Phenotypes Associated with This Genotype

Genotype
MGI:3583344

• Allelic Composition: Irs2^tm1Tka/Irs2^tm1Tka
• Genetic Background: involves: C57BL/6 * CBA

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

cellular

abnormal cell differentiation ( J:68004 )

• 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/body

growth/size/body region phenotype ( J:65485 )

N • homozygotes display normal birth size and body weight relative to wild-type mice

homeostasis/metabolism

abnormal vascular wound healing ( J:99746 )

• at 8 weeks, Irs2^tm1Tka homozygotes display greater vascular neointima formation than Irs1^tm1Tka homozygotes and wild-type mice in response to vessel injury after cuff placement around the femoral artery

• at 20 weeks, Irs2^tm1Tka homozygotes exhibit type 2 diabetes and show greater vascular neointima formation than Irs1^tm1Tka homozygotes, which show more enhanced neointima formation than wild-type mice; at this age, Irs1^tm1Tka homozygotes are not diabetic

increased insulin secretion ( J:65485 )

• despite decreased beta-cell mass, individual beta-cells from homozygotes display increased glucose-induced insulin secretion in vitro; insulin content per islet remains normal

hyperglycemia ( J:99746 )

• at 20 weeks, Irs2^tm1Tka homozygotes exhibit higher fasting blood glucose levels than Irs1^tm1Tka homozygotes or wild-type mice, indicating development of type 2 diabetes

increased circulating insulin level ( J:65485 )

• 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

increased circulating cholesterol level ( J:99746 )

• at 8 and 20 weeks, Irs2^tm1Tka homozygotes exhibit higher fasting plasma total cholesterol levels than Irs1^tm1Tka homozygotes or wild-type mice

increased circulating HDL cholesterol level ( J:99746 )

• at 8 and 20 weeks, Irs2^tm1Tka homozygotes exhibit higher fasting plasma HDL levels than Irs1^tm1Tka homozygotes or wild-type mice

increased circulating free fatty acids level ( J:99746 )

• at 8 weeks, Irs2^tm1Tka homozygotes exhibit significantly higher fasting plasma free fatty acid levels than wild-type mice but do not differ significantly from Irs1^tm1Tka homozygotes

• no significant differences are detected among Irs1^tm1Tka , Irs2^tm1Tka and wild-type mice at 20 weeks

increased circulating triglyceride level ( J:99746 )

• at 8 and 20 weeks, homozygotes display significantly higher fasting plasma triglyceride levels than wild-type mice

impaired glucose tolerance ( J:65485 )

• 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

insulin resistance ( J:65485 , J:99746 )

• 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

abnormal pancreatic beta cell morphology ( J:65485 )

• homozygotes fail to show compensatory hyperplasia of pancreatic beta-cells in response to insulin resistance and become diabetic

decreased pancreatic beta cell mass ( J:65485 )

• 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

increased insulin secretion ( J:65485 )

• 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

increased systemic arterial systolic blood pressure ( J:99746 )

• at 8 and 20 weeks, homozygotes exhibit significantly higher systolic blood pressure than wild-type mice; in contrast, pulse rates do not differ significantly

decreased vasodilation ( J:99746 )

• at 20 weeks (but NOT at 8 weeks), homozygotes show significantly impaired endothelium-dependent vascular relaxation in response to acetylcholine relative to Irs1^tm1Tka homozygotes or wild-type mice

abnormal vascular wound healing ( J:99746 )

• at 8 weeks, Irs2^tm1Tka homozygotes display greater vascular neointima formation than Irs1^tm1Tka homozygotes and wild-type mice in response to vessel injury after cuff placement around the femoral artery

• at 20 weeks, Irs2^tm1Tka homozygotes exhibit type 2 diabetes and show greater vascular neointima formation than Irs1^tm1Tka homozygotes, which show more enhanced neointima formation than wild-type mice; at this age, Irs1^tm1Tka homozygotes are not diabetic

muscle

decreased vasodilation ( J:99746 )

• at 20 weeks (but NOT at 8 weeks), homozygotes show significantly impaired endothelium-dependent vascular relaxation in response to acetylcholine relative to Irs1^tm1Tka homozygotes or wild-type mice

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
type 2 diabetes mellitus		DOID:9352	OMIM:125853 OMIM:601283 OMIM:601407 OMIM:603694 OMIM:608036	J:65485