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Impact of Genetic Background and Ablation of Insulin Receptor Substrate (IRS)-3 on IRS-2 Knock-out Mice
Ist Teil von
The Journal of biological chemistry, 2003-04, Vol.278 (16), p.14284-14290
Ort / Verlag
United States: Elsevier Inc
Erscheinungsjahr
2003
Quelle
EZB-FREE-00999 freely available EZB journals
Beschreibungen/Notizen
Although we and others have generated IRS-2 knock-out (IRS-2−/−) mice, significant differences were seen between the two lines ofIRS-2−/− mice in the severity of diabetes and alterations of β-cell mass. It has been reported that although IRS-1 and IRS-3 knock-out mice showed normal blood glucose levels, IRS-1/IRS-3 double knock-out mice exhibited marked hyperglycemia. Thus, IRS-1 and IRS-3 compensate each other's functions in maintaining glucose homeostasis. To assess the effect of genetic background and also ablation of IRS-3 on IRS-2−/−, we generated IRS-2/IRS-3 double knock-out (IRS-2−/−IRS-3−/−) mice by crossing IRS-3−/− mice (129/Sv and C57Bl/6 background) with our IRS-2−/− mice (CBA and C57Bl/6 background). Intercrosses ofIRS-2+/−IRS-3+/− mice yielded nine genotypes, and all of them includingIRS-2−/−IRS-3−/− mice were apparently healthy and showed normal growth. However, at 10–20 weeks of age, 20–30% mice carrying a null mutation for theIRS-2 gene, irrespective of the IRS-3 genotype, developed diabetes. When mice with diabetes were excluded from the analysis of glucose and insulin tolerance test,IRS-2−/−IRS-3−/− showed a degree of glucose intolerance and insulin resistance similar to those of IRS-2−/− mice. BothIRS-2−/− andIRS-2−/−IRS-3−/− mice had moderately reduced β-cell mass despite having insulin resistance. Insulin-positive β-cells were decreased to nearly zero inIRS-2−/− mice with diabetes. Although Pdx1 and glucose transporter 2 expressions were essentially unaltered in islets from IRS-2−/− mice without diabetes, they were dramatically decreased in IRS-2−/− mice with diabetes. Taken together, these observations indicate that IRS-3 does not play a role compensating for the loss of IRS-2 in maintaining glucose homeostasis and that the severity of diabetes inIRS-2−/− mice depends upon genetic background, suggesting the existence of modifier gene(s) for diabetes in mice of the 129/Sv genetic strain.