Genetic analysis of late-onset type 2 diabetes in a mouse model of human complex trait.
Type 2 diabetes is a complex trait with both genes and environmental factors contributing to susceptibility. Except for rare subtypes with monogenic inheritance, the genetic basis of type 2 diabetes is unknown because of the complex and heterogeneous nature of the disease. By using the NSY mouse, an inbred mouse model of type 2 diabetes, we genetically dissected late-onset type 2 diabetes and demonstrated age-dependent changes in the genetic control of type 2 diabetes as well as polygenic inheritance. Three major loci (Nidd1nsy, Nidd2nsy, Nidd3nsy) were mapped on mouse chromosomes (Chr) 11, 14, and 6, respectively. The existence of a fourth locus (Nidd4nsy) with an age-dependent effect was suggested by longitudinal, but not cross-sectional, analysis of linkage data. Nidd1nsy and Nidd4nsy appear to affect insulin secretion, whereas Nidd2nsy and Nidd3nsy appear to affect insulin sensitivity. A locus on Chr 6 was significantly linked to epididymal fat weight. A candidate disease gene (Tcf2) on Chr 11, encoding hepatic nuclear factor-1beta, was shown to have a rare sequence variant in the DNA binding domain in the model. The mouse model we used will serve as a useful model for future studies on the etiology of late-onset polygenic type 2 diabetes in humans.
Ueda
H
H
Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan.
Ikegami
H
H
Kawaguchi
Y
Y
Fujisawa
T
T
Yamato
E
E
Shibata
M
M
Ogihara
T
T
D000273:Adipose Tissue / Q000033:anatomy & histology; D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002874:Chromosome Mapping; D004268:DNA-Binding Proteins / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D004195:Disease Models, Animal; D004822:Epididymis; D005260:Female; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics; D000078790:Insulin Secretion; D008137:Longitudinal Studies; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009929:Organ Size; D014157:Transcription Factors / Q000235:genetics
D001786:Blood Glucose; D004268:DNA-Binding Proteins; C496495:HNF1B protein, human; C496496:Hnf1b protein, mouse; D007328:Insulin; D014157:Transcription Factors; D051539:Hepatocyte Nuclear Factor 1-beta