title: Direct evidence for susceptibility genes for type 2 diabetes on mouse chromosomes 11 and 14.
abstract: OBJECTIVE
  Diabetogenic loci for type 2 diabetes have been mapped to mouse chromosome (Chr) 11 and 14 in the Nagoya-Shibata-Yasuda (NSY) mouse, an animal model of type 2 diabetes. We aimed to obtain direct evidence of these genes on each chromosome and to clarify their function and interaction in conferring susceptibility to type 2 diabetes.
  
  
  METHODS
  We established three consomic strains homozygous for diabetogenic NSY-Chr11, NSY-Chr14 or both on the control C3H background (C3H-11(NSY), C3H-14(NSY) and C3H-11(NSY)14(NSY), respectively), and monitored diabetes-related phenotypes longitudinally. The glucokinase gene was sequenced as a positional candidate gene on Chr11.
  
  
  RESULTS
  C3H-11(NSY) mice showed hyperglycaemia associated with impaired insulin secretion and age-dependent insulin resistance without obesity. C3H-14(NSY) mice exhibited hyperglycaemia mainly due to insulin resistance, with a slight increase in percentage body fat. C3H-11(NSY)14(NSY) double consomic mice showed marked hyperglycaemia and obesity, which was not observed in single consomic strains. Sequences of the glucokinase gene were allelically variant between NSY and C3H mice.
  
  
  CONCLUSIONS
  These data provide direct evidence that Chr11 and Chr14 harbour major susceptibility genes for type 2 diabetes. These two chromosomes interact to cause more severe hyperglycaemia and obesity, which was not observed with the presence of either single chromosome, indicating different modes of gene-gene interaction depending on the phenotype. Marked changes in the phenotypes retained in the consomic strains will facilitate fine mapping and the identification of the responsible genes and their interaction with each other, other genes and environmental factors.
authors.affiliation: Department of Endocrinology, Metabolism and Diabetes, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Babaya
authors.forename: T
authors.initials: T
authors.lastname: Fujisawa
authors.forename: K
authors.initials: K
authors.lastname: Nojima
authors.forename: M
authors.initials: M
authors.lastname: Itoi-Babaya
authors.forename: K
authors.initials: K
authors.lastname: Yamaji
authors.forename: K
authors.initials: K
authors.lastname: Yamada
authors.forename: M
authors.initials: M
authors.lastname: Kobayashi
authors.forename: H
authors.initials: H
authors.lastname: Ueda
authors.forename: Y
authors.initials: Y
authors.lastname: Hiromine
authors.forename: S
authors.initials: S
authors.lastname: Noso
authors.forename: H
authors.initials: H
authors.lastname: Ikegami
mesh_terms: D000818:Animals; D033481:Chromosomes, Mammalian / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006943:Hyperglycemia / Q000235:genetics; D051379:Mice; D010641:Phenotype
references.citation: Eur J Endocrinol. 1998 Dec;139(6):654-61
references.pmid: 9916873
references.citation: Biochem Biophys Res Commun. 2005 Mar 4;328(1):158-64
references.pmid: 15670764
references.citation: Diabetes. 2004 Dec;53(12):3274-85
references.pmid: 15561960
references.citation: Diabetes. 1988 Jun;37(6):707-13
references.pmid: 3289991
references.citation: Mamm Genome. 2006 Sep;17(9):927-40
references.pmid: 16964447
references.citation: Diabetes Res Clin Pract. 2001 Aug;53(2):67-71
references.pmid: 11403854
references.citation: Hum Mol Genet. 2003 Aug 1;12(15):1865-73
references.pmid: 12874106
references.citation: Diabetes. 2004 Feb;53(2):486-91
references.pmid: 14747302
references.citation: Tohoku J Exp Med. 1980 Feb;130(2):139-42
references.pmid: 6446173
references.citation: J Biol Chem. 1989 Sep 25;264(27):15936-42
references.pmid: 2550428
references.citation: Endocr J. 2001 Apr;48(2):241-7
references.pmid: 11456274
references.citation: Diabetologia. 2009 Sep;52(9):1866-70
references.pmid: 19533084
references.citation: Diabetes. 2000 Mar;49(3):513-6
references.pmid: 10868977
references.citation: Diabetes. 2004 May;53(5):1369-74
references.pmid: 15111508
references.citation: Hum Mutat. 2003 Nov;22(5):353-62
references.pmid: 14517946
references.citation: Diabetologia. 1995 May;38(5):503-8
references.pmid: 7489831
references.citation: Diabetes. 2004 Jun;53(6):1577-83
references.pmid: 15161764
references.citation: Science. 2004 Apr 16;304(5669):445-8
references.pmid: 15031436
references.citation: Nature. 2006 Jan 26;439(7075):484-9
references.pmid: 16400329
references.citation: Diabetes. 2003 Jun;52(6):1535-43
references.pmid: 12765967
references.citation: Nat Genet. 2009 Jan;41(1):77-81
references.pmid: 19060907
references.citation: Nature. 1992 Mar 12;356(6365):162-4
references.pmid: 1545870
references.citation: Cell. 1998 Mar 6;92(5):593-6
references.pmid: 9506512
references.citation: Diabetes. 2001 Mar;50(3):675-80
references.pmid: 11246890
references.citation: Am J Hum Genet. 2003 Aug;73(2):323-35
references.pmid: 12851856
references.citation: Am J Hum Genet. 1999 Apr;64(4):1127-40
references.pmid: 10090898
references.citation: Metabolism. 2001 Nov;50(11):1282-5
references.pmid: 11699045
references.citation: Nat Genet. 2009 Jan;41(1):89-94
references.pmid: 19060909
references.citation: Diabetologia. 2007 Aug;50(8):1641-8
references.pmid: 17549450
references.citation: Hum Mol Genet. 2004 Jun 1;13(11):1147-57
references.pmid: 15102714
references.citation: Diabetologia. 2000 Jul;43(7):932-8
references.pmid: 10952468
references.citation: Diabetes. 1999 May;48(5):1168-74
references.pmid: 10331425
references.citation: J Exp Med. 1994 Nov 1;180(5):1705-13
references.pmid: 7964456
references.citation: Diabetes. 1998 Aug;47(8):1287-95
references.pmid: 9703330
references.citation: Metabolism. 2000 May;49(5):651-6
references.pmid: 10831178
references.citation: Nat Genet. 1997 Nov;17(3):280-4
references.pmid: 9354790
references.citation: Diabetologia. 2005 Apr;48(4):675-86
references.pmid: 15729571
references.citation: ILAR J. 2004;45(3):268-77
references.pmid: 15229374
references.citation: Diabetes. 2005 Oct;54(10):3026-31
references.pmid: 16186409
references.citation: Diabetes. 1999 May;48(5):1183-91
references.pmid: 10331427
references.citation: Am J Physiol Endocrinol Metab. 2008 Feb;294(2):E232-40
references.pmid: 18056790
references.citation: J Biol Chem. 1995 Dec 22;270(51):30253-6
references.pmid: 8530440
references.citation: Nature. 1991 Jun 13;351(6327):542-7
references.pmid: 1675432
references.citation: Genome Res. 2000 Oct;10(10):1568-78
references.pmid: 11042154
references.citation: Nat Genet. 1993 Aug;4(4):404-9
references.pmid: 8401590
references.citation: Nucleic Acids Res. 1998 Jan 1;26(1):362-7
references.pmid: 9399875
references.citation: Nat Genet. 2009 Jan;41(1):82-8
references.pmid: 19060908
references.citation: Trends Genet. 2008 Dec;24(12):613-21
references.pmid: 18952314