Phenotypes associated with this allele

• Allele Symbol: Irs1^tm1Jos
• Allele Name: targeted mutation 1, Joslin Diabetes Center
• Allele ID: MGI:2136455
• Summary: 5 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Irs1^tm1Jos/Irs1^tm1Jos	involves: 129S2/SvPas * C57BL/6	MGI:2174963
cn2	Irs1^tm1Jos/Irs1^+ Irs2^tm2Mfw/Irs2^tm2Mfw Tg(Ins2-cre)25Mgn/0	involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:3510670
cx3	Irs1^tm1Jos/Irs1^tm1Jos Irs3^tm1Lhd/Irs3^tm1Lhd	involves: 129S2/SvPas * 129S4/SvJae * C57BL/6	MGI:3583264
cx4	Irs1^tm1Jos/Irs1^tm1Jos Irs4^tm1Lhd/Y	involves: 129S2/SvPas * 129S4/SvJae * C57BL/6	MGI:3583265
cx5	Irs1^tm1Jos/Irs1^tm1Jos Irs4^tm1Lhd/Irs4^tm1Lhd	involves: 129S2/SvPas * 129S4/SvJae * C57BL/6	MGI:3583266

Genotype
MGI:2174963

hm1

• Allelic Composition: Irs1^tm1Jos/Irs1^tm1Jos
• Genetic Background: involves: 129S2/SvPas * C57BL/6

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

growth/size/body

decreased birth weight ( J:21374 )

• at birth, the body weights of homozygotes are 40-60% of those found in wild-type or heterozygous mutant littermates

decreased body size ( J:21374 )

• homozygotes are viable, fertile, and nurse successfully but grow in proportion to a smaller body size relative to wild-type mice

decreased body weight ( J:21374 )

• up to 4 months of age, the body weights of homozygotes are 50-60% of those found in wild-type littermates

postnatal growth retardation ( J:80976 )

homeostasis/metabolism

increased circulating insulin level ( J:21374 )

• in homozygotes, fasting plasma insulin levels are elevated 2.3-fold relative to wild-type levels

impaired glucose tolerance ( J:21374 )

• homozygotes have normal fasting glucose levels but exhibit a mild impairment in glucose tolerance

insulin resistance ( J:21374 )

• homozygotes exhibit a mild insulin and insulin-like growth factor-1 (IGF1) resistance

• the hypoglycemic response to insulin and IGF1 is significantly attenuated concomitant with a significant reduction in insulin-stimulated glucose transport in isolated adipocytes

skeleton

skeleton phenotype ( J:21374 )

N • homozygotes display normal ossification of long bones relative to wild-type mice

vision/eye

vision/eye phenotype ( J:98107 )

N • mice show no changes in the retina

Genotype
MGI:3510670

cn2

• Allelic Composition: Irs1^tm1Jos/Irs1⁺; Irs2^tm2Mfw/Irs2^tm2Mfw; Tg(Ins2-cre)25Mgn/0
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6

endocrine/exocrine glands

abnormal pancreatic beta cell morphology ( J:93415 )

• at 6 months beta cell content is decreased 8-fold

growth/size/body

decreased body weight ( J:93415 )

homeostasis/metabolism

hyperglycemia ( J:93415 )

• diabetes and progressive severe hyperglycemia are seen starting at 4 weeks of age

decreased circulating insulin level ( J:93415 )

• severe, progressive hypoinsulinemia is seen

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:93415

Genotype
MGI:3583264

cx3

• Allelic Composition: Irs1^tm1Jos/Irs1^tm1Jos; Irs3^tm1Lhd/Irs3^tm1Lhd
• Genetic Background: involves: 129S2/SvPas * 129S4/SvJae * C57BL/6

mortality/aging

mortality/aging ( J:80976 )

N • double mutant progeny are obtained at about half the expected frequency (3.4% vs. 6.25%), suggesting increased prenatal and/or early postnatal lethality

growth/size/body

postnatal growth retardation ( J:80976 )

• double homozygous males and females show severe growth retardation throughout life relative to wild-type mice

homeostasis/metabolism

hyperglycemia ( J:80976 )

• as early as 5 weeks, double homozygotes show increased blood glucose levels in both the fasted and the fed states

• notably, injection of leptin adenovirus leads to normalization of blood glucose levels in double mutant but not in wild-type mice

increased circulating insulin level ( J:80976 )

• as early as 5 weeks, double homozygotes show increased plasma insulin levels in both the fasted and fed states

• notably, injection of leptin adenovirus leads to normalization of plasma insulin levels in double mutant but not in wild-type mice

decreased circulating leptin level ( J:80976 )

• in 2-month-old double homozygotes, fed plasma leptin levels are reduced relative to wild-type and single mutant mice; fasted plasma leptin levels are also reduced, albeit to a lesser extent than in the fed state

decreased circulating free fatty acids level ( J:80976 )

• at 2 months, fasted plasma free fatty acid levels are significantly reduced in both male and female double homozygotes relative to wild-type mice, and in double homozygous males relative to Irs1^tm1Jos and Irs3^tm1Lhd mice

impaired glucose tolerance ( J:80976 )

• at 6 weeks, double homozygous males exhibit significant glucose intolerance

insulin resistance ( J:80976 )

• at 6 weeks, double homozygous males exhibit severe insulin resistance

decreased triglyceride level ( J:80976 )

• in double homozygous males, whole-body triglyceride content is reduced by ~75%, ~45%, and ~70% relative to wild-type, Irs1^tm1Jos, and Irs3^tm1Lhd mice, respectively

decreased circulating triglyceride level ( J:80976 )

• at 2 months, fasted plasma triglyceride levels are markedly reduced in both male and female double homozygotes relative to wild-type and Irs3^tm1Lhd mice, and in double homozygous females relative to Irs1^tm1Jos mice

• although double mutant livers tend to contain less triglycerides than wild-type livers, this difference is statistically insignificant; skeletal muscle triglyceride content remains normal

adipose tissue

decreased white adipose tissue amount ( J:80976 )

• in double homozygotes, perigonadal (white) fat pad mass is decreased by ~95%, ~80%, and ~85% relative to wild-type, Irs1^tm1Jos, and Irs3^tm1Lhd mice, respectively

• in contrast, the interscapular brown fat pad appears unaffected with respect to color and size

• notably, injection of leptin adenovirus leads to a further reduction in white adipose tissue mass (reduced perigonadal fat pads); no significant body weight changes are observed

abnormal gonadal fat pad morphology ( J:80976 )

• double homozygotes exhibit reduced adipocyte size of perigonadal fat pads relative to wild-type, Irs1^tm1Jos and Irs3^tm1Lhd mice

endocrine/exocrine glands

increased pancreatic beta cell mass ( J:80976 )

• double homozygotes exhibit an increase in pancreatic beta-cell mass

pancreatic islet hyperplasia ( J:80976 )

• both male and female double homozygotes display severe islet (beta-cell) hyperplasia, with a 4.3-fold increase relative wild-type and Irs3^tm1Lhd mice, and a 1.9-fold increase relative to Irs1^tm1Jos mice

• notably, the mass and distribution of non-beta-cells is similar between the various groups of mice

liver/biliary system

liver/biliary system phenotype ( J:80976 )

N • double mutant livers appear normal in color; no increased fat deposition is observed

Genotype
MGI:3583265

cx4

• Allelic Composition: Irs1^tm1Jos/Irs1^tm1Jos; Irs4^tm1Lhd/Y
• Genetic Background: involves: 129S2/SvPas * 129S4/SvJae * C57BL/6

growth/size/body

postnatal growth retardation ( J:80976 )

♂ • these mutant males display no significant differences from Irs1^tm1Jos homozygous males with respect to growth or organ size

homeostasis/metabolism

increased circulating insulin level ( J:80976 )

♂ • at 10-17-weeks, these mutant males show no significant differences from Irs1^tm1Jos homozygous males with respect to fed and fasted plasma insulin levels

impaired glucose tolerance ( J:80976 )

♂ • at 9-12 weeks, double mutant males and Irs1^tm1Jos homozygous males show no significant differences in fed and fasted blood glucose levels; both groups display a comparable (mild) reponse when subjected to glucose tolerance tests

insulin resistance ( J:80976 )

♂ • at 9-12 weeks, double mutant males and Irs1^tm1Jos homozygous males show a comparable (mild) reponse when subjected to insulin tolerance tests

Genotype
MGI:3583266

cx5

• Allelic Composition: Irs1^tm1Jos/Irs1^tm1Jos; Irs4^tm1Lhd/Irs4^tm1Lhd
• Genetic Background: involves: 129S2/SvPas * 129S4/SvJae * C57BL/6

growth/size/body

postnatal growth retardation ( J:80976 )

♀ • double homozygous females display no significant differences from Irs1^tm1Jos homozygous females with respect to growth or organ size

homeostasis/metabolism

increased circulating insulin level ( J:80976 )

♀ • at 10-17-weeks, double homozygous females show no significant differences from Irs1^tm1Jos homozygous females with respect to fed and fasted plasma insulin levels

impaired glucose tolerance ( J:80976 )

♀ • at 9-12 weeks, double mutant females and Irs1^tm1Jos homozygous females show no significant differences in fed and fasted blood glucose levels; both groups display a comparable (mild) reponse when subjected to glucose tolerance tests

insulin resistance ( J:80976 )

♀ • at 9-12 weeks, double mutant females and Irs1^tm1Jos homozygous females show a comparable (mild) reponse when subjected to insulin tolerance tests