TY - JOUR
T1 - Impact of genetic background and ablation of insulin receptor substrate (IRS)-3 on IRS-2 knock-out mice
AU - Terauchi, Yasuo
AU - Matsui, Junji
AU - Suzuki, Ryo
AU - Kubota, Naoto
AU - Komeda, Kajuro
AU - Aizawa, Shinichi
AU - Eto, Kazuhiro
AU - Kimura, Satoshi
AU - Nagai, Ryozo
AU - Tobe, Kazuyuki
AU - Lienhard, Gustav E.
AU - Kadowaki, Takashi
PY - 2003/4/18
Y1 - 2003/4/18
N2 - Although we and others have generated IRS-2 knock-out (IRS-2-/-) mice, significant differences were seen between the two lines of IRS-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 C57B1/6 background) with our IRS-2-/- mice (CBA and C57B1/6 background). Intercrosses of IRS-2-/-IRS-3+/- mice yielded nine genotypes, and all of them including IRS-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 the IRS-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. Both IRS-2-/- and IRS-2-/-IRS-3-/- mice had moderately reduced β-cell mass despite having insulin resistance. Insulin-positive β-cells were decreased to nearly zero in IRS-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 in IRS-2-/- mice depends upon genetic background, suggesting the existence of modifier gene(s) for diabetes in mice of the 129/Sv genetic strain.
AB - Although we and others have generated IRS-2 knock-out (IRS-2-/-) mice, significant differences were seen between the two lines of IRS-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 C57B1/6 background) with our IRS-2-/- mice (CBA and C57B1/6 background). Intercrosses of IRS-2-/-IRS-3+/- mice yielded nine genotypes, and all of them including IRS-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 the IRS-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. Both IRS-2-/- and IRS-2-/-IRS-3-/- mice had moderately reduced β-cell mass despite having insulin resistance. Insulin-positive β-cells were decreased to nearly zero in IRS-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 in IRS-2-/- mice depends upon genetic background, suggesting the existence of modifier gene(s) for diabetes in mice of the 129/Sv genetic strain.
UR - http://www.scopus.com/inward/record.url?scp=0038529802&partnerID=8YFLogxK
U2 - 10.1074/jbc.M211045200
DO - 10.1074/jbc.M211045200
M3 - 学術論文
C2 - 12493745
AN - SCOPUS:0038529802
SN - 0021-9258
VL - 278
SP - 14284
EP - 14290
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 16
ER -
