AIMS/HYPOTHESIS: 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/ INTERPRETATION: 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.
AIMS/HYPOTHESIS: 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/ INTERPRETATION: 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: Guowen Cai; Shelley A Cole; Jeanne H Freeland-Graves; Jean W MacCluer; John Blangero; Anthony G Comuzzie Journal: Diabetes Date: 2004-05 Impact factor: 9.461
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Authors: Valeriya Lyssenko; Cecilia L F Nagorny; Michael R Erdos; Nils Wierup; Anna Jonsson; Peter Spégel; Marco Bugliani; Richa Saxena; Malin Fex; Nicolo Pulizzi; Bo Isomaa; Tiinamaija Tuomi; Peter Nilsson; Johanna Kuusisto; Jaakko Tuomilehto; Michael Boehnke; David Altshuler; Frank Sundler; Johan G Eriksson; Anne U Jackson; Markku Laakso; Piero Marchetti; Richard M Watanabe; Hindrik Mulder; Leif Groop Journal: Nat Genet Date: 2008-12-07 Impact factor: 38.330
Authors: Florence Demenais; Timo Kanninen; Cecilia M Lindgren; Steven Wiltshire; Stéphane Gaget; Candice Dandrieux; Peter Almgren; Marketa Sjögren; Andrew Hattersley; Christian Dina; Tiinamaija Tuomi; Mark I McCarthy; Philippe Froguel; Leif C Groop Journal: Hum Mol Genet Date: 2003-08-01 Impact factor: 6.150