Impaired enteroendocrine development in intestinal-specific Islet1 mouse mutants causes impaired glucose homeostasis

American Journal of Physiology - Gastrointestinal and Liver Physiology

Volumn 307, Issue 10, 2014, Pages G979-G991

  Terry, Natalie A ^a,b,c   Walp, Erik R ^a,c   Lee, Randall A ^a,b   Kaestner, Klaus H ^d   May, Catherine Lee ^a,b,c  

^a CHILDREN S HOSPITAL OF PHILADELPHIA   (United States)

^b Div Pediat Gastroenterol Nutr   (United States)

^c Department of Pathology and Laboratory Medicine ^*  (United States)

^d UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

Enteroendocrine; Glucose regulation; Incretins; Islet1

Indexed keywords

CHOLECYSTOKININ; CHROMOGRANIN A; CRE RECOMBINASE; GASTRIC INHIBITORY POLYPEPTIDE; GLUCAGON LIKE PEPTIDE 1; GLUCOSE; INCRETIN; SEROTONIN; SOMATOSTATIN; VILLIN; ACTIN BINDING PROTEIN; BIOLOGICAL MARKER; CHROMOGRANIN A, MOUSE; FAT INTAKE; GASTRIN; GHRELIN; GLUCOSE BLOOD LEVEL; INSULIN GENE ENHANCER BINDING PROTEIN ISL-1; INTEGRASE; LIM HOMEODOMAIN PROTEIN; TRANSCRIPTION FACTOR;

ADULT; ALLELE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CELL MATURATION; CONTROLLED STUDY; DIARRHEA; ENTEROENDOCRINE CELL; FEMALE; GENE; GENE DELETION; GLUCOSE HOMEOSTASIS; GLYCEMIC CONTROL; IMMUNOHISTOCHEMISTRY; IMPAIRED GLUCOSE TOLERANCE; ISLET1 GENE; LIPID ABSORPTION; MALE; MOLECULAR PATHOLOGY; MOUSE; NEWBORN; NONHUMAN; PANCREAS ISLET BETA CELL; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; AGE; ANIMAL; BLOOD; C57BL MOUSE; DEFICIENCY; DISORDERS OF CARBOHYDRATE METABOLISM; FAT INTAKE; GENETICS; GENOTYPE; GLUCOSE BLOOD LEVEL; GLUCOSE TOLERANCE TEST; INTESTINE ABSORPTION; INTESTINE MUCOSA; KNOCKOUT MOUSE; MALABSORPTION; METABOLISM; PATHOLOGY; PHENOTYPE; SMALL INTESTINE; WEIGHT GAIN;

AGE FACTORS; ANIMALS; ANIMALS, NEWBORN; BIOLOGICAL MARKERS; BLOOD GLUCOSE; CHOLECYSTOKININ; CHROMOGRANIN A; DIARRHEA; DIETARY FATS; ENTEROENDOCRINE CELLS; FEMALE; GASTRIC INHIBITORY POLYPEPTIDE; GASTRINS; GENOTYPE; GHRELIN; GLUCAGON-LIKE PEPTIDE 1; GLUCOSE METABOLISM DISORDERS; GLUCOSE TOLERANCE TEST; INTEGRASES; INTESTINAL ABSORPTION; INTESTINAL MUCOSA; INTESTINE, SMALL; LIM-HOMEODOMAIN PROTEINS; MALABSORPTION SYNDROMES; MALE; MICE, INBRED C57BL; MICE, KNOCKOUT; MICROFILAMENT PROTEINS; PHENOTYPE; SEROTONIN; SOMATOSTATIN; TRANSCRIPTION FACTORS; WEIGHT GAIN;

EID: 84922392337     PISSN: 01931857     EISSN: 15221547     Source Type: Journal    
DOI: 10.1152/ajpgi.00390.2013     Document Type: Article

References (73)

1. Ahlgren U, Pfaff SL, Jessell TM, Edlund T, Edlund H. Independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells. Nature 385: 257-260, 1997.
2. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 132: 2131-2157, 2007.
3. Barat-Houari M, Clement K, Vatin V, Dina C, Bonhomme G, Vasseur F, Guy-Grand B, Froguel P. Positional candidate gene analysis of Lim domain homeobox gene (Isl-1) on chromosome 5q11-q13 in a French morbidly obese population suggests indication for association with type 2 diabetes. Diabetes 51: 1640-1643, 2002.
4. Beucher A, Gjernes E, Collin C, Courtney M, Meunier A, Collombat P, Gradwohl G. The homeodomain-containing transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice. PLoS One 7: e36449, 2012.
5. Bradley WD, Zwingelstein C, Rondinone CM. The emerging role of the intestine in metabolic diseases. Arch Physiol Biochem 117: 165-176, 2011.
6. Bu L, Jiang X, Martin-Puig S, Caron L, Zhu S, Shao Y, Roberts DJ, Huang PL, Domian IJ, Chien KR. Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages. Nature 460: 113-117, 2009.
7. Canani RB, Terrin G. Recent progress in congenital diarrheal disorders. Curr Gastroenterol Rep 13: 257-264, 2011. INTESTINAL ISL1 REGULATION OF GLUCOSE HOMEOSTASIS G989 AJP-Gastrointest Liver Physiol • doi:10.1152/ajpgi.00390.2013 • www.ajpgi.org
8. Cetin Y, Muller-Koppel L, Aunis D, Bader MF, Grube D. Chromogranin A (CgA) in the gastro-entero-pancreatic (GEP) endocrine system. II. CgA in mammalian entero-endocrine cells. Histochemistry 92: 265- 275, 1989.
9. Collombat P, Hecksher-Sorensen J, Broccoli V, Krull J, Ponte I, Mundiger T, Smith J, Gruss P, Serup P, Mansouri A. The simultaneous loss of Arx and Pax4 genes promotes a somatostatin-producing cell fate specification at the expense of the alpha- and beta-cell lineages in the mouse endocrine pancreas. Development 132: 2969-2980, 2005.
10. Collombat P, Mansouri A, Hecksher-Sorensen J, Serup P, Krull J, Gradwohl G, Gruss P. Opposing actions of Arx and Pax4 in endocrine pancreas development. Genes Dev 17: 2591-2603, 2003.
11. Corleto VD. Somatostatin and the gastrointestinal tract. Curr Opin Endocrinol Diabetes Obes 17: 63-68, 2010.
12. Das P, May CL. Expression analysis of the Islet-1 gene in the developing and adult gastrointestinal tract. Gene Expr Patterns 11: 244-254, 2011.
13. Desai S, Loomis Z, Pugh-Bernard A, Schrunk J, Doyle MJ, Minic A, McCoy E, Sussel L. Nkx2.2 regulates cell fate choice in the enteroendocrine cell lineages of the intestine. Dev Biol 313: 58-66, 2008.
14. Dirksen C, Jorgensen NB, Bojsen-Moller KN, Jacobsen SH, Hansen DL, Worm D, Holst JJ, Madsbad S. Mechanisms of improved glycaemic control after Roux-en-Y gastric bypass. Diabetologia 55: 1890-1901, 2012.
15. Drucker DJ, Asa S. Glucagon gene expression in vertebrate brain. J Biol Chem 263: 13475-13478, 1988.
16. Du A, Hunter CS, Murray J, Noble D, Cai CL, Evans SM, Stein R, May CL. Islet-1 is required for the maturation, proliferation, and survival of the endocrine pancreas. Diabetes 58: 2059-2069, 2009.
17. Du A, McCracken KW, Walp ER, Terry NA, Klein TJ, Han A, Wells JM, May CL. Arx is required for normal enteroendocrine cell development in mice and humans. Dev Biol 365: 175-188, 2012.
18. Egerod KL, Engelstoft MS, Grunddal KV, Nohr MK, Secher A, Sakata I, Pedersen J, Windelov JA, Fuchtbauer EM, Olsen J, Sundler F, Christensen JP, Wierup N, Olsen JV, Holst JJ, Zigman JM, Poulsen SS, Schwartz TW. A major lineage of enteroendocrine cells coexpress CCK, secretin, GIP, GLP-1, PYY, and neurotensin but not somatostatin. Endocrinology 153: 5782-5795.
19. Ehm MG, Karnoub MC, Sakul H, Gottschalk K, Holt DC, Weber JL, Vaske D, Briley D, Briley L, Kopf J, McMillen P, Nguyen Q, Reisman M, Lai EH, Joslyn G, Shepherd NS, Bell C, Wagner MJ, Burns DK. Genomewide search for type 2 diabetes susceptibility genes in four American populations. Am J Hum Genet 66: 1871-1881, 2000.
20. Ehrman LA, Mu X, Waclaw RR, Yoshida Y, Vorhees CV, Klein WH, Campbell K. The LIM homeobox gene Isl1 is required for the correct development of the striatonigral pathway in the mouse. Proc Natl Acad Sci USA 110: E4026-4035, 2013.
21. el Marjou F, Janssen KP, Chang BH, Li M, Hindie V, Chan L, Louvard D, Chambon P, Metzger D, Robine S. Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis 39: 186-193, 2004.
22. Elrick H, Stimmler L, Hlad CJ, Jr., Arai Y. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab 24: 1076-1082, 1964.
23. Gelling RW, Du XQ, Dichmann DS, Romer J, Huang H, Cui L, Obici S, Tang B, Holst JJ, Fledelius C, Johansen PB, Rossetti L, Jelicks LA, Serup P, Nishimura E, Charron MJ. Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci USA 100: 1438-1443, 2003.
24. Gierl MS, Karoulias N, Wende H, Strehle M, Birchmeier C. The zinc-finger factor Insm1 (IA-1) is essential for the development of pancreatic beta cells and intestinal endocrine cells. Genes Dev 20: 2465-2478, 2006.
25. Gradwohl G, Dierich A, LeMeur M, Guillemot F. Neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci USA 97: 1607-1611, 2000.
26. Habib AM, Richards P, Cairns LS, Rogers GJ, Bannon CA, Parker HE, Morley TC, Yeo GS, Reimann F, Gribble FM. Overlap of endocrine hormone expression in the mouse intestine revealed by transcriptional profiling and flow cytometry. Endocrinology 153: 3054-3065, 2012.
27. Hancock AS, Du A, Liu J, Miller M, May CL. Glucagon deficiency reduces hepatic glucose production and improves glucose tolerance in adult mice. Mol Endocrinol 24: 1605-1614, 2010.
28. Hansotia T, Baggio LL, Delmeire D, Hinke SA, Yamada Y, Tsukiyama K, Seino Y, Holst JJ, Schuit F, Drucker DJ. Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors. Diabetes 53: 1326-1335, 2004.
29. Hansotia T, Drucker DJ. GIP and GLP-1 as incretin hormones: lessons from single and double incretin receptor knockout mice. Regul Pept 128: 125-134, 2005.
30. Hayashi Y, Yamamoto M, Mizoguchi H, Watanabe C, Ito R, Yamamoto S, Sun XY, Murata Y. Mice deficient for glucagon genederived peptides display normoglycemia and hyperplasia of islet α-cells but not of intestinal L-cells. Mol Endocrinol 23: 1990-1999, 2009.
31. Herrmann C, Goke R, Richter G, Fehmann HC, Arnold R, Goke B. Glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide plasma levels in response to nutrients. Digestion 56: 117-126, 1995.
32. Holst JJ, Vilsboll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol 297: 127-136, 2009.
33. Hunter CS, Rhodes SJ. LIM-homeodomain genes in mammalian development and human disease. Mol Biol Rep 32: 67-77, 2005.
34. Jackson RS, Creemers JW, Farooqi IS, Raffin-Sanson ML, Varro A, Dockray GJ, Holst JJ, Brubaker PL, Corvol P, Polonsky KS, Ostrega D, Becker KL, Bertagna X, Hutton JC, White A, Dattani MT, Hussain K, Middleton SJ, Nicole TM, Milla PJ, Lindley KJ, O'Rahilly S. Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. J Clin Invest 112: 1550-1560, 2003.
35. Jenny M, Uhl C, Roche C, Duluc I, Guillermin V, Guillemot F, Jensen J, Kedinger M, Gradwohl G. Neurogenin3 is differentially required for endocrine cell fate specification in the intestinal and gastric epithelium. EMBO J 21: 6338-6347, 2002.
36. Jin T. Mechanisms underlying proglucagon gene expression. J Endocrinol 198: 17-28, 2008.
37. Kato M, Dobyns WB. X-linked lissencephaly with abnormal genitalia as a tangential migration disorder causing intractable epilepsy: proposal for a new term, "interneuronopathy". J Child Neurol 20: 392-397, 2005.
38. Kawakami Y, Marti M, Kawakami H, Itou J, Quach T, Johnson A, Sahara S, O'Leary DD, Nakagawa Y, Lewandoski M, Pfaff S, Evans SM, Izpisua Belmonte JC. Islet1-mediated activation of the beta-catenin pathway is necessary for hindlimb initiation in mice. Development 138: 4465-4473, 2011.
39. Larsson LI, St-Onge L, Hougaard DM, Sosa-Pineda B, Gruss P. Pax 4 and 6 regulate gastrointestinal endocrine cell development. Mech Dev 79: 153-159, 1998.
40. Lee CS, Perreault N, Brestelli JE, Kaestner KH. Neurogenin 3 is essential for the proper specification of gastric enteroendocrine cells and the maintenance of gastric epithelial cell identity. Genes Dev 16: 1488- 1497, 2002.
41. Leonard J, Serup P, Gonzalez G, Edlund T, Montminy M. The LIM family transcription factor Isl-1 requires cAMP response element binding protein to promote somatostatin expression in pancreatic islet cells. Proc Natl Acad Sci USA 89: 6247-6251, 1992.
42. Liu J, Hunter CS, Du A, Ediger B, Walp E, Murray J, Stein R, May CL. Islet-1 regulates Arx transcription during pancreatic islet alpha-cell development. J Biol Chem 286: 15352-15360, 2011.
43. Lo CM, King A, Samuelson LC, Kindel TL, Rider T, Jandacek RJ, Raybould HE, Woods SC, Tso P. Cholecystokinin knockout mice are resistant to high-fat diet-induced obesity. Gastroenterology 138: 1997- 2005, 2010.
44. Lu KM, Evans SM, Hirano S, Liu FC. Dual role for Islet-1 in promoting striatonigral and repressing striatopallidal genetic programs to specify striatonigral cell identity. Proc Natl Acad Sci USA 111: E168-177, 2014.
45. Martin MG, Lindberg I, Solorzano-Vargas RS, Wang J, Avitzur Y, Bandsma R, Sokollik C, Lawrence S, Pickett LA, Chen Z, Egritas O, Dalgic B, Albornoz V, de Ridder L, Hulst J, Gok F, Aydogan A, Al-Hussaini A, Gok DE, Yourshaw M, Wu SV, Cortina G, Stanford S, Georgia S. Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort. Gastroenterology 145: 138-148, 2013.
46. May CL, Kaestner KH. Gut endocrine cell development. Mol Cell Endocrinol 323: 70-75, 2010.
47. McIntyre N, Holdsworth CD, Turner DS. New interpretation of oral glucose tolerance. Lancet 2: 20-21, 1964.
48. Mellitzer G, Beucher A, Lobstein V, Michel P, Robine S, Kedinger M, Gradwohl G. Loss of enteroendocrine cells in mice alters lipid absorption and glucose homeostasis and impairs postnatal survival. J Clin Invest 120: 1708-1721, 2010.
49. Mellitzer G, Gradwohl G. Enteroendocrine cells and lipid absorption. Curr Opin Lipidol 22: 171-175, 2011.
50. Miyawaki K, Yamada Y, Yano H, Niwa H, Ban N, Ihara Y, Kubota A, Fujimoto S, Kajikawa M, Kuroe A, Tsuda K, Hashimoto H, Yamashita T, Jomori T, Tashiro F, Miyazaki J, Seino Y. Glucose intolerance caused by a defect in the entero-insular axis: a study in gastric inhibitory polypeptide receptor knockout mice. Proc Natl Acad Sci USA 96: 14843-14847, 1999.
51. Moran GW, Leslie FC, Levison SE, Worthington J, McLaughlin JT. Enteroendocrine cells: neglected players in gastrointestinal disorders? Therap Adv Gastroenterol 1: 51-60, 2008.
52. Mutoh H, Fung BP, Naya FJ, Tsai MJ, Nishitani J, Leiter AB. The basic helix-loop-helix transcription factor BETA2/NeuroD is expressed in mammalian enteroendocrine cells and activates secretin gene expression. Proc Natl Acad Sci USA 94: 3560-3564, 1997.
53. Naya FJ, Huang HP, Qiu Y, Mutoh H, DeMayo FJ, Leiter AB, Tsai MJ. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev 11: 2323-2334, 1997.
54. Pedersen J, Ugleholdt RK, Jorgensen SM, Windelov JA, Grunddal KV, Schwartz TW, Fuchtbauer EM, Poulsen SS, Holst PJ, Holst JJ. Glucose metabolism is altered after loss of L cells and α-cells but not influenced by loss of K cells. Am J Physiol Endocrinol Metab 304: E60-E73, 2013.
55. Phillips LK, Prins JB. Update on incretin hormones. Ann NY Acad Sci 1243: E55-74, 2011.
56. Pinney SE, Oliver-Krasinski J, Ernst L, Hughes N, Patel P, Stoffers DA, Russo P, De Leon DD. Neonatal diabetes and congenital malabsorptive diarrhea attributable to a novel mutation in the human neurogenin-3 gene coding sequence. J Clin Endocrinol Metab 96: 1960-1965, 2011.
57. Portela-Gomes GM, Stridsberg M. Chromogranin A in the human gastrointestinal tract: an immunocytochemical study with region-specific antibodies. J Histochem Cytochem 50: 1487-1492, 2002.
58. Rindi G, Buffa R, Sessa F, Tortora O, Solcia E. Chromogranin A, B and C immunoreactivities of mammalian endocrine cells. Distribution, distinction from costored hormones/prohormones and relationship with the argyrophil component of secretory granules. Histochemistry 85: 19-28, 1986.
59. Roy SA, Langlois MJ, Carrier JC, Boudreau F, Rivard N, Perreault N. Dual regulatory role for phosphatase and tensin homolog in specification of intestinal endocrine cell subtypes. World J Gastroenterol 18: 1579-1589.
60. Saxena R, Hivert MF, Langenberg C, Tanaka T, Pankow JS, Vollenweider P, Lyssenko V, Bouatia-Naji N, Dupuis J, Jackson AU, Kao WH, Li M, Glazer NL, Manning AK, Luan J, Stringham HM, Prokopenko I, Johnson T, Grarup N, Boesgaard TW, Lecoeur C, Shrader P, O'Connell J, Ingelsson E, Couper DJ, Rice K, Song K, Andreasen CH, Dina C, Kottgen A, Le Bacquer O, Pattou F, Taneera J, Steinthorsdottir V, Rybin D, Ardlie K, Sampson M, Qi L, van Hoek M, Weedon MN, Aulchenko YS, Voight BF, Grallert H, Balkau B, Bergman RN, Bielinski SJ, Bonnefond A, Bonnycastle LL, Borch- Johnsen K, Bottcher Y, Brunner E, Buchanan TA, Bumpstead SJ, Cavalcanti-Proenca C, Charpentier G, Chen YD, Chines PS, Collins FS, Cornelis M, J Crawford G, Delplanque J, Doney A, Egan JM, Erdos MR, Firmann M, Forouhi NG, Fox CS, Goodarzi MO, Graessler J, Hingorani A, Isomaa B, Jorgensen T, Kivimaki M, Kovacs P, Krohn K, Kumari M, Lauritzen T, Levy-Marchal C, Mayor V, McAteer JB, Meyre D, Mitchell BD, Mohlke KL, Morken MA, Narisu N, Palmer CN, Pakyz R, Pascoe L, Payne F, Pearson D, Rathmann W, Sandbaek A, Sayer AA, Scott LJ, Sharp SJ, Sijbrands E, Singleton A, Siscovick DS, Smith NL, Sparso T, Swift AJ, Syddall H, Thorleifsson G, Tonjes A, Tuomi T, Tuomilehto J, Valle TT, Waeber G, Walley A, Waterworth DM, Zeggini E, Zhao JH, Illig T, Wichmann HE, Wilson JF, van Duijn C, Hu FB, Morris AD, Frayling TM, Hattersley AT, Thorsteinsdottir U, Stefansson K, Nilsson P, Syvanen AC, Shuldiner AR, Walker M, Bornstein SR, Schwarz P, Williams GH, Nathan DM, Kuusisto J, Laakso M, Cooper C, Marmot M, Ferrucci L, Mooser V, Stumvoll M, Loos RJ, Altshuler D, Psaty BM, Rotter JI, Boerwinkle E, Hansen T, Pedersen O, Florez JC, McCarthy MI, Boehnke M, Barroso I, Sladek R, Froguel P, Meigs JB, Groop L, Wareham NJ, Watanabe RM. Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat Genet 42: 142-148, 2010.
61. Scrocchi LA, Brown TJ, MaClusky N, Brubaker PL, Auerbach AB, Joyner AL, Drucker DJ. Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene. Nat Med 2: 1254-1258, 1996.
62. Scrocchi LA, Marshall BA, Cook SM, Brubaker PL, Drucker DJ. Identification of glucagon-like peptide 1 (GLP-1) actions essential for glucose homeostasis in mice with disruption of GLP-1 receptor signaling. Diabetes 47: 632-639, 1998.
63. Shimomura H, Sanke T, Hanabusa T, Tsunoda K, Furuta H, Nanjo K. Nonsense mutation of islet-1 gene (Q310X) found in a type 2 diabetic patient with a strong family history. Diabetes 49: 1597-1600, 2000.
64. Sjolund K, Sanden G, Hakanson R, Sundler F. Endocrine cells in human intestine: an immunocytochemical study. Gastroenterology 85: 1120-1130, 1983.
65. Sun Y, Dykes IM, Liang X, Eng SR, Evans SM, Turner EE. A central role for Islet1 in sensory neuron development linking sensory and spinal gene regulatory programs. Nat Neurosci 11: 1283-1293, 2008.
66. Ugleholdt R, Zhu X, Deacon CF, Orskov C, Steiner DF, Holst JJ. Impaired intestinal proglucagon processing in mice lacking prohormone convertase 1. Endocrinology 145: 1349-1355, 2004.
67. Wang J, Cortina G, Wu SV, Tran R, Cho JH, Tsai MJ, Bailey TJ, Jamrich M, Ament ME, Treem WR, Hill ID, Vargas JH, Gershman G, Farmer DG, Reyen L, Martin MG. Mutant neurogenin-3 in congenital malabsorptive diarrhea. N Engl J Med 355: 270-280, 2006.
68. Wang M, Drucker DJ. The LIM domain homeobox gene isl-1 is a positive regulator of islet cell-specific proglucagon gene transcription. J Biol Chem 270: 12646-12652, 1995.
69. Wang S, Liu J, Li L, Wice BM. Individual subtypes of enteroendocrine cells in the mouse small intestine exhibit unique patterns of inositol 1,4,5-trisphosphate receptor expression. J Histochem Cytochem 52: 53-63, 2004.
70. Wiltshire S, Hattersley AT, Hitman GA, Walker M, Levy JC, Sampson M, O'Rahilly S, Frayling TM, Bell JI, Lathrop GM, Bennett A, Dhillon R, Fletcher C, Groves CJ, Jones E, Prestwich P, Simecek N, Rao PV, Wishart M, Bottazzo GF, Foxon R, Howell S, Smedley D, Cardon LR, Menzel S, McCarthy MI. A genomewide scan for loci predisposing to type 2 diabetes in a UK population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q. Am J Hum Genet 69: 553-569, 2001.
71. Ye DZ, Kaestner KH. Foxa1 and Foxa2 control the differentiation of goblet and enteroendocrine L- and D-cells in mice. Gastroenterology 137: 2052-2062, 2009.
72. Yokoi N, Kanamori M, Horikawa Y, Takeda J, Sanke T, Furuta H, Nanjo K, Mori H, Kasuga M, Hara K, Kadowaki T, Tanizawa Y, Oka Y, Iwami Y, Ohgawara H, Yamada Y, Seino Y, Yano H, Cox NJ, Seino S. Association studies of variants in the genes involved in pancreatic beta-cell function in type 2 diabetes in Japanese subjects. Diabetes 55: 2379-2386, 2006.
73. Zhu X, Zhou A, Dey A, Norrbom C, Carroll R, Zhang C, Laurent V, Lindberg I, Ugleholdt R, Holst JJ, Steiner DF. Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc Natl Acad Sci USA 99: 10293-10298, 2002.