Phenotypes associated with this allele

• Allele Symbol: Irs1^tm1Tka
• Allele Name: targeted mutation 1, Takashi Kadowaki
• Allele ID: MGI:2136643
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Irs1^tm1Tka/Irs1^tm1Tka	involves: C57BL/6 * CBA	MGI:3583343
hm2	Irs1^tm1Tka/Irs1^tm1Tka	Not Specified	MGI:2174965
cx3	Gck^tm1Tka/Gck^+ Irs1^tm1Tka/Irs1^tm1Tka	involves: 129X1/SvJ * C57BL/6 * CBA * ICR	MGI:3583687
cx4	Irs1^tm1Tka/Irs1^tm1Tka Irs2^tm1Tka/Irs2^tm1Tka	involves: C57BL/6 * CBA	MGI:3583345

Genotype
MGI:3583343

hm1

• Allelic Composition: Irs1^tm1Tka/Irs1^tm1Tka
• Genetic Background: involves: C57BL/6 * CBA

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

limbs/digits/tail

short femur ( J:61479 )

• at 8 weeks, mutant femur length is reduced by ~20% relative to wild-type

short tibia ( J:61479 )

• at 8 weeks, mutant tibial length is reduced by ~20% relative to wild-type

skeleton

abnormal osteoclast differentiation ( J:61479 )

• in a coculture system of bone marrow cells and primary osteoblasts, homozygotes show reduced differentiation of mutant osteoclasts

abnormal osteoblast physiology ( J:61479 )

• mutant osteoblasts exhibit neither phosphorylation of cellular proteins nor IRS1 induced by IGF1 or insulin

• in culture, osteoblasts from neonatal calvariae of homozygotes fail to show stimulation of proliferation and differentiation by IGF-I or insulin

abnormal osteoclast physiology ( J:61479 )

• homozygotes exhibit a significant decrease (~50-60%) in bone resorption parameters

• reduced bone resorption is caused by a defect in osteoblasts to support osteoclast differentiation rather than intrinsic abnormalities of osteoclast progenitors or reduced activity/survival of mature osteoclasts

abnormal bone healing ( J:89532 )

• after tibial fracture, homozygotes show neither callus formation nor bridging between fracture stumps at the early healing stage

• at 3 weeks after fracture, homozygotes show impaired fracture healing: only 3 of 15 homozygotes show bone union with reduced soft callus size and density whereas the remaining 12 mutants exhibit an atrophic fracture site with no bone union even at 10 weeks

• injection of an adenovirus vector carrying the human IRS1 gene to the fracture site restores bone union at 3 weeks after injection

short femur ( J:61479 )

• at 8 weeks, mutant femur length is reduced by ~20% relative to wild-type

short tibia ( J:61479 )

• at 8 weeks, mutant tibial length is reduced by ~20% relative to wild-type

abnormal long bone epiphyseal plate proliferative zone ( J:89532 )

• after tibial fracture, reduced callus formation at the mutant fracture site is associated with reduced chondrocyte proliferation

abnormal long bone hypertrophic chondrocyte zone ( J:89532 )

• after tibial fracture, reduced callus formation at the mutant fracture site is associated with increased hypertrophic differentiation and apoptosis

decreased long bone epiphyseal plate size ( J:61479 )

• homozygotes show a moderate decrease in thickness of the growth plate at the proximal tibiae relative to wild-type mice

decreased bone mineral content ( J:89532 )

• after tibial fracture, homozygotes exhibit reduced callus area and bone mineral content (BMC) at the early stage of healing indicating impaired bone modeling

• injection of an adenovirus vector carrying the human IRS1 gene to the fracture site restores the callus area at 1 and 3 weeks, and the callus BMC at 3 weeks after injection

decreased bone mineral density ( J:61479 )

• homozygotes exhibit severe osteopenia in long bones (femur and tibia) and in vertebral bodies

• at 4, 8, 12, and 16 weeks of age, the bone mineral density of mutant whole femora and tibiae is reduced by >30% relative to wild-type; trabecular and cortex bones are equally affected

• in homozygotes, the pathophysiology of osteopenia is similar to that in low-turnover osteoporosis in aged humans

decreased bone mineral density of femur ( J:61479 )

• at 4, 8, 12, and 16 weeks of age, the bone mineral density of mutant whole femora is reduced by >30% relative to wild-type; trabecular and cortex bones are equally affected

decreased compact bone thickness ( J:61479 )

• in mutant tibiae, cortical thickness is reduced by 45% relative to wild-type

decreased osteoblast cell number ( J:61479 )

• homozygotes exhibit a significant decrease (~70-85%) in bone formation parameters

abnormal trabecular bone morphology ( J:61479 )

• proximal tibiae of 8-week-old homozygotes display reduced trabecular bones, osteoid surface, and TRAP-positive osteoclasts

• in mutant tibiae, trabecular thickness is reduced by 51% relative to wild-type

decreased chondrocyte number ( J:61479 )

• mutant chondrocytes of various differentiation stages are arranged regularly in a cartilaginous column; however, the number of columns and that of chondrocytes per column are reduced by ~20% and 30%, respectively

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:61479 )

N • at 8 weeks, homozygotes display normal serum IGF1 and IGF2 levels relative to wild-type mice

abnormal vascular wound healing ( J:99746 )

• homozygotes fail to exhibit greater neointima formation than wild-type mice at 8 weeks but do show greater neointima formation at 20 weeks after cuff placement around the femoral artery

• at 20 weeks, Irs1^tm1Tka homozygotes are non-diabetic and show reduced neointima formation relative to Irs2^tm1Tka homozygotes

decreased insulin secretion ( J:65485 )

• despite increased beta-cell mass, individual beta-cells from homozygotes display decreased glucose-induced insulin secretion in vitro

• insulin content per islet is also decreased relative to wild-type content

increased circulating insulin level ( J:61479 )

• at 8 weeks, serum insulin levels are significantly higher in homozygotes than in wild-type littermates both before and after glucose load

insulin resistance ( J:99746 )

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

abnormal lipid level ( J:47029 )

• at 6-12 months, homozygous females exhibit reduced lipoprotein lipase activity in postheparin plasma as well as in adipose tisse, leading to decreased hydrolysis of lipoprotein triglycerides

decreased circulating HDL cholesterol level ( J:47029 )

• at 6-12 months, homozygous females show a significant decrease in plasma HDL cholesterol levels relative to wild-type

increased circulating free fatty acids level ( J:99746 )

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

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

increased circulating triglyceride level ( J:47029 , J:99746 )

• homozygous females display a significant increase in fasting plasma triglyceride levels relative to wild-type (1.6-fold at 2-3 months; 1.7-fold at 4-5 months) (J:47029)

• in contrast, fasting plasma cholesterol and free fatty acid levels remain unaffected (J:47029)

• at 8 and 20 weeks, homozygotes display significantly higher fasting plasma triglyceride levels than wild-type mice (J:99746)

impaired lipolysis ( J:47029 )

• in homozygous females, impaired lipolysis is associated with a greater increase in plasma triglyceride levels after fat loading relative to wild-type mice

abnormal bone healing ( J:89532 )

• after tibial fracture, homozygotes show neither callus formation nor bridging between fracture stumps at the early healing stage

• at 3 weeks after fracture, homozygotes show impaired fracture healing: only 3 of 15 homozygotes show bone union with reduced soft callus size and density whereas the remaining 12 mutants exhibit an atrophic fracture site with no bone union even at 10 weeks

• injection of an adenovirus vector carrying the human IRS1 gene to the fracture site restores bone union at 3 weeks after injection

endocrine/exocrine glands

decreased insulin secretion ( J:65485 )

• despite increased beta-cell mass, individual beta-cells from homozygotes display decreased glucose-induced insulin secretion in vitro

• insulin content per islet is also decreased relative to wild-type content

cellular

abnormal cell differentiation ( J:68004 )

• upon induction of adipocyte differentiation, the ability of mutant embryonic fibroblasts to differentiate into adipocytes is ~60% lower than that of wild-type cells

abnormal osteoclast differentiation ( J:61479 )

• in a coculture system of bone marrow cells and primary osteoblasts, homozygotes show reduced differentiation of mutant osteoclasts

decreased cell proliferation ( J:89532 )

• in culture, primary chondrocytes isolated from mutant growth plates display impaired mitogenic ability and Akt phosphorylation relative to wild-type chondrocytes; the reduction in chondrocyte proliferation is enhanced in the presence of IGF1

• addition of an Akt inhibitor reduces IGF1-stimulated DNA synthesis of chondrocytes more potently in wild-type than in mutant cell cultures

abnormal osteoblast physiology ( J:61479 )

• mutant osteoblasts exhibit neither phosphorylation of cellular proteins nor IRS1 induced by IGF1 or insulin

• in culture, osteoblasts from neonatal calvariae of homozygotes fail to show stimulation of proliferation and differentiation by IGF-I or insulin

growth/size/body

decreased body weight ( J:47029 )

• female homozygotes weigh significantly less than wild-type females; however, their mesenteric fat mass remains unchanged

cardiovascular system

hypertension ( J:47029 )

• under unrestrained conditions, 58 month-old homozygous females display significantly higher mean arterial blood pressure relative to wild-type mice (11012 mmHg vs 9910 mmHg)

• at 56 months, hypertension is associated with impaired acetylcholine-induced (endothelium-dependent) vascular relaxation in aortic rings

increased systemic arterial diastolic blood pressure ( J:47029 )

• under unrestrained conditions, 58 month-old homozygous females display significantly higher diastolic blood pressure relative to wild-type

increased systemic arterial systolic blood pressure ( J:47029 , J:99746 )

• under both restrained and unrestrained conditions, 58 month-old homozygous females display significantly higher systolic arterial blood pressure relative to wild-type (J:47029)

• at 8 and 20 weeks, homozygotes exhibit significantly higher systolic blood pressure than wild-type mice; in contrast, pulse rates do not differ significantly (J:99746)

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 wild-type mice

abnormal vascular wound healing ( J:99746 )

• homozygotes fail to exhibit greater neointima formation than wild-type mice at 8 weeks but do show greater neointima formation at 20 weeks after cuff placement around the femoral artery

• at 20 weeks, Irs1^tm1Tka homozygotes are non-diabetic and show reduced neointima formation relative to Irs2^tm1Tka homozygotes

immune system

abnormal osteoclast differentiation ( J:61479 )

• in a coculture system of bone marrow cells and primary osteoblasts, homozygotes show reduced differentiation of mutant osteoclasts

abnormal osteoclast physiology ( J:61479 )

• homozygotes exhibit a significant decrease (~50-60%) in bone resorption parameters

• reduced bone resorption is caused by a defect in osteoblasts to support osteoclast differentiation rather than intrinsic abnormalities of osteoclast progenitors or reduced activity/survival of mature osteoclasts

hematopoietic system

abnormal osteoclast differentiation ( J:61479 )

• in a coculture system of bone marrow cells and primary osteoblasts, homozygotes show reduced differentiation of mutant osteoclasts

abnormal osteoclast physiology ( J:61479 )

• homozygotes exhibit a significant decrease (~50-60%) in bone resorption parameters

• reduced bone resorption is caused by a defect in osteoblasts to support osteoclast differentiation rather than intrinsic abnormalities of osteoclast progenitors or reduced activity/survival of mature osteoclasts

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 wild-type mice

Genotype
MGI:2174965

hm2

• Allelic Composition: Irs1^tm1Tka/Irs1^tm1Tka
• Genetic Background: Not Specified

growth/size/body

abnormal postnatal growth/weight/body size ( J:21373 )

decreased body weight ( J:21373 )

• at 3, 8, and 15 weeks, the weights of homozygotes are ~30% less than those of wild-type or heterozygous littermates

postnatal growth retardation ( J:21373 )

• homozygotes are viable and fertile but exhibit a growth retardation at 3, 8, and 15 weeks of age

decreased fetal weight ( J:21373 )

• at E18.5, the weights of homozygotes are ~80% of those of wild-type or heterozygous controls

fetal growth retardation ( J:21373 )

• at E15.5, homozygotes display growth retardation relative to wild-type controls

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:21373 )

N • homozygotes display normal serum IGF1, IGF2 and growth hormone levels relative to wild-type mice

abnormal glucose homeostasis ( J:21373 )

• homozygotes maintain normal fasting glucose and glucose tolerance (by compensatory beta-cell hyperplasia)

• homozygotes exhibit a higher basal glucose transport of adipocytes relative to wild-type mice; in contrast, insulin-stimulated glucose transport of mutant adipocytes is significantly impaired

increased circulating insulin level ( J:21373 )

• the serum insulin levels of homozygotes before and after glucose load are significantly higher than those of wild-type and heterozygous mutant mice

insulin resistance ( J:21373 )

• homozygotes exhibit a mild to moderate insulin, IGF1, and IGF2 resistance

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:21373

Genotype
MGI:3583687

cx3

• Allelic Composition: Gck^tm1Tka/Gck⁺; Irs1^tm1Tka/Irs1^tm1Tka
• Genetic Background: involves: 129X1/SvJ * C57BL/6 * CBA * ICR

growth/size/body

decreased body weight ( J:38899 )

• these mice exhibit a body weight that is ~70% of that of wild-type mice throughout life

postnatal growth retardation ( J:38899 )

• these mutants display a similar degree of growth retardation as Irs1^tm1Tka homozygous mutant mice

homeostasis/metabolism

increased circulating insulin level ( J:38899 )

• these mutants exhibit higher, although not statistically significant, fasting insulin levels (148% of wild-type levels)

impaired glucose tolerance ( J:38899 )

• at 15 weeks of age, these mutants display a similar degree of glucose intolerance to Gck^tm1Tka heterozygotes

• however, at 30-40 weeks, these mutants exhibit a "diabetic" glucose tolerance i.e. an exacerbated glucose intolerance relative to Gck^tm1Tka heterozygotes of the same genetic background

insulin resistance ( J:38899 )

• these mutants exhibit insulin resistance relative to Gck^tm1Tka heterozygotes of the same genetic background

endocrine/exocrine glands

increased pancreatic beta cell mass ( J:38899 )

• in these mutants, beta-cell mass per pancreas is 216% of wild-type in terms of area

• in contrast, the non-beta (i.e. alpha and delta) cell mass remains unchanged relative to wild-type

pancreatic islet hyperplasia ( J:38899 )

• a portion of pancreatic islets from these mutant mice appear enlarged due to beta-cell hyperplasia

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:38899

Genotype
MGI:3583345

cx4

• Allelic Composition: Irs1^tm1Tka/Irs1^tm1Tka; Irs2^tm1Tka/Irs2^tm1Tka
• Genetic Background: involves: C57BL/6 * CBA

adipose tissue

decreased white adipose tissue amount ( J:68004 )

• at 8 hours after birth, double homozygotes show a severe reduction in white adipose tissue mass relative to wild-type newborns

• in contrast, brown adipose tissue mass remains unaffected

cellular

abnormal cell differentiation ( J:68004 )

• surprisingly, embryonic fibroblasts from double homozygotes are completely unable to differentiate into adipocytes upon in vitro induction of adipocyte differentiation