joost, and M. B. Schulze, “Whole-grain consumption and transcription factor-7-like 2 (TCF7L2) rs7903146: gene-diet interaction in modulating type 2 diabetes risk,” British Journal of Nutrition, vol. 101, no. 4, pp. 478–481, 2009. View at Publisher · View at Google Scholar · View at Scopus
  126. A. Haupt, C. Thamer, M. Heni et al., “Gene variants of TCF7L2 influence weight loss and body composition during lifestyle intervention in a population at risk for type 2 diabetes,” Diabetes, vol. 59, no. 3, pp. 747–750, 2010. View at Publisher · View at Google Scholar · View at Scopus
  127. T. Reinehr, S. Friedel, T. D. Mueller, A. M. Toschke, J. Hebebrand, and A. Hinney, “Evidence for an influence of TCF7L2 polymorphism rs7903146 on insulin resistance and sensitivity indices in overweight children and adolescents during a lifestyle intervention,” International Journal of Obesity, vol. 32, no. 10, pp. 1521–1524, 2008. View at Publisher · View at Google Scholar · View at Scopus
  128. D. Thomas, “Gene—environment-wide association studies: emerging approaches,” Nature Reviews Genetics, vol. 11, no. 4, pp. 259–272, 2010. View at Publisher · View at Google Scholar · View at Scopus
  129. U. Smith and E. A. M. Gale, “Cancer and diabetes: are we ready for prime time?” Diabetologia, vol. 53, no. 8, pp. 1541–1544, 2010. View at Publisher · View at Google Scholar · View at Scopus
  130. W. Y. Kim and N. E. Sharpless, “The Regulation of INK4/ARF in Cancer and Aging,” Cell, vol. 127, no. 2, pp. 265–275, 2006. View at Publisher · View at Google Scholar · View at Scopus
  131. J. Krishnamurthy, M. R. Ramsey, K. L. Ligon et al., “p16INK4a induces an age-dependent decline in islet regenerative potential,” Nature, vol. 443, no. 7110, pp. 453–457, 2006. View at Publisher · View at Google Scholar · View at Scopus
  132. S. G. Rane, P. Dubus, R. V. Mettus et al., “Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in β-islet cell hyperplasia,” Nature Genetics, vol. 22, no. 1, pp. 44–54, 1999. View at Publisher · View at Google Scholar · View at Scopus
  133. L. M. Holdt and D. Teupser, “Recent studies of the human chromosome 9p21 locus, which is associated with atherosclerosis in human populations,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 32, pp. 196–206, 2012. View at Google Scholar
  134. E. Pasmant, I. Laurendeau, D. Héron, M. Vidaud, D. Vidaud, and I. Bièche, “Characterization of a germ-line deletion, including the entire INK4/ARF locus, in a melanoma-neural system tumor family: identification of ANRIL, an antisense noncoding RNA whose expression coclusters with ARF,” Cancer Research, vol. 67, no. 8, pp. 3963–3969, 2007. View at Publisher · View at Google Scholar · View at Scopus
  135. A. Visel, Y. Zhu, D. May et al., “Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice,” Nature, vol. 464, no. 7287, pp. 409–412, 2010. View at Publisher · View at Google Scholar · View at Scopus
  136. J. Gudmundsson, P. Sulem, V. Steinthorsdottir et al., “Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes,” Nature Genetics, vol. 39, no. 8, pp. 977–983, 2007. View at Publisher · View at Google Scholar · View at Scopus
  137. G. Thomas, K. B. Jacobs, M. Yeager et al., “Multiple loci identified in a genome-wide association study of prostate cancer,” Nature Genetics, vol. 40, pp. 310–315, 2008. View at Google Scholar
  138. P. Ravassard, Y. Hazhouz, S. Pechberty et al., “A genetically engineered human pancreatic beta cell line exhibiting glucose-inducible insulin secretion,” Journal of Clinical Investigation, vol. 121, pp. 3589–3597, 2011. View at Google Scholar
  139. B. Seidler, A. Schmidt, U. Mayr et al., “A Cre-loxP-based mouse model for conditional somatic gene expression and knockdown in vivo by using avian retroviral vectors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 29, pp. 10137–10142, 2008. View at Publisher · View at Google Scholar · View at Scopus