Mouse Genome Informatics
hm
    Irs2tm1Tka/Irs2tm1Tka
involves: C57BL/6 * CBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
cellular
• upon induction of adipocyte differentiation, the ability of mutant embryonic fibroblasts to differentiate into adipocytes is ~15% lower than that of wild-type cells

growth/size
N
• homozygotes display normal birth size and body weight relative to wild-type mice (J:65485)

homeostasis/metabolism
• at 8 weeks, Irs2tm1Tka homozygotes display greater vascular neointima formation than Irs1tm1Tka homozygotes and wild-type mice in response to vessel injury after cuff placement around the femoral artery
• at 20 weeks, Irs2tm1Tka homozygotes exhibit type 2 diabetes and show greater vascular neointima formation than Irs1tm1Tka homozygotes, which show more enhanced neointima formation than wild-type mice; at this age, Irs1tm1Tka homozygotes are not diabetic
• despite decreased beta-cell mass, individual beta-cells from homozygotes display increased glucose-induced insulin secretion in vitro; insulin content per islet remains normal
• at 20 weeks, Irs2tm1Tka homozygotes exhibit higher fasting blood glucose levels than Irs1tm1Tka homozygotes or wild-type mice, indicating development of type 2 diabetes
• as early as 6 weeks of age, homozygotes display higher plasma insulin levels than wild-type mice both before and after a glucose load
• at 20 weeks, female homozygotes display reduced fasting plasma insulin levels relative to male homozygotes
• at 8 and 20 weeks, Irs2tm1Tka homozygotes exhibit higher fasting plasma total cholesterol levels than Irs1tm1Tka homozygotes or wild-type mice
• at 8 and 20 weeks, Irs2tm1Tka homozygotes exhibit higher fasting plasma HDL levels than Irs1tm1Tka homozygotes or wild-type mice
• at 8 weeks, Irs2tm1Tka homozygotes exhibit significantly higher fasting plasma free fatty acid levels than wild-type mice but do not differ significantly from Irs1tm1Tka homozygotes
• no significant differences are detected among Irs1tm1Tka , Irs2tm1Tka and wild-type mice at 20 weeks
• at 8 and 20 weeks, homozygotes display significantly higher fasting plasma triglyceride levels than wild-type mice
• in >10-week-old homozygotes, blood glucose levels both before and after a glucose load become gradually higher than wild-type levels and fail to descend with age; no significant differences are noted at 6 weeks
• at 20 weeks of age, female homozygotes maintain a minimally impaired glucose tolerance
• as early as 6 weeks of age, homozygotes display insulin resistance (J:65485)
• insulin resistance appears to be associated with a defect in the insulin-stimulated signaling pathway in liver but not in skeletal muscle (J:65485)
• homozygotes progressively develop type II diabetes at 10 weeks of age (J:65485)
• at 8 and 20 weeks, homozygotes exhibit significantly higher fasting plasma insulin levels than wild-type mice (J:99746)

endocrine/exocrine glands
• homozygotes fail to show compensatory hyperplasia of pancreatic beta-cells in response to insulin resistance and become diabetic
• at 6 weeks, the beta-cell mass of homozygotes is reduced to 83% of wild-type beta-cell mass
• at 12 weeks, the beta-cell mass of homozygotes is reduced to 51% of wild-type beta-cell mass; in contrast, non-beta-cell mass remains unaffected
• despite decreased beta-cell mass, individual beta-cells from homozygotes display increased glucose-induced insulin secretion in vitro; insulin content per islet remains normal

cardiovascular system
• at 20 weeks (but NOT at 8 weeks), homozygotes show significantly impaired endothelium-dependent vascular relaxation in response to acetylcholine relative to Irs1tm1Tka homozygotes or wild-type mice
• at 8 weeks, Irs2tm1Tka homozygotes display greater vascular neointima formation than Irs1tm1Tka homozygotes and wild-type mice in response to vessel injury after cuff placement around the femoral artery
• at 20 weeks, Irs2tm1Tka homozygotes exhibit type 2 diabetes and show greater vascular neointima formation than Irs1tm1Tka homozygotes, which show more enhanced neointima formation than wild-type mice; at this age, Irs1tm1Tka homozygotes are not diabetic
• at 8 and 20 weeks, homozygotes exhibit significantly higher systolic blood pressure than wild-type mice; in contrast, pulse rates do not differ significantly

muscle
• at 20 weeks (but NOT at 8 weeks), homozygotes show significantly impaired endothelium-dependent vascular relaxation in response to acetylcholine relative to Irs1tm1Tka homozygotes or wild-type mice

Mouse Models of Human Disease
OMIM IDRef(s)
Diabetes Mellitus, Noninsulin-Dependent; NIDDM 125853 J:65485