International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

G13. New Susceptibility Locus for Type 2 Diabetes in Spontaneously Diabetic NSY Mouse

Michiko Itoi1, Hiroshi Ikegami1, Hironori Ueda1, Yoshihiko Kawaguchi1, Tomomi Fujisawa1, Koji Nojima1, Kazunori Yamada1, Naru Babaya1, Masao Shibata2, Toshio Ogihara1
1Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Osaka, Japan; 2College of General Education, Aichi-Gakuin University, Aichi, Japan

The NSY mouse strain is an inbred animal model with spontaneous development of type 2 diabetes, established by selective breeding for glucose intolerance from outbred Jcl:ICR mice. The NSY mouse exhibits diabetes elated phenotypes, including mild obesity, abdominal fat accumulation, insulin resistance, and impaired secretion of insulin. By whole genome mapping for glucose intolerance, we previously mapped three major loci (Nidd1n, Nidd2n, Nidd3n) to mouse chromosomes (Chr) 11, 14, and 6, respectively. These three loci, however, can explain only 54% of the genetic variance (MAPMAKER/QTL program). In this study we mapped a new quantitative trait locus (QTL) for glucose intolerance other than Nidd1-3n. Intraperitoneal glucose tolerance test was performed on 307 F2 (C3H/He NSY) mice at 12, 24, 36, and 48 weeks of age, and area under the glucose curve (AUC) after glucose load was calculated. At 48 weeks of age, body mass index (BMI) was calculated as body weight divided by the square of body length, and the epididymal fat pads were dissected. In our initial whole genome screening using 93 F2 progeny, comprising 46 mice with the lowest AUC values and 47 mice with the highest values of the 307 mice at 48 weeks, Chr 1 was suggested to possess a locus for glucose intolerance. Therefore, linkage analysis (using microsatellite markers spanning 20cM intervals) of Chr 1 was carried out in all F2 mice. Significant evidence of linkage was found in the region near D1Mit14, with maximum LOD score (MLS) of 6.3 for AUC, and 5.7 for fasting blood glucose level at 12 weeks of age. This locus also had significant linkage to blood glucose levels at 60, 90 and 120 min, with MLS of 4.8, 5.1 and 4.9, respectively, and suggestive linkage at 30 min (MLS: 4.1) at 12 weeks of age. None of the tested markers on Chr 1 were linked to body weight, plasma insulin, BMI or fat-pad weight. The region of Chr 1 containing this QTL has homology to human Chr 1q. These data not only demonstrated a new QTL for type 2 diabetes on Chr 1 in the NSY mouse, but also indicated the importance of considering age-dependent changes in phenotypes in the genetic analysis of polygenic traits.

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