Impact of Genetic Background and Ablation of Insulin Receptor Substrate (IRS)-3 on IRS-2 Knock-out Mice

• Published in: The Journal of biological chemistry Vol. 278; no. 16; pp. 14284 - 14290
• Main Authors: Terauchi, Yasuo, Matsui, Junji, Suzuki, Ryo, Kubota, Naoto, Komeda, Kajuro, Aizawa, Shinichi, Eto, Kazuhiro, Kimura, Satoshi, Nagai, Ryozo, Tobe, Kazuyuki, Lienhard, Gustav E., Kadowaki, Takashi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.04.2003; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Blood Glucose - metabolism; Crosses, Genetic; Diabetes Mellitus - genetics; Dose-Response Relationship, Drug; Female; Genotype; Glucose - metabolism; Glucose Transporter Type 2; Homeodomain Proteins; Hyperglycemia - genetics; Immunohistochemistry; Insulin - metabolism; Insulin Receptor Substrate Proteins; Intracellular Signaling Peptides and Proteins; Islets of Langerhans - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Monosaccharide Transport Proteins - metabolism; Mutation; Phosphoproteins - genetics; Phosphoproteins - physiology; Species Specificity; Time Factors; Trans-Activators - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M211045200

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.