| Popis: |
New Zealand Obese (NZO) mice exhibit a polygenic syndrome of morbid obesity, insulin resistance, and arterial hypertension that resembles the human metabolic syndrome. In addition, adult NZO-males are severely hyperglycemic and hypoinsulinemic. In order to localize the genes responsible for this polygenic syndrome, an outcross model of NZO mice with the lean, arteriosclerosis-resistant SJL strain was established. A total of 400 male backcross mice were monitored over a time period of 22 weeks (increment of body weight and body mass index, blood glucose, serum insulin, serum lipids). In a genome wide scan with more than 100 polymorphic microsatellite markers, a significant susceptibility locus (Nidd/SJL, LOD score >8) for hyperglycemia with hypoinsulinemia was identified on the distal end of chromosome 4. This SJL-derived locus was responsible for a major part (60%) of the total prevalence of diabetes in the backcross population, apparently concealing the effects of other NZO-derived diabetogenic genes. Nidd/SJL leads to a histologically detectable destruction of the b-cells in the islets of Langerhans. However, the diabetogenic allele does not affect obesity or serum insulin levels prior to the onset of diabetes. The allele appears to lower the threshold of obesity required for the development of the type 2 diabetes-like syndrome, and accelerates the onset of diabetes in mice with rapid weight gain. In the male backcross population, a high fat diet significantly enhanced the development of obesity as well as the diabetogenic effects of Nidd/SJL (difference in body weight approx. 12g, onset of diabetes approx. 5 weeks earlier). A second diabetogenic locus (Nidd/NZO) was identified on mouse chromosome 15. The NZO-derived Nidd/NZO-allele seems to interact with Nidd/SJL in an additive manner; the combined effects of both alleles explain almost 90% of the total prevalence of diabetes observed in the backcross. In conclusion, the present data localize a gene variant which, when present on an obese background, is responsible for a type 2 diabetes-like hyperglycemia. Furthermore, obesity and insulin resistance are required, but not sufficient, to produce diabetes in this mouse model. Additional diabetes genes which selectively cause b-cell degeneration are necessary for the type 2 diabetes-like decompensation of glucose homeostasis. |
