Mouse Genome Informatics
hm1
    Irs1tm1Tka/Irs1tm1Tka
involves: C57BL/6 * CBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
limbs/digits/tail
• at 8 weeks, mutant femur length is reduced by ~20% relative to wild-type
• at 8 weeks, mutant tibial length is reduced by ~20% relative to wild-type

skeleton
• in a coculture system of bone marrow cells and primary osteoblasts, homozygotes show reduced differentiation of mutant osteoclasts
• 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
• 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
• at 8 weeks, mutant femur length is reduced by ~20% relative to wild-type
• at 8 weeks, mutant tibial length is reduced by ~20% relative to wild-type
• after tibial fracture, reduced callus formation at the mutant fracture site is associated with reduced chondrocyte proliferation
• after tibial fracture, reduced callus formation at the mutant fracture site is associated with increased hypertrophic differentiation and apoptosis
• homozygotes show a moderate decrease in thickness of the growth plate at the proximal tibiae relative to wild-type mice
• 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
• 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
• in mutant tibiae, cortical thickness is reduced by 45% relative to wild-type
• homozygotes exhibit a significant decrease (~70-85%) in bone formation parameters
• 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
• 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
• 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

homeostasis/metabolism
N
• at 8 weeks, homozygotes display normal serum IGF1 and IGF2 levels relative to wild-type mice (J:61479)
• 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, Irs1tm1Tka homozygotes are non-diabetic and show reduced neointima formation relative to Irs2tm1Tka homozygotes
• 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
• at 8 weeks, serum insulin levels are significantly higher in homozygotes than in wild-type littermates both before and after glucose load
• at 8 and 20 weeks, homozygotes exhibit significantly higher fasting plasma insulin levels than wild-type mice
• 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
• at 6-12 months, homozygous females show a significant decrease in plasma HDL cholesterol levels relative to wild-type
• at 8 weeks, Irs1tm1Tka homozygotes exhibit significantly higher fasting plasma free fatty acid levels than wild-type mice but do not differ significantly from Irs2tm1Tka homozygotes
• no significant differences are detected among Irs1tm1Tka, Irs2tm1Tka and wild-type mice at 20 weeks
• 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)
• in homozygous females, impaired lipolysis is associated with a greater increase in plasma triglyceride levels after fat loading relative to wild-type mice
• 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
• 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
• upon induction of adipocyte differentiation, the ability of mutant embryonic fibroblasts to differentiate into adipocytes is ~60% lower than that of wild-type cells
• in a coculture system of bone marrow cells and primary osteoblasts, homozygotes show reduced differentiation of mutant osteoclasts
• 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

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

cardiovascular system
• 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
• 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, Irs1tm1Tka homozygotes are non-diabetic and show reduced neointima formation relative to Irs2tm1Tka homozygotes
• 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
• under unrestrained conditions, 58 month-old homozygous females display significantly higher diastolic blood pressure relative to wild-type
• 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)

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


Mouse Genome Informatics
hm2
    Irs1tm1Tka/Irs1tm1Tka
Not Specified
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size
• at 3, 8, and 15 weeks, the weights of homozygotes are ~30% less than those of wild-type or heterozygous littermates
• homozygotes are viable and fertile but exhibit a growth retardation at 3, 8, and 15 weeks of age
• at E18.5, the weights of homozygotes are ~80% of those of wild-type or heterozygous controls
• at E15.5, homozygotes display growth retardation relative to wild-type controls

homeostasis/metabolism
N
• homozygotes display normal serum IGF1, IGF2 and growth hormone levels relative to wild-type mice (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
• the serum insulin levels of homozygotes before and after glucose load are significantly higher than those of wild-type and heterozygous mutant mice
• homozygotes exhibit a mild to moderate insulin, IGF1, and IGF2 resistance

Mouse Models of Human Disease
OMIM IDRef(s)
Diabetes Mellitus, Noninsulin-Dependent; NIDDM 125853 J:21373


Mouse Genome Informatics
cx3
    Gcktm1Tka/Gck+
Irs1tm1Tka/Irs1tm1Tka

involves: 129X1/SvJ * C57BL/6 * CBA * ICR
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size
• these mice exhibit a body weight that is ~70% of that of wild-type mice throughout life
• these mutants display a similar degree of growth retardation as Irs1tm1Tka homozygous mutant mice

homeostasis/metabolism
• these mutants exhibit higher, although not statistically significant, fasting insulin levels (148% of wild-type levels)
• at 15 weeks of age, these mutants display a similar degree of glucose intolerance to Gcktm1Tka heterozygotes
• however, at 30-40 weeks, these mutants exhibit a "diabetic" glucose tolerance i.e. an exacerbated glucose intolerance relative to Gcktm1Tka heterozygotes of the same genetic background
• these mutants exhibit insulin resistance relative to Gcktm1Tka heterozygotes of the same genetic background

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

Mouse Models of Human Disease
OMIM IDRef(s)
Diabetes Mellitus, Noninsulin-Dependent; NIDDM 125853 J:38899


Mouse Genome Informatics
cx4
    Irs1tm1Tka/Irs1tm1Tka
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
adipose tissue
• 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
• surprisingly, embryonic fibroblasts from double homozygotes are completely unable to differentiate into adipocytes upon in vitro induction of adipocyte differentiation