From genetic association to molecular mechanism

Current Diabetes Reports

Volumn 10, Issue 6, 2010, Pages 452-466

  Van De Bunt, Martijn ^a   Gloyn, Anna L ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

cell; ABCC8; ENU mutagenesis; FTO; G6PC2; GCKR; Genetics; Genome wide association study; Insulin; KCNJ11; Knockout mice; Molecular mechanism; SLC30A8; TCF7L2; Type 2 diabetes

Indexed keywords

ADENOSINE TRIPHOSPHATE SENSITIVE POTASSIUM CHANNEL; GLUCOKINASE; GLUCOKINASE REGULATOR PROTEIN; GLUCOSE 6 PHOSPHATE; GLUCOSE 6 PHOSPHATE CATALYTIC DOMAIN PROTEIN; INWARDLY RECTIFYING POTASSIUM CHANNEL SUBUNIT KIR6.2; PROTEIN FTO; REGULATOR PROTEIN; SULFONYLUREA RECEPTOR 1; TRANSCRIPTION FACTOR 7 LIKE 2; UNCLASSIFIED DRUG; ZINC TRANSPORTER; ZINC TRANSPORTER PROTEIN MEMBER 8;

GENE DELETION; GENE EXPRESSION; GENE FUNCTION; GENE IDENTIFICATION; GENE LOCATION; GENE LOCUS; GENETIC ASSOCIATION; GENETIC RISK; GENETIC SUSCEPTIBILITY; GENETIC VARIABILITY; HUMAN; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PATHOGENESIS; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM;

ANIMALS; CATION TRANSPORT PROTEINS; DIABETES MELLITUS, TYPE 2; GENETIC PREDISPOSITION TO DISEASE; GENOME-WIDE ASSOCIATION STUDY; HUMANS; POTASSIUM CHANNELS, INWARDLY RECTIFYING;

EID: 77958498526     PISSN: 15344827     EISSN: None     Source Type: Journal    
DOI: 10.1007/s11892-010-0150-2     Document Type: Review

References (105)

1. Köbberling J, Tillil H: Empirical risk figures for first degree relatives of non-insulin-dependent diabetics. In The Genetics of Diabetes Mellitus. Edited by Köbberling J, Tattersall R. London: Academic Press; 1982:201-209.
2. • Voight BF, Scott LJ, Steinthorsdottir V, et al.: Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 2010, 42:579-589. This is the most recent meta-analysis of GWAS for T2D.
3. Gloyn AL, Weedon MN, Owen KR, et al.: Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes 2003, 52:568-572.
4. D Altshuler JN Hirschhorn M Klannemark, et al. 2000 The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes Nat Genet 26 76 80 1:CAS:528:DC%2BD3cXmsVKku7k%3D 10.1038/79839 10973253
5. SF Grant G Thorleifsson I Reynisdottir, et al. 2006 Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes Nat Genet 38 320 323 1:CAS:528:DC%2BD28XhslCjtrw%3D 10.1038/ng1732 16415884
6. LJ Scott KL Mohlke LL Bonnycastle, et al. 2007 A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants Science 316 1341 1345 1:CAS:528:DC%2BD2sXmtVyitrY%3D 10.1126/science.1142382 17463248 (Pubitemid 46871655)
7. R Saxena BF Voight V Lyssenko, et al. 2007 Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels Science 316 1331 1336 1:CAS:528:DC%2BD2sXmtVyitrk%3D 10.1126/science.1142358 17463246 (Pubitemid 46871653)
8. E Zeggini MN Weedon CM Lindgren, et al. 2007 Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes Science 316 1336 1341 1:CAS:528:DC%2BD2sXmtVymtb0%3D 10.1126/science.1142364 17463249 (Pubitemid 46871654)
9. R Sladek G Rocheleau J Rung, et al. 2007 A genome-wide association study identifies novel risk loci for type 2 diabetes Nature 445 881 885 1:CAS:528:DC%2BD2sXhvFGiurw%3D 10.1038/nature05616 17293876
10. V Steinthorsdottir G Thorleifsson I Reynisdottir, et al. 2007 A variant in CDKAL1 influences insulin response and risk of type 2 diabetes Nat Genet 39 770 775 1:CAS:528:DC%2BD2sXlvVSgtL4%3D 10.1038/ng2043 17460697 (Pubitemid 46848592)
11. E Zeggini LJ Scott R Saxena, et al. 2008 Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes Nat Genet 40 638 645 1:CAS:528:DC%2BD1cXltFylurY%3D 10.1038/ng.120 18372903 (Pubitemid 351601209)
12. J Dupuis C Langenberg I Prokopenko, et al. 2010 New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk Nat Genet 42 105 116 1:CAS:528:DC%2BC3cXntVCqsw%3D%3D 10.1038/ng.520 20081858
13. A Kong V Steinthorsdottir G Masson, et al. 2009 Parental origin of sequence variants associated with complex diseases Nature 462 868 874 1:CAS:528:DC%2BD1MXhsFOhtbvJ 10.1038/nature08625 20016592
14. •• Nicolson TJ, Bellomo EA, Wijesekara N, 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 2009, 58:2070-2083. This is one of the only reports of the functional study of a T2D-associated SNP arising from a GWAS.
15. •• Beer NL, Tribble ND, McCulloch LJ, et al.: The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum Mol Genet 2009, 18:4081-4088. This is one of the only reports of the functional study of a T2D-associated SNP arising from a GWAS.
16. R Bort JP Martinez-Barbera RS Beddington, et al. 2004 Hex homeobox gene-dependent tissue positioning is required for organogenesis of the ventral pancreas Development 131 797 806 1:CAS:528:DC%2BD2cXitVGiurk%3D 10.1242/dev.00965 14736744 (Pubitemid 38263195)
17. DY Hwang S Seo Y Kim, et al. 2007 Significant change in insulin production, glucose tolerance and ER stress signaling in transgenic mice coexpressing insulin-siRNA and human IDE Int J Mol Med 19 65 73 1:CAS:528:DC%2BD2sXht1altrk%3D 17143549
18. J Krishnamurthy MR Ramsey KL Ligon, et al. 2006 p16INK4a induces an age-dependent decline in islet regenerative potential Nature 443 453 457 1:CAS:528:DC%2BD28XhtVSns7bE 10.1038/nature05092 16957737 (Pubitemid 44477281)
19. HM Broadbent JF Peden S Lorkowski, et al. 2008 Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p Hum Mol Genet 17 806 814 1:CAS:528: DC%2BD1cXis1Gltb4%3D 10.1093/hmg/ddm352 18048406 (Pubitemid 351359697)
20. E Pasmant I Laurendeau D Heron, et al. 2007 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 Res 67 3963 3969 1:CAS:528: DC%2BD2sXkt1Khsro%3D 10.1158/0008-5472.CAN-06-2004 17440112 (Pubitemid 46762186)
21. • Ingelsson E, Langenberg C, Hivert MF, et al.: Detailed physiologic characterization reveals diverse mechanisms for novel genetic Loci regulating glucose and insulin metabolism in humans. Diabetes 2010, 59:1266-1275. This is an elegant study looking at the effects of genetic variants on insulin secretion and action that provides important insights into the pathways and genes that the variants are working through.
22. •• Hamming KS, Soliman D, Matemisz LC, et al.: Coexpression of the type 2 diabetes susceptibility gene variants KCNJ11 E23K and ABCC8 S1369A alter the ATP and sulfonylurea sensitivities of the ATP-sensitive K(+) channel. Diabetes 2009, 58:2419-2424. This is the only study to look at the combined risk haplotype of KCNJ11 E23K and ABCC8 S169A.
23. SE Flanagan S Clauin C Bellanne-Chantelot, et al. 2009 Update of mutations in the genes encoding the pancreatic beta-cell K(ATP) channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism Hum Mutat 30 170 180 1:CAS:528:DC%2BD1MXjtFKmsLw%3D 10.1002/humu.20838 18767144
24. JC Florez N Burtt PI de Bakker, et al. 2004 Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region Diabetes 53 1360 1368 1:CAS:528:DC%2BD2cXjslKhs78%3D 10.2337/diabetes.53.5.1360 15111507 (Pubitemid 38569024)
25. Schwanstecher C, Meyer U,Schwanstecher M: K(IR)6.2 polymorphism predisposes to type 2 diabetes by inducing overactivity of pancreatic beta-cell ATP-sensitive K(+) channels. Diabetes 2002, 51:875-879.
26. H Sakura N Wat V Horton, et al. 1996 Sequence variations in the human Kir6.2 gene, a subunit of the beta-cell ATP-sensitive K-channel: no association with NIDDM in while Caucasian subjects or evidence of abnormal function when expressed in vitro Diabetologia 39 1233 1236 1:CAS:528:DyaK28XmsVGqt7w%3D 10.1007/BF02658512 8897013
27. Riedel MJ, Boora P, Steckley D, et al.: Kir6.2 polymorphisms sensitize beta-cell ATP-sensitive potassium channels to activation by acyl CoAs: a possible cellular mechanism for increased susceptibility to type 2 diabetes? Diabetes 2003, 52:2630-2635.
28. DT Villareal JC Koster H Robertson, et al. 2009 Kir6.2 variant E23K increases ATP-sensitive K∈+∈channel activity and is associated with impaired insulin release and enhanced insulin sensitivity in adults with normal glucose tolerance Diabetes 58 1869 1878 1:CAS:528:DC%2BD1MXpsV2mtbY%3D 10.2337/db09-0025 19491206
29. JM Wenzlau K Juhl L Yu, et al. 2007 The cation efflux transporter ZnT8 (Slc30α8) is a major autoantigen in human type 1 diabetes Proc Natl Acad Sci U S A 104 17040 17045 1:CAS:528:DC%2BD2sXht1KgtLfM 10.1073/pnas.0705894104 17942684 (Pubitemid 350210987)
30. JM Wenzlau Y Liu L Yu, et al. 2008 A common nonsynonymous single nucleotide polymorphism in the SLC30A8 gene determines ZnT8 autoantibody specificity in type 1 diabetes Diabetes 57 2693 2697 1:CAS:528: DC%2BD1MXhs1Kntrw%3D 10.2337/db08-0522 18591387
31. N Wijesekara FF Dai AB Hardy, et al. 2010 Beta cell-specific Znt8 deletion in mice causes marked defects in insulin processing, crystallisation and secretion Diabetologia 53 1656 1668 1:CAS:528:DC%2BC3cXotVKgs7k%3D 10.1007/s00125-010-1733-9 20424817
32. LD Pound SA Sarkar RK Benninger, et al. 2009 Deletion of the mouse Slc30α8 gene encoding zinc transporter-8 results in impaired insulin secretion Biochem J 421 371 376 1:CAS:528:DC%2BD1MXosV2hurs%3D 10.1042/BJ20090530 19450229
33. K Lemaire MA Ravier A Schraenen, et al. 2009 Insulin crystallization depends on zinc transporter ZnT8 expression, but is not required for normal glucose homeostasis in mice Proc Natl Acad Sci U S A 106 14872 14877 1:CAS:528:DC%2BD1MXhtFGrt7%2FI 10.1073/pnas.0906587106 19706465
34. M Orho-Melander O Melander C Guiducci, et al. 2008 Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations Diabetes 57 3112 3121 1:CAS:528:DC%2BD1MXhsleis7Y%3D 10.2337/db08-0516 18678614
35. J Grimsby JW Coffey MT Dvorozniak, et al. 2000 Characterization of glucokinase regulatory protein-deficient mice J Biol Chem 275 7826 7831 1:CAS:528:DC%2BD3cXitVylsbg%3D 10.1074/jbc.275.11.7826 10713097 (Pubitemid 30159689)
36. RM O'Doherty DL Lehman S Telemaque-Potts, et al. 1999 Metabolic impact of glucokinase overexpression in liver: lowering of blood glucose in fed rats is accompanied by hyperlipidemia Diabetes 48 2022 2027 10.2337/diabetes.48.10.2022 10512368 (Pubitemid 29458366)
37. ED Slosberg UJ Desai B Fanelli, et al. 2001 Treatment of type 2 diabetes by adenoviral-mediated overexpression of the glucokinase regulatory protein Diabetes 50 1813 1820 1:CAS:528:DC%2BD3MXlslKnu7g%3D 10.2337/diabetes.50.8.1813 11473043
38. M Veiga-da-Cunha J Delplanque A Gillain, et al. 2003 Mutations in the glucokinase regulatory protein gene in 2p23 in obese French Caucasians Diabetologia 46 704 711 1:CAS:528:DC%2BD3sXksFKmu7c%3D 12739015
39. M Veiga-da-Cunha E Van Schaftingen 2002 Identification of fructose 6-phosphate- and fructose 1-phosphate-binding residues in the regulatory protein of glucokinase J Biol Chem 277 8466 8473 1:CAS:528:DC%2BD38XitFymtb0%3D 10.1074/jbc.M105984200 11756407 (Pubitemid 34968308)
40. KJ Brocklehurst RA Davies L Agius 2004 Differences in regulatory properties between human and rat glucokinase regulatory protein Biochem J 378 693 697 1:CAS:528:DC%2BD2cXisVajtL4%3D 10.1042/BJ20031414 14627435 (Pubitemid 38367261)
41. •• Gaulton KJ, Nammo T, Pasquali L, et al.: A map of open chromatin in human pancreatic islets. Nat Genet 2010, 42:255-259. This is an elegant study and the first of its kind providing not only a map of open chromatin in human islets but also a molecular mechanisms for TCF7L2 variants.
42. TM Frayling NJ Timpson MN Weedon, et al. 2007 A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity Science 316 889 894 1:CAS:528:DC%2BD2sXltVentL0%3D 10.1126/science. 1141634 17434869 (Pubitemid 46764279)
43. T Peters K Ausmeier U Ruther 1999 Cloning of Fatso (Fto), a novel gene deleted by the Fused toes (Ft) mouse mutation Mamm Genome 10 983 986 1:CAS:528:DyaK1MXmtlCru7k%3D 10.1007/s003359901121 10501967 (Pubitemid 29470916)
44. T Gerken CA Girard YC Tung, et al. 2007 The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase Science 318 1469 1472 1:CAS:528:DC%2BD2sXhtlGmtLbI 10.1126/science.1151710 17991826 (Pubitemid 350208961)
45. C Church S Lee EA Bagg, et al. 2009 A mouse model for the metabolic effects of the human fat mass and obesity associated FTO gene PLoS Genet 5 e1000599 10.1371/journal.pgen.1000599 19680540
46. •• Fischer J, Koch L, Emmerling C, et al.: Inactivation of the Fto gene protects from obesity. Nature 2009, 458:894-898. This study provided the best evidence that the obesity-associated signals were working through FTO.
47. Speakman JR: FTO effect on energy demand versus food intake. Nature 2010, 464:E1; discussion E2.
48. JR Speakman KA Rance AM Johnstone 2008 Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure Obesity (Silver Spring) 16 1961 1965 1:CAS:528:DC%2BD1cXptFOrtbo%3D 10.1038/oby.2008.318
49. S Boissel O Reish K Proulx, et al. 2009 Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations Am J Hum Genet 85 106 111 1:CAS:528:DC%2BD1MXhtVeltL7P 10.1016/j.ajhg.2009.06.002 19559399
50. D Meyre K Proulx H Kawagoe-Takaki, et al. 2010 Prevalence of loss-of-function FTO mutations in lean and obese individuals Diabetes 59 311 318 1:CAS:528:DC%2BC3cXmtVKltg%3D%3D 10.2337/db09-0703 19833892
51. CY Logan R Nusse 2004 The Wnt signaling pathway in development and disease Annu Rev Cell Dev Biol 20 781 810 1:CAS:528:DC%2BD2cXhtVejsr7I 10.1146/annurev.cellbio.20.010403.113126 15473860 (Pubitemid 39488658)
52. V Korinek N Barker P Moerer, et al. 1998 Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4 Nat Genet 19 379 383 1:CAS:528:DyaK1cXlt1Cisrg%3D 10.1038/1270 9697701 (Pubitemid 28357912)
53. F Yi PL Brubaker T Jin 2005 TCF-4 mediates cell type-specific regulation of proglucagon gene expression by beta-catenin and glycogen synthase kinase-3beta J Biol Chem 280 1457 1464 1:CAS:528:DC%2BD2MXitFCktw%3D%3D 10.1074/jbc.M411487200 15525634
54. V Lyssenko R Lupi P Marchetti, et al. 2007 Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes J Clin Invest 117 2155 2163 1:CAS:528:DC%2BD2sXoslOnsrk%3D 10.1172/JCI30706 17671651 (Pubitemid 47219560)
55. L Shu NS Sauter FT Schulthess, et al. 2008 Transcription factor 7-like 2 regulates beta-cell survival and function in human pancreatic islets Diabetes 57 645 653 1:CAS:528:DC%2BD1cXjt1Chtbo%3D 10.2337/db07-0847 18071026
56. da Silva Xavier G, Loder MK, McDonald A, et al.: TCF7L2 regulates late events in insulin secretion from pancreatic islet beta-cells. Diabetes 2009, 58:894-905.
57. N Bouatia-Naji G Rocheleau L Van Lommel, et al. 2008 A polymorphism within the G6PC2 gene is associated with fasting plasma glucose levels Science 320 1085 1088 1:CAS:528:DC%2BD1cXmtVKnsLc%3D 10.1126/science.1156849 18451265 (Pubitemid 351929551)
58. Y Wang CC Martin JK Oeser, et al. 2007 Deletion of the gene encoding the islet-specific glucose-6-phosphatase catalytic subunit-related protein autoantigen results in a mild metabolic phenotype Diabetologia 50 774 778 1:CAS:528:DC%2BD2sXitlOntL8%3D 10.1007/s00125-006-0564-1 17265032 (Pubitemid 46355820)
59. WM Chen MR Erdos AU Jackson, et al. 2008 Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels J Clin Invest 118 2620 2628 1:CAS:528:DC%2BD1cXot1Onu74%3D 18521185
60. SM Lieberman AM Evans B Han, et al. 2003 Identification of the beta cell antigen targeted by a prevalent population of pathogenic CD8+ T cells in autoimmune diabetes Proc Natl Acad Sci U S A 100 8384 8388 1:CAS:528: DC%2BD3sXlsFGntL8%3D 10.1073/pnas.0932778100 12815107 (Pubitemid 36842554)
61. C Dos Santos P Bougneres D Fradin 2009 A single-nucleotide polymorphism in a methylatable Foxa2 binding site of the G6PC2 promoter is associated with insulin secretion in vivo and increased promoter activity in vitro Diabetes 58 489 492 10.2337/db08-0587 18984742
62. •• Bouatia-Naji N, Bonnefond A, Baerenwald DA, et al.: Genetic and functional assessment of the role of the rs13431652-A and rs573225-A alleles in the G6PC2 promoter that strongly associate with elevated fasting glucose levels. Diabetes 2010 Jul 9 [Epub ahead of print]. This is one of the few studies functionally characterizing risk alleles associated with glycemic traits.
63. TA Manolio FS Collins NJ Cox, et al. 2009 Finding the missing heritability of complex diseases Nature 461 747 753 1:CAS:528:DC%2BD1MXht1CisbrF 10.1038/nature08494 19812666
64. M Braun R Ramracheya M Bengtsson, et al. 2008 Voltage-gated ion channels in human pancreatic beta-cells: electrophysiological characterization and role in insulin secretion Diabetes 57 1618 1628 1:CAS:528:DC%2BD1cXnsF2isrg%3D 10.2337/db07-0991 18390794
65. D Bosco M Armanet P Morel, et al. 2010 Unique arrangement of alpha- and beta-cells in human islets of Langerhans Diabetes 59 1202 1210 1:CAS:528:DC%2BC3cXmtFegsbc%3D 10.2337/db09-1177 20185817
66. N Fiaschi-Taesch TA Bigatel B Sicari, et al. 2009 Survey of the human pancreatic beta-cell G1/S proteome reveals a potential therapeutic role for cdk-6 and cyclin D1 in enhancing human beta-cell replication and function in vivo Diabetes 58 882 893 1:CAS:528:DC%2BD1MXktleiurs%3D 10.2337/db08-0631 19136653
67. M Borowiak DA Melton 2009 How to make beta cells? Curr Opin Cell Biol 21 727 732 1:CAS:528:DC%2BD1MXhsV2ksLjO 10.1016/j.ceb.2009.08.006 19781928
68. AM Simonis-Bik G Nijpels TW van Haeften, et al. 2010 Gene variants in the novel type 2 diabetes loci CDC123/CAMK1D, THADA, ADAMTS9, BCL11A, and MTNR1B affect different aspects of pancreatic beta-cell function Diabetes 59 293 301 1:CAS:528:DC%2BC3cXmtVKlsA%3D%3D 10.2337/db09-1048 19833888
69. BH Koo DM Coe LJ Dixon, et al. 2010 ADAMTS9 is a cell-autonomously acting, anti-angiogenic metalloprotease expressed by microvascular endothelial cells Am J Pathol 176 1494 1504 1:CAS:528:DC%2BC3cXktVOisbc%3D 10.2353/ajpath.2010.090655 20093484
70. RM Freathy DO Mook-Kanamori U Sovio, et al. 2010 Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight Nat Genet 42 430 435 1:CAS:528:DC%2BC3cXktlSgu7k%3D 10.1038/ng.567 20372150
71. VG Sankaran J Xu T Ragoczy, et al. 2009 Developmental and species-divergent globin switching are driven by BCL11A Nature 460 1093 1097 1:CAS:528:DC%2BD1MXpsVersLY%3D 10.1038/nature08243 19657335
72. X Wang VS Pankratz Z Fredericksen, et al. 2010 Common variants associated with breast cancer in genome wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers Hum Mol Genet 19 2886 2897 1:CAS:528:DC%2BC3cXotlSmurg%3D 10.1093/hmg/ddq174 20418484
73. S Verploegen L Ulfman HW van Deutekom, et al. 2005 Characterization of the role of CaMKI-like kinase (CKLiK) in human granulocyte function Blood 106 1076 1083 1:CAS:528:DC%2BD2MXntVSms7w%3D 10.1182/blood-2004-09-3755 15840691 (Pubitemid 41076457)
74. MJ Groenewoud JM Dekker A Fritsche, et al. 2008 Variants of CDKAL1 and IGF2BP2 affect first-phase insulin secretion during hyperglycaemic clamps Diabetologia 51 1659 1663 1:CAS:528:DC%2BD1cXpsVGitb4%3D 10.1007/s00125-008- 1083-z 18618095
75. R Saxena MF Hivert C Langenberg, et al. 2010 Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge Nat Genet 42 142 148 1:CAS:528:DC%2BC3cXntVCksw%3D%3D 10.1038/ng.521 20081857
76. N Grarup CS Rose EA Andersson, et al. 2007 Studies of association of variants near the HHEX, CDKN2A/B, and IGF2BP2 genes with type 2 diabetes and impaired insulin release in 10, 705 Danish subjects: validation and extension of genome-wide association studies Diabetes 56 3105 3111 1:CAS:528: DC%2BD2sXhsValurjL 10.2337/db07-0856 17827400 (Pubitemid 350223649)
77. GS Wang LM Kauri C Patrick, et al. 2010 Enhanced islet expansion by beta-cell proliferation in young diabetes-prone rats fed a protective diet J Cell Physiol 224 501 508 1:CAS:528:DC%2BC3cXmslWiurY%3D 10.1002/jcp.22151 20432450
78. F Campa HY Yoon VL Ha, et al. 2009 A PH domain in the Arf GTPase-activating protein (GAP) ARAP1 binds phosphatidylinositol 3, 4, 5-trisphosphate and regulates Arf GAP activity independently of recruitment to the plasma membranes J Biol Chem 284 28069 28083 1:CAS:528:DC%2BD1MXht1SqsbzF 10.1074/jbc.M109.028266 19666464
79. KJ Martell AF Seasholtz SP Kwak, et al. 1995 hVH-5: a protein tyrosine phosphatase abundant in brain that inactivates mitogen-activated protein kinase J Neurochem 65 1823 1833 1:CAS:528:DyaK2MXotFOksLc%3D 10.1046/j.1471-4159.1995. 65041823.x 7561881
80. B Emanuelli D Eberle R Suzuki, et al. 2008 Overexpression of the dual-specificity phosphatase MKP-4/DUSP-9 protects against stress-induced insulin resistance Proc Natl Acad Sci U S A 105 3545 3550 1:CAS:528: DC%2BD1cXjtlals7s%3D 10.1073/pnas.0712275105 18296638 (Pubitemid 351723589)
81. KK Osbak K Colclough C Saint-Martin, et al. 2009 Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia Hum Mutat 30 1512 1526 1:CAS:528:DC%2BD1MXhsVyqsrfN 10.1002/humu.21110 19790256
82. J Zhao JP Bradfield H Zhang, et al. 2010 Examination of all type 2 diabetes GWAS loci reveals HHEX-IDE as a locus influencing pediatric BMI Diabetes 59 751 755 1:CAS:528:DC%2BC3cXjslensr0%3D 10.2337/db09-0972 19933996
83. Y Tay S Peter I Rigoutsos, et al. 2009 Insights into the regulation of a common variant of HMGA2 associated with human height during embryonic development Stem Cell Rev 5 328 333 1:CAS:528:DC%2BC3cXjtlalsQ%3D%3D 10.1007/s12015-009-9095-8 20058197
84. J Ferrer 2002 A genetic switch in pancreatic beta-cells: implications for differentiation and haploinsufficiency Diabetes 51 2355 2362 1:CAS:528:DC%2BD38XlvFKitbY%3D 10.2337/diabetes.51.8.2355 12145145
85. C Haumaitre E Barbacci M Jenny, et al. 2005 Lack of TCF2/vHNF1 in mice leads to pancreas agenesis Proc Natl Acad Sci U S A 102 1490 1495 1:CAS:528:DC%2BD2MXhs1Klt7w%3D 10.1073/pnas.0405776102 15668393 (Pubitemid 40209196)
86. IS Haldorsen M Vesterhus H Raeder, et al. 2008 Lack of pancreatic body and tail in HNF1B mutation carriers Diabet Med 25 782 787 1:CAS:528: DC%2BD1cXpvFyiur4%3D 10.1111/j.1464-5491.2008.02460.x 18644064
87. J Christiansen AM Kolte TO Hansen, et al. 2009 IGF2 mRNA-binding protein 2: biological function and putative role in type 2 diabetes J Mol Endocrinol 43 187 195 1:CAS:528:DC%2BD1MXhsF2qt7vE 10.1677/JME-09-0016 19429674
88. JR Brants TA Ayoubi K Chada, et al. 2004 Differential regulation of the insulin-like growth factor II mRNA-binding protein genes by architectural transcription factor HMGA2 FEBS Lett 569 277 283 1:CAS:528:DC%2BD2cXlt1amu74%3D 10.1016/j.febslet.2004.05.075 15225648 (Pubitemid 38844632)
89. D LeRoith O Gavrilova 2006 Mouse models created to study the pathophysiology of type 2 diabetes Int J Biochem Cell Biol 38 904 912 1:CAS:528:DC%2BD28Xit1Ohurc%3D 10.1016/j.biocel.2005.01.019 16103004 (Pubitemid 43363420)
90. S Prudente E Morini V Trischitta 2009 Insulin signaling regulating genes: effect on T2DM and cardiovascular risk Nat Rev Endocrinol 5 682 693 1:CAS:528:DC%2BD1MXhsVentLrO 10.1038/nrendo.2009.215 19924153
91. J Rung S Cauchi A Albrechtsen, et al. 2009 Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia Nat Genet 41 1110 1115 1:CAS:528:DC%2BD1MXhtV2gsb%2FL 10.1038/ng.443 19734900
92. K Yasuda K Miyake Y Horikawa, et al. 2008 Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus Nat Genet 40 1092 1097 1:CAS:528:DC%2BD1cXhtVGgt77M 10.1038/ng.207 18711367
93. V Hertveldt S Louryan T van Reeth, et al. 2008 The development of several organs and appendages is impaired in mice lacking Sp6 Dev Dyn 237 883 892 1:CAS:528:DC%2BD1cXltFaktbw%3D 10.1002/dvdy.21355 18297738 (Pubitemid 351542287)
94. H Mulder CL Nagorny V Lyssenko, et al. 2009 Melatonin receptors in pancreatic islets: good morning to a novel type 2 diabetes gene Diabetologia 52 1240 1249 1:CAS:528:DC%2BD1MXms1yhsrY%3D 10.1007/s00125-009-1359-y 19377888
95. H Nakhai JT Siveke B Klein, et al. 2008 Conditional ablation of Notch signaling in pancreatic development Development 135 2757 2765 1:CAS:528:DC%2BD1cXhtFKgsbvI 10.1242/dev.013722 18635610
96. ED Rosen RN Kulkarni P Sarraf, et al. 2003 Targeted elimination of peroxisome proliferator-activated receptor gamma in beta cells leads to abnormalities in islet mass without compromising glucose homeostasis Mol Cell Biol 23 7222 7229 1:CAS:528:DC%2BD3sXotVSrurs%3D 10.1128/MCB.23.20.7222-7229. 2003 14517292 (Pubitemid 37214026)
97. T Courtheoux G Gay Y Gachet, et al. 2009 Ase1/Prc1-dependent spindle elongation corrects merotely during anaphase in fission yeast J Cell Biol 187 399 412 1:CAS:528:DC%2BD1MXhsValt7jK 10.1083/jcb.200902093 19948483
98. KH Song T Li JY Chiang 2006 A Prospero-related homeodomain protein is a novel co-regulator of hepatocyte nuclear factor 4alpha that regulates the cholesterol 7alpha-hydroxylase gene J Biol Chem 281 10081 10088 1:CAS:528:DC%2BD28Xjt1Kguro%3D 10.1074/jbc.M513420200 16488887 (Pubitemid 43864543)
99. J Wang G Kilic M Aydin, et al. 2005 Prox1 activity controls pancreas morphogenesis and participates in the production of "secondary transition" pancreatic endocrine cells Dev Biol 286 182 194 1:CAS:528:DC%2BD2MXhtVGrsbzM 10.1016/j.ydbio.2005.07.021 16122728 (Pubitemid 41394056)
100. M Gironella M Seux MJ Xie, et al. 2007 Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development Proc Natl Acad Sci U S A 104 16170 16175 1:CAS:528:DC%2BD2sXhtF2hu7fK 10.1073/pnas.0703942104 17911264 (Pubitemid 350099380)
101. Z Jarikji LD Horb F Shariff, et al. 2009 The tetraspanin Tm4sf3 is localized to the ventral pancreas and regulates fusion of the dorsal and ventral pancreatic buds Development 136 1791 1800 1:CAS:528:DC%2BD1MXot1aktLk%3D 10.1242/dev.032235 19403659
102. SG Fonseca S Ishigaki CM Oslowski, et al. 2010 Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells J Clin Invest 120 744 755 1:CAS:528:DC%2BC3cXjtV2ns7s%3D 10.1172/JCI39678 20160352
103. MS Sandhu MN Weedon KA Fawcett, et al. 2007 Common variants in WFS1 confer risk of type 2 diabetes Nat Genet 39 951 953 1:CAS:528: DC%2BD2sXot1CmsL8%3D 10.1038/ng2067 17603484 (Pubitemid 47185173)
104. T Chen M Li Y Ding, et al. 2009 Identification of zinc-finger BED domain-containing 3 (Zbed3) as a novel Axin-interacting protein that activates Wnt/beta-catenin signaling J Biol Chem 284 6683 6689 1:CAS:528: DC%2BD1MXislWrtLY%3D 10.1074/jbc.M807753200 19141611
105. W Duan B Sun TW Li, et al. 2000 Cloning and characterization of AWP1, a novel protein that associates with serine/threonine kinase PRK1 in vivo Gene 256 113 121 1:CAS:528:DC%2BD3cXosVGitr0%3D 10.1016/S0378-1119(00)00365-6 11054541