title: Impact of genetic background and ablation of insulin receptor substrate (IRS)-3 on IRS-2 knock-out mice.
abstract: 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 beta-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 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 beta-cell mass despite having insulin resistance. Insulin-positive beta-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.
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
authors.forename: Junji
authors.initials: J
authors.lastname: Matsui
authors.forename: Ryo
authors.initials: R
authors.lastname: Suzuki
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.forename: Kajuro
authors.initials: K
authors.lastname: Komeda
authors.forename: Shinichi
authors.initials: S
authors.lastname: Aizawa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Eto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kimura
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tobe
authors.forename: Gustav E
authors.initials: GE
authors.lastname: Lienhard
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003433:Crosses, Genetic; D003920:Diabetes Mellitus / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; D006943:Hyperglycemia / Q000235:genetics; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics* / Q000502:physiology; D013045:Species Specificity; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; C108872:Irs3 protein, mouse; D009004:Monosaccharide Transport Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D005947:Glucose