Phenotypes associated with this allele

• Allele Symbol: Ins2^Akita
• Allele Name: Akita
• Allele ID: MGI:1857572
• Summary: 25 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Ins2^Akita/Ins2^Akita	C57BL/6-Ins2^Akita	MGI:3583906
hm2	Ins2^Akita/Ins2^Akita	C57BL/6-Ins2^Akita/J	MGI:3625075
hm3	Ins2^Akita/Ins2^Akita	C.B6N-Ins2^Akita	MGI:5508894
hm4	Ins2^Akita/Ins2^Akita	involves: C57BL/6NSlc	MGI:4421500
ht5	Ins2^Akita/Ins2^+	C57BL/6-Ins2^Akita	MGI:3583904
ht6	Ins2^Akita/Ins2^+	C57BL/6-Ins2^Akita/J	MGI:3583907
ht7	Ins2^Akita/Ins2^+	C.B6N-Ins2^Akita	MGI:5508895
ht8	Ins2^Akita/Ins2^+	involves: C3H * C57BL/6NJcl * C57BL/6NSlc	MGI:3583905
ht9	Ins2^Akita/Ins2^+	involves: C57BL/6NSlc	MGI:5510482
cn10	Cebpb^tm1.1Maka/Cebpb^tm1.1Maka Ins2^Akita/Ins2^Akita Tg(Ins2-cre)23Herr/0	involves: 129P2/OlaHsd * C57BL/6J * C57BL/6NSlc * CBA/J	MGI:4421497
cn11	Ins2^Akita/Ins2^Akita Jazf1^tm1c(EUCOMM)Wtsi/Jazf1^tm1c(EUCOMM)Wtsi Tg(Ins2-cre)23Herr/0	involves: 129S4/SvJaeSor * C57BL/6N * C57BL/6NSlc * CBA/J	MGI:6690322
cx12	Bdkrb2^tm1Jfh/Bdkrb2^tm1Jfh Ins2^Akita/Ins2^+	B6.Cg-Ins2^Akita Bdkrb2^tm1Jfh	MGI:3626074
cx13	Ins2^Akita/Ins2^Akita Ldlr^tm1Her/Ldlr^tm1Her	B6.Cg-Ins2^Akita Ldlr^tm1Her	MGI:5286555
cx14	Ins2^Akita/Ins2^+ Or12d17^em1Cya/Or12d17^em1Cya	C57BL/6-Ins2^Akita Or12d17^em1Cya	MGI:7664100
cx15	Ins2^Akita/Ins2^Akita Itga1^tm1Gdnr/Itga1^tm1Gdnr	C.Cg-Ins2^Akita Itga1^tm1Gdnr	MGI:5508896
cx16	Ins2^Akita/Ins2^Akita Rpl13a^tm1.1Jesc/Rpl13a^tm1.1Jesc	FVB.Cg-Rpl13a^tm1.1Jesc Ins2^Akita	MGI:5881940
cx17	Ero1b^Gt(P077G11)Wrst/Ero1b^+ Ins2^Akita/Ins2^+	involves: 129S2/SvPas * C57BL/6NSlc	MGI:4441480
cx18	Gast^tm1(INS)Ez/Gast^+ Ins2^Akita/Ins2^+	involves: 129S4/SvJae * C57BL/6NSlc	MGI:3583903
cx19	Dbm1^A/J/Dbm1^A/J Ins2^Akita/Ins2^+	involves: A/J * C57BL/6J * C57BL/6NSlc	MGI:3664324
cx20	Dbm4^C57BL/6J/? Ins2^Akita/Ins2^+	involves: A/J * C57BL/6J * C57BL/6NSlc	MGI:3664327
cx21	Dbm3^C57BL/6J/? Ins2^Akita/Ins2^+	involves: A/J * C57BL/6J * C57BL/6NSlc	MGI:3664326
cx22	Ins2^Akita/Ins2^+ Rnf213^tm1.1Akoi/Rnf213^tm1.1Akoi	involves: C57BL/6N * C57BL/6NSlc	MGI:5510483
cx23	Ins2^Akita/Ins2^+ Prf1^tm1Sdz/Prf1^tm1Sdz Rag1^tm1Mom/Rag1^tm1Mom	NOD.Cg-Rag1^tm1Mom Ins2^Akita Prf1^tm1Sdz	MGI:3817777
cx24	Ins2^Akita/Ins2^Akita Prf1^tm1Sdz/Prf1^tm1Sdz Rag1^tm1Mom/Rag1^tm1Mom	NOD.Cg-Rag1^tm1Mom Ins2^Akita Prf1^tm1Sdz	MGI:3817776
ot25	Ins2^Akita/?	involves: C57BL/6NSlc	MGI:5504442

Genotype
MGI:3583906

hm1

• Allelic Composition: Ins2^Akita/Ins2^Akita
• Genetic Background: C57BL/6-Ins2^Akita

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

mortality/aging

postnatal lethality ( J:47883 )

homeostasis/metabolism

decreased insulin secretion ( J:47883 )

• the pancreatic ratio of insulin to glucagon is decreased to 0.21 and 0.01 at birth and 14 days of age, respectively, compared to 1.17 and 1.11 in wild-type mice

hyperglycemia ( J:47883 )

• blood glucose levels are slightly higher at 1 day of age and much higher at 14 days of age with no gender differences seen

endocrine/exocrine glands

abnormal pancreatic alpha cell morphology ( J:47883 )

• alpha cell density is markedly increased

abnormal pancreatic beta cell morphology ( J:47883 )

• density of beta cells is decreased within 24 hours of birth and at 2 weeks of age

• beta cell granules are fewer in number and smaller and mitochondrial swelling and an increase in endoplasmic reticulum are seen at 2 weeks of age

small pancreatic islets ( J:47883 )

• islet area is reduced

decreased insulin secretion ( J:47883 )

• the pancreatic ratio of insulin to glucagon is decreased to 0.21 and 0.01 at birth and 14 days of age, respectively, compared to 1.17 and 1.11 in wild-type mice

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
permanent neonatal diabetes mellitus		DOID:0060639	OMIM:606176	J:47883

Genotype
MGI:3625075

hm2

• Allelic Composition: Ins2^Akita/Ins2^Akita
• Genetic Background: C57BL/6-Ins2^Akita/J

mortality/aging

premature death ( J:76224 )

• untreated homozygous mice rarely survive past 12 weeks of age, with death resulting from extreme hyperglycemia;

homeostasis/metabolism

hyperglycemia ( J:76224 )

• homozygous mice rapidly become hyperglycemic

Genotype
MGI:5508894

hm3

• Allelic Composition: Ins2^Akita/Ins2^Akita
• Genetic Background: C.B6N-Ins2^Akita

mortality/aging

premature death ( J:198186 )

• approximately 20% of mutants fail to thrive and are sacrificed at 6 months of age

cardiovascular system

abnormal glomerular capillary morphology ( J:198186 )

• mice show a decrease in CD31 positive structures in the glomeruli, indicating collapse of the glomerular tufts

growth/size/body

decreased body weight ( J:198186 )

• reduced body weight at 4 and 6 months of age

homeostasis/metabolism

hyperglycemia ( J:198186 )

albuminuria ( J:198186 )

• 3-fold increase in albumin-to-creatine ratio at 4 months of age; albuminuria persists in mutants at 6 months of age

renal/urinary system

abnormal glomerular capillary morphology ( J:198186 )

• mice show a decrease in CD31 positive structures in the glomeruli, indicating collapse of the glomerular tufts

albuminuria ( J:198186 )

• 3-fold increase in albumin-to-creatine ratio at 4 months of age; albuminuria persists in mutants at 6 months of age

increased renal glomerulus basement membrane thickness ( J:198186 )

expanded mesangial matrix ( J:198186 )

• mesangial matrix expansion is seen at 4 months of age and is more pronounced than in heterozygous mice

glomerulosclerosis ( J:198186 )

• same degree of glomerular injury as in heterozygotes at 6 months of age

renal glomerular protein deposits ( J:198186 )

• increase in glomerular collagen IV deposition at 6 months of age

abnormal kidney interstitium morphology ( J:198186 )

• small increase in collagen I in the tubulointerstitial compartment of the kidney

• however, tubulointerstitial fibrosis is not observed

increased renal glomerular filtration rate ( J:198186 )

• glomerular filtration rate is increased at 4 months of age but decreased by 6 months of age to normal levels

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
type 1 diabetes mellitus		DOID:9744	OMIM:222100	J:198186

Genotype
MGI:4421500

hm4

• Allelic Composition: Ins2^Akita/Ins2^Akita
• Genetic Background: involves: C57BL/6NSlc

Abnormal glucose and insulin homeostasis in Ins2^Akita/Ins2^Akita and Ins2^Akita/Ins2^Akita Cebpb^tm1.1Maka/Cebpb^tm1.1Maka Tg(Ins2-cre)23Herr/0 but not Cebpb^tm1.1Maka/Cebpb^tm1.1Maka Tg(Ins2-cre)23Herr/0 mice.

endocrine/exocrine glands

decreased pancreatic beta cell mass ( J:156725 )

• in 50% of mice at 8 weeks

abnormal pancreas physiology ( J:156725 )

• expression of a proliferation marker in the pancreas islet is decreased compared to in wild-type mice

increased pancreatic islet cell apoptosis ( J:156725 )

• expression of apoptosis markers in the pancreas islet is increased compared to in wild-type mice

decreased insulin secretion ( J:156725 )

• pancreas insulin levels are lower than in Cebpb^tm1.1Maka homozygotes

homeostasis/metabolism

decreased insulin secretion ( J:156725 )

• pancreas insulin levels are lower than in Cebpb^tm1.1Maka homozygotes

hyperglycemia ( J:156725 )

decreased circulating insulin level ( J:156725 )

cardiovascular system

hematoma ( J:168556 )

• greater hematoma expansion induced by autologous blood injection in diabetic mice

cellular

increased pancreatic islet cell apoptosis ( J:156725 )

• expression of apoptosis markers in the pancreas islet is increased compared to in wild-type mice

Genotype
MGI:3583904

ht5

• Allelic Composition: Ins2^Akita/Ins2⁺
• Genetic Background: C57BL/6-Ins2^Akita

mortality/aging

premature death ( J:40063 , J:108948 )

• mice have much shorter lifespan than wild-type; 909 days (wt) vs 373 days (mutant) (J:108948)

♂ • 50% survival time in males is reduced to 305 days but survival time is not reduced for females through 370 days of age (J:40063)

homeostasis/metabolism

decreased insulin secretion ( J:40063 , J:47883 )

• hyposecretion of insulin is seen; however, islet area is not reduced (J:40063)

• the pancreatic ratio of insulin to glucagon is decreased to 0.42 and 0.54 at birth and 14 days of age, respectively compared to 1.17 and 1.11 in wild-type mice (J:47883)

hyperglycemia ( J:40063 , J:125256 )

• develops soon after weaning and is more severe in males (J:40063)

♂ • blood glucose in fed 7-8 week old males measures 544+/-11 mg/dl (J:125256)

decreased circulating insulin level ( J:40063 )

• insulin levels are decreased in the blood and pancreas

impaired glucose tolerance ( J:40063 )

endocrine/exocrine glands

abnormal pancreatic beta cell morphology ( J:47883 )

• density of beta cells is decreased at 14 days of age

• beta cells have increased amounts of endoplasmic reticulum and Golgi complexes, more and enlarged mitochondria, and partial degranulation

degranulated pancreatic beta cells ( J:47883 )

• partial degranulation

abnormal Leydig cell morphology ( J:108948 )

♂ • mutant males display some pigmented vacuoles in Leydig cells in the testes, but to a lesser extent than in double mutant males at 12 months of age

decreased insulin secretion ( J:40063 , J:47883 )

• hyposecretion of insulin is seen; however, islet area is not reduced (J:40063)

• the pancreatic ratio of insulin to glucagon is decreased to 0.42 and 0.54 at birth and 14 days of age, respectively compared to 1.17 and 1.11 in wild-type mice (J:47883)

renal/urinary system

hydronephrosis ( J:40063 )

• seen in all diabetic males but only 5 of 20 diabetic females

polyuria ( J:40063 )

• develops soon after weaning and is more severe in males

behavior/neurological

increased fluid intake ( J:125256 )

♂ • 7-8 week old males consume 7 fold more water as compared to controls (33.28 ml/day v. 4.68 ml/day)

polydipsia ( J:40063 )

• develops soon after weaning and is more severe in males

polyphagia ( J:125256 )

♂ • 7-8 week old males consume 2 fold more food as compared to controls (8.16 g/day v. 4.48 g/day)

increased anxiety-related response ( J:125256 )

♂ • 7-8 week old males exhibit greater anxiety behavior in elevated plus maze

♂ • total number and total time of entries in the open arms is significantly decreased as compared to controls

akinesia ( J:125256 )

♂ • 7-8 week old males exhibit increased immobility time as measured in open field test

decreased locomotor activity ( J:125256 )

♂ • 7-8 week old males exhibit decreased locomotor activity as measured in open field test

♂ • number of total entries in elevated plus maze is decreased in 7-8 week old males as compared to controls

growth/size/body

decreased body weight ( J:125256 )

♂ • 7-8 week old males exhibit decreased weight as compared to controls (24g v. 26g)

postnatal growth retardation ( J:40063 )

• weight gain is normal through 18 weeks of age but then no further weight gain is seen and by 30 weeks weight loss is observed

adipose tissue

decreased subcutaneous adipose tissue amount ( J:108948 )

• mutants have almost no subcutaneous fat

cellular

abnormal mitochondrial morphology ( J:108948 )

• mutant mice show greater mitochondrial damage than wild-type or Bdkrb2-deficient mice at 12 months of age

reproductive system

abnormal Leydig cell morphology ( J:108948 )

♂ • mutant males display some pigmented vacuoles in Leydig cells in the testes, but to a lesser extent than in double mutant males at 12 months of age

skeleton

kyphosis ( J:108948 )

• diabetic mice display kyphosis but to a lesser extent than double mutant mice

decreased bone mineral density ( J:108948 )

• mutants have significantly reduced bone density compared to wild-type or Bdkrb2-deficient mice

integument

decreased subcutaneous adipose tissue amount ( J:108948 )

• mutants have almost no subcutaneous fat

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
maturity-onset diabetes of the young		DOID:0050524	OMIM:606391	J:40063

Genotype
MGI:3583907

ht6

• Allelic Composition: Ins2^Akita/Ins2⁺
• Genetic Background: C57BL/6-Ins2^Akita/J

homeostasis/metabolism

hyperglycemia ( J:76224 , J:99412 )

• heterozygous males and females are hyperglycemic by 6 weeks of age (plasma glucose - 325 mg/dL); at 12 and 18 weeks of age, plasma glucose levels in males have appproximately doubled (645 mg/dL and 666 mg/dL) while levels in female mutants have increased much less (341 and 298 mg/dL respectively) (J:76224)

decreased circulating insulin level ( J:321591 )

• mice show decreased glucose-induced plasma insulin levels during glucose tolerance testing

increased energy expenditure ( J:321591 )

• mice exhibit increased energy expenditure in the dark photo-period at 2 to 3 months of age

decreased respiratory quotient ( J:321591 )

• mice present reduced respiratory quotient values at 2 to 3 months of age

impaired glucose tolerance ( J:321591 )

• mice exhibit increased blood glucose levels after glucose injection in glucose tolerance tests

• treatment with a pepducin based on Or12d17 sequence, o109-i2-2, significantly ameliorates the glucose metabolism disorder seen in mutants

increased insulin sensitivity ( J:76224 )

• diabetic males that are hyperglycemic (plasma glucose - ~660 mg/dL) at 12 weeks show a return to euglycemia one hour after receiving 1 unit of insulin, demonstrating insulin sensitivity

immune system

increased leukocyte cell number ( J:99412 )

• after 31-36 weeks of hyperglycemia, the number of leukocytes per retina is increased

abnormal microglial cell morphology ( J:99412 )

• after 31-36 weeks of hyperglycemia, retinal microglia have a reactive morphology

abnormal response to transplant ( J:76224 )

• hyperglycemic male mice transplanted with pancreatic islets from wild-type B6 males become euglycemic in one week after transplant and remain euglycemic until removal of the graft (8 weeks); male mice receiving an allogeneic transplant of BALB/c wild-type islets initially become euglycemic but revert to hyperglycemia because of rejection of the graft

cardiovascular system

abnormal retina vasculature morphology ( J:99412 )

• after 31-36 weeks of hyperglycemia, a modest increase in the number of acellular capillaries is seen in the retina

increased vascular permeability ( J:99412 )

• vascular permeability is increased in the retina

growth/size/body

decreased body weight ( J:99412 , J:321591 )

• at death heterozygous males weigh significantly less than wild-type males (J:99412)

• body weight is decreased at 2 to 3 months of age (J:321591)

nervous system

abnormal microglial cell morphology ( J:99412 )

• after 31-36 weeks of hyperglycemia, retinal microglia have a reactive morphology

abnormal astrocyte morphology ( J:99412 )

• after 31-36 weeks of hyperglycemia, astrocytes close to large caliber superficial blood vessels in the retina have short projections that do not conjoin with the vessel

vision/eye

abnormal retina vasculature morphology ( J:99412 )

• after 31-36 weeks of hyperglycemia, a modest increase in the number of acellular capillaries is seen in the retina

increased retina apoptosis ( J:99412 )

• after 31-36 weeks of hyperglycemia, significantly more caspase-3 positive cells are seen

abnormal retina neuronal layer morphology ( J:99412 )

• after 22 weeks of hyperglycemia, in the peripheral regions the inner nuclear layer and inner plexiform layer thickness are reduced by 15.6% and 27%, respectively, and in the central region the thickness of the inner plexiform layer is reduced by 16.7%

abnormal retina ganglion layer morphology ( J:99412 )

• after 22 weeks of hyperglycemia, the number of nuclei in the retinal ganglion cell layer is reduced by 23.4%

hematopoietic system

increased leukocyte cell number ( J:99412 )

• after 31-36 weeks of hyperglycemia, the number of leukocytes per retina is increased

abnormal microglial cell morphology ( J:99412 )

• after 31-36 weeks of hyperglycemia, retinal microglia have a reactive morphology

cellular

increased retina apoptosis ( J:99412 )

• after 31-36 weeks of hyperglycemia, significantly more caspase-3 positive cells are seen

endocrine/exocrine glands

abnormal pancreatic islet morphology ( J:321591 )

• mice exhibit a large reduction in insulin content of islets

• population of CD11c+ macrophages in islets is increased by about 3-fold compared to wild-type mice

decreased pancreatic beta cell number ( J:321591 )

• marker analysis indicates that mice show reduced pancreatic beta cells in islets

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
maturity-onset diabetes of the young		DOID:0050524	OMIM:606391	J:99412

Genotype
MGI:5508895

ht7

• Allelic Composition: Ins2^Akita/Ins2⁺
• Genetic Background: C.B6N-Ins2^Akita

homeostasis/metabolism

albuminuria ( J:198186 )

• 3-fold increase in albumin-to-creatine ratio at 4 months of age, however albuminuria does not persist at 6 months of age

renal/urinary system

albuminuria ( J:198186 )

• 3-fold increase in albumin-to-creatine ratio at 4 months of age, however albuminuria does not persist at 6 months of age

expanded mesangial matrix ( J:198186 )

• mesangial matrix expansion is seen at 4 months of age

glomerulosclerosis ( J:198186 )

• same degree of glomerular injury as in homozygotes at 6 months of age

increased renal glomerular filtration rate ( J:198186 )

• glomerular filtration rate is increased at 6 months of age

Genotype
MGI:3583905

ht8

• Allelic Composition: Ins2^Akita/Ins2⁺
• Genetic Background: involves: C3H * C57BL/6NJcl * C57BL/6NSlc

homeostasis/metabolism

hyperglycemia ( J:40063 )

• progressive increase in morning blood glucose level is seen

impaired glucose tolerance ( J:40063 )

Genotype
MGI:5510482

ht9

• Allelic Composition: Ins2^Akita/Ins2⁺
• Genetic Background: involves: C57BL/6NSlc

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:200802 )

N • mice exhibit normal insulin sensitivity

decreased insulin secretion ( J:200802 )

• decreased total pancreatic insulin and prolinsulin content

increased circulating glucose level ( J:200802 )

decreased circulating leptin level ( J:200802 )

endocrine/exocrine glands

abnormal pancreatic islet morphology ( J:200802 )

• beta cells contain a small number of secretory granules, a tubulovesicular structure comprised of enlarged endoplasmic reticulum, and swelling or disruption of mitochondria

decreased insulin secretion ( J:200802 )

• decreased total pancreatic insulin and prolinsulin content

growth/size/body

decreased body weight ( J:200802 )

behavior/neurological

increased food intake ( J:200802 )

Genotype
MGI:4421497

cn10

• Allelic Composition: Cebpb^tm1.1Maka/Cebpb^tm1.1Maka; Ins2^Akita/Ins2^Akita; Tg(Ins2-cre)23Herr/0
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6J * C57BL/6NSlc * CBA/J

Abnormal glucose and insulin homeostasis in Ins2^Akita/Ins2^Akita and Ins2^Akita/Ins2^Akita Cebpb^tm1.1Maka/Cebpb^tm1.1Maka Tg(Ins2-cre)23Herr/0 but not Cebpb^tm1.1Maka/Cebpb^tm1.1Maka Tg(Ins2-cre)23Herr/0 mice.

endocrine/exocrine glands

abnormal pancreatic islet cell apoptosis ( J:156725 )

• expression of apoptosis markers in the pancreas islet is decreased compared to in Ins2^Akita homozygotes

abnormal pancreatic beta cell mass ( J:156725 )

• mice exhibit improved beta cell mass compared to in Ins2^Akita homozygotes

decreased insulin secretion ( J:156725 )

• pancreatic insulin levels are decreased compared to in wild-type mice

• however, pancreatic insulin content is 8-fold higher than in Ins2^Akita homozygotes

homeostasis/metabolism

decreased insulin secretion ( J:156725 )

• pancreatic insulin levels are decreased compared to in wild-type mice

• however, pancreatic insulin content is 8-fold higher than in Ins2^Akita homozygotes

increased circulating glucose level ( J:156725 )

• mice exhibit increased circulating glucose levels compared to in wild-type mice

• however, glucose serum level are increased compared to in Ins2^Akita homozygotes

decreased circulating insulin level ( J:156725 )

• mice exhibit decreased circulating glucose levels compared to in wild-type mice

• however, insulin serum level are increased compared to in Ins2^Akita homozygotes

cellular

abnormal pancreatic islet cell apoptosis ( J:156725 )

• expression of apoptosis markers in the pancreas islet is decreased compared to in Ins2^Akita homozygotes

Genotype
MGI:6690322

cn11

• Allelic Composition: Ins2^Akita/Ins2^Akita; Jazf1^{tm1c(EUCOMM)Wtsi}/Jazf1^{tm1c(EUCOMM)Wtsi}; Tg(Ins2-cre)23Herr/0
• Genetic Background: involves: 129S4/SvJaeSor * C57BL/6N * C57BL/6NSlc * CBA/J

cellular

increased pancreatic beta cell apoptosis ( J:303318 )

• at age 8 weeks

decreased pancreatic beta cell proliferation ( J:303318 )

• 70% reduction

endocrine/exocrine glands

increased pancreatic beta cell apoptosis ( J:303318 )

• at age 8 weeks

decreased pancreatic beta cell proliferation ( J:303318 )

• 70% reduction

decreased pancreatic beta cell mass ( J:303318 )

• 50% reduction

growth/size/body

growth/size/body region phenotype ( J:303318 )

N • normal body weight

homeostasis/metabolism

abnormal glucose homeostasis ( J:303318 )

• increased proinsulin levels

increased circulating glucose level ( J:303318 )

Genotype
MGI:3626074

cx12

• Allelic Composition: Bdkrb2^tm1Jfh/Bdkrb2^tm1Jfh; Ins2^Akita/Ins2⁺
• Genetic Background: B6.Cg-Ins2^Akita Bdkrb2^tm1Jfh

mortality/aging

premature death ( J:108948 )

• mice have much shorter lifespan than wild-type; 909 days (wt) vs 246 days (mutant)

cellular

abnormal spermatogonia morphology ( J:108948 )

♂ • in double mutant males, severe loss of spermatogonia is observed and atrophy of spermatic cords is prevalent at 12 months of age

abnormal mitochondrial chromosome morphology ( J:108948 )

• mutants display increased mitochondrial DNA damage compared to single mutants or wild-type mice at 12 months of age

endocrine/exocrine glands

abnormal seminiferous tubule morphology ( J:108948 )

♂ • double mutants have an increased frequency of apoptotic cells in the seminiferous tubules at 12 months of age

abnormal Leydig cell morphology ( J:108948 )

♂ • double mutant males display numerous pigmented vacuoles in Leydig cells in the testes at 12 months of age

reproductive system

abnormal spermatogonia morphology ( J:108948 )

♂ • in double mutant males, severe loss of spermatogonia is observed and atrophy of spermatic cords is prevalent at 12 months of age

abnormal seminiferous tubule morphology ( J:108948 )

♂ • double mutants have an increased frequency of apoptotic cells in the seminiferous tubules at 12 months of age

abnormal Leydig cell morphology ( J:108948 )

♂ • double mutant males display numerous pigmented vacuoles in Leydig cells in the testes at 12 months of age

abnormal spermatic cord morphology ( J:108948 )

♂ • double mutant males show atrophy of the spermatic cords at 12 months of age

digestive/alimentary system

abnormal intestinal epithelium morphology ( J:108948 )

• intestinal villi in mutants have a greater frequency of apoptotic cells

adipose tissue

decreased subcutaneous adipose tissue amount ( J:108948 )

• mutants have almost no subcutaneous fat

skeleton

kyphosis ( J:108948 )

• double mutants exhibit marked kyphosis

decreased bone mineral density ( J:108948 )

• double mutants have significantly reduced bone density compared to wild-type or single mutant mice

integument

decreased subcutaneous adipose tissue amount ( J:108948 )

• mutants have almost no subcutaneous fat

alopecia ( J:108948 )

• most mutants show significant alopecia by 12 months of age

Genotype
MGI:5286555

cx13

• Allelic Composition: Ins2^Akita/Ins2^Akita; Ldlr^tm1Her/Ldlr^tm1Her
• Genetic Background: B6.Cg-Ins2^Akita Ldlr^tm1Her

mortality/aging

premature death ( J:174983 )

• compared with Ldlr^tm1Her homozygotes

homeostasis/metabolism

hyperglycemia ( J:174983 )

• severe compared with Ldlr^tm1Her homozygotes

decreased circulating insulin level ( J:174983 )

• in fasting mice compared with Ldlr^tm1Her homozygotes

increased circulating cholesterol level ( J:174983 )

• in fasting mice compared with Ldlr^tm1Her homozygotes

increased circulating HDL cholesterol level ( J:174983 )

• in female mice compared with Ldlr^tm1Her homozygotes

increased circulating LDL cholesterol level ( J:174983 )

• 2-fold in male mice and 24% in female mice compared with Ldlr^tm1Her homozygotes

increased circulating VLDL cholesterol level ( J:174983 )

• 7-fold in male mice and 1.8-fold in female mice compared with Ldlr^tm1Her homozygotes

increased circulating triglyceride level ( J:174983 )

• in fasting mice compared with Ldlr^tm1Her homozygotes

impaired glucose tolerance ( J:174983 )

• compared with Ldlr^tm1Her homozygotes

growth/size/body

decreased body weight ( J:174983 )

• in male, but not female, mice at 20 weeks of age compared with Ldlr^tm1Her homozygotes

cardiovascular system

increased susceptibility to atherosclerosis ( J:174983 )

• accelerated in mice fed a high-fat diet compared with similarly treated Ldlr^tm1Her homozygotes

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
diabetic angiopathy		DOID:11713		J:174983

Genotype
MGI:7664100

cx14

• Allelic Composition: Ins2^Akita/Ins2⁺; Or12d17^em1Cya/Or12d17^em1Cya
• Genetic Background: C57BL/6-Ins2^Akita Or12d17^em1Cya

endocrine/exocrine glands

endocrine/exocrine gland phenotype ( J:321591 )

N • islets show increased expression of pancreatic beta cell markers in islets than that seen in Ins2^Akita mice, indicating rescue of the reduced pancreatic beta cells in islets

abnormal pancreatic islet morphology ( J:321591 )

• mice show partial rescue of the decreased insulin content in islets seen in Ins2^Akita mice but insulin content is still lower than in wild-type mice

• mice show partial rescue of the increased CD11c+ macrophages in islets of Ins2^Akita mice

growth/size/body

growth/size/body region phenotype ( J:321591 )

N • mice show rescue of the decreased body weight seen in heterozygous Ins2^Akita mice

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:321591 )

N • mice show reversal of the increased energy expenditure and reduced respiratory quotient seen in the dark photo-period of heterozygous Ins2^Akita mice

decreased circulating insulin level ( J:321591 )

• mice show improved glucose-induced plasma insulin levels at 8 weeks of age compared to heterozygous Ins2^Akita mice but not fully to wild-type levels

impaired glucose tolerance ( J:321591 )

• mice show markedly improved glucose tolerance at 8 weeks of age compared to heterozygous Ins2^Akita mice but not fully to wild-type levels

Genotype
MGI:5508896

cx15

• Allelic Composition: Ins2^Akita/Ins2^Akita; Itga1^tm1Gdnr/Itga1^tm1Gdnr
• Genetic Background: C.Cg-Ins2^Akita Itga1^tm1Gdnr

mortality/aging

premature death ( J:198186 )

• about 40% of mutants fail to thrive and have to be euthanized before 6 months of age

cardiovascular system

abnormal glomerular capillary morphology ( J:198186 )

• mice show a a greater decrease in CD31 positive structures in the glomeruli than in single Ins2^Akita homozygotes, indicating collapse of the glomerular tufts

growth/size/body

decreased body weight ( J:198186 )

• decreased body weight at 4 and 6 months of age compared to wild-type mice or single Itgal1^tm1Gdnr homozygotes

homeostasis/metabolism

hyperglycemia ( J:198186 )

• develop a similar level of hyperglycemia as in single Ins2^Akita homozygotes

albuminuria ( J:198186 )

• 16-fold increase in albumin-to-creatine ratio at 4 months of age

renal/urinary system

abnormal glomerular capillary morphology ( J:198186 )

• mice show a a greater decrease in CD31 positive structures in the glomeruli than in single Ins2^Akita homozygotes, indicating collapse of the glomerular tufts

albuminuria ( J:198186 )

• 16-fold increase in albumin-to-creatine ratio at 4 months of age

increased renal glomerulus basement membrane thickness ( J:198186 )

• glomerular basement membrane thickening is more severe than in single Ins2^Akita homozygotes

abnormal glomerular mesangium morphology ( J:198186 )

• excessive fibrillar collagen deposition in diffuse and nodular mesangial lesions

expanded mesangial matrix ( J:198186 )

• increase in mesangial matrix expansion at 4 and 6 months of age is greater than in single Ins2^Akita homozygotes

• diffuse and nodular mesangial sclerosis

mesangiolysis ( J:198186 )

glomerulosclerosis ( J:198186 )

• severe

renal glomerular protein deposits ( J:198186 )

• increase in glomerular collagen IV deposition at 6 months of age is more abundant than in single Ins2^Akita homozygotes

abnormal kidney interstitium morphology ( J:198186 )

• small increase in collagen I in the tubulointerstitial compartment of the kidney

• however tubulointerstitial fibrosis is not observed

increased renal glomerular filtration rate ( J:198186 )

• glomerular filtration rate is increased at 4 months of age to a similar level as in single Ins2^Akita homozygotes

• by 6 months of age, glomerular filtration rate is decreased compared to controls, with an overall 50% decline compared to at 4 months

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
type 1 diabetes mellitus		DOID:9744	OMIM:222100	J:198186

Genotype
MGI:5881940

cx16

• Allelic Composition: Ins2^Akita/Ins2^Akita; Rpl13a^tm1.1Jesc/Rpl13a^tm1.1Jesc
• Genetic Background: FVB.Cg-Rpl13a^tm1.1Jesc Ins2^Akita

homeostasis/metabolism

abnormal circulating glucose level ( J:237822 )

• mice exhibit increased glucose levels as compared to wild-type, however levels are decreased as compared to mice carrying only the Ins2^Akita allele

Genotype
MGI:4441480

cx17

• Allelic Composition: Ero1b^{Gt(P077G11)Wrst}/Ero1b⁺; Ins2^Akita/Ins2⁺
• Genetic Background: involves: 129S2/SvPas * C57BL/6NSlc

homeostasis/metabolism

decreased insulin secretion ( J:158805 )

• in the pancreas

increased circulating glucose level ( J:158805 )

• plasma glucose levels are higher than in Ins2^Akita heterozygotes

impaired glucose tolerance ( J:158805 )

• glucose intolerance is worse than in Ins2^Akita heterozygotes

endocrine/exocrine glands

small pancreatic islets ( J:158805 )

decreased insulin secretion ( J:158805 )

• in the pancreas

Genotype
MGI:3583903

cx18

• Allelic Composition: Gast^tm1(INS)Ez/Gast⁺; Ins2^Akita/Ins2⁺
• Genetic Background: involves: 129S4/SvJae * C57BL/6NSlc

mortality/aging

mortality/aging ( J:99270 )

N • double heterozygotes live over 13 months compared to Ins2^Akita single heterozygotes which have a median survival time of 10.3 months

homeostasis/metabolism

abnormal circulating glucose level ( J:99270 )

• a significant decrease in fasting hyperglycemia is seen in double heterozygotes compared to Ins2^Akita single heterozygotes

Genotype
MGI:3664324

cx19

• Allelic Composition: Dbm1^A/J/Dbm1^A/J; Ins2^Akita/Ins2⁺
• Genetic Background: involves: A/J * C57BL/6J * C57BL/6NSlc

homeostasis/metabolism

increased circulating glucose level ( J:112869 )

• increased fasting plasma glucose concentration in males

• increased plasma glucose at all time points of the intraperitoneal glucose tolerance test in males

increased circulating insulin level ( J:112869 )

• increased plasma insulin concentration in males

growth/size/body

increased body weight ( J:112869 )

• increased body weight in males

Genotype
MGI:3664327

cx20

• Allelic Composition: Dbm4^C57BL/6J/?; Ins2^Akita/Ins2⁺
• Genetic Background: involves: A/J * C57BL/6J * C57BL/6NSlc

homeostasis/metabolism

abnormal circulating glucose level ( J:112869 )

• increased fasting plasma glucose concentration in males

• increased plasma glucose at 30, 60, and 120 minutes of the intraperitoneal glucose tolerance test in males

Genotype
MGI:3664326

cx21

• Allelic Composition: Dbm3^C57BL/6J/?; Ins2^Akita/Ins2⁺
• Genetic Background: involves: A/J * C57BL/6J * C57BL/6NSlc

homeostasis/metabolism

abnormal circulating glucose level ( J:112869 )

• increased fasting plasma glucose concentration in males

• increased plasma glucose at 30, 60, and 120 minutes of the intraperitoneal glucose tolerance test in males

Genotype
MGI:5510483

cx22

• Allelic Composition: Ins2^Akita/Ins2⁺; Rnf213^tm1.1Akoi/Rnf213^tm1.1Akoi
• Genetic Background: involves: C57BL/6N * C57BL/6NSlc

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:200802 )

N • mice exhibit normal insulin sensitivity and insulin plasma levels

decreased insulin secretion ( J:200802 )

• decreased total pancreatic insulin and prolinsulin content that is not as severe as in Ins2^Akita heterozygotes

increased circulating glucose level ( J:200802 )

• not as severe as in Ins2^Akita heterozygotes from 6 to 20 weeks

decreased circulating leptin level ( J:200802 )

impaired glucose tolerance ( J:200802 )

• not as severe as in Ins2^Akita heterozygotes

endocrine/exocrine glands

abnormal pancreatic islet morphology ( J:200802 )

• beta cells exhibit mild endoplasmic reticulum enlargement and slight mitochondria swelling that not as severe as in Ins2^Akita heterozygotes

decreased pancreatic beta cell number ( J:200802 )

• not as severe as in Ins2^Akita heterozygotes

decreased insulin secretion ( J:200802 )

• decreased total pancreatic insulin and prolinsulin content that is not as severe as in Ins2^Akita heterozygotes

behavior/neurological

increased food intake ( J:200802 )

• ot as much as in Ins2^Akita heterozygotes

growth/size/body

decreased body weight ( J:200802 )

• at 6 and 9 weeks but not 10 weeks compared with Ins2^Akita heterozygotes

• compared with Rnf213^tm1.1Akoi homozygotes

Genotype
MGI:3817777

cx23

• Allelic Composition: Ins2^Akita/Ins2⁺; Prf1^tm1Sdz/Prf1^tm1Sdz; Rag1^tm1Mom/Rag1^tm1Mom
• Genetic Background: NOD.Cg-Rag1^tm1Mom Ins2^Akita Prf1^tm1Sdz

endocrine/exocrine glands

abnormal pancreatic islet morphology ( J:138005 )

• islets exhibit progressively altered morphology

• insulin level is lower compared to Ins2-wild-type mice at 50 days of age and continues to diminish with age

hematopoietic system

increased erythrocyte cell number ( J:138005 )

• erythrocyte/erythocyte lineages (Ter 119+) are increased as compared to NOD controls

increased granulocyte number ( J:138005 )

• percentage of granulocytes is elevated compared to NOD/Lt

absent mature B cells ( J:138005 )

• lacking in mutant animals

absent T cells ( J:138005 )

• mature T cells are absent in mutant animals

increased macrophage cell number ( J:138005 )

• percentage of granulocytes is elevated

increased monocyte cell number ( J:138005 )

• percentage of granulocytes is elevated

immune system

increased granulocyte number ( J:138005 )

• percentage of granulocytes is elevated compared to NOD/Lt

absent mature B cells ( J:138005 )

• lacking in mutant animals

absent T cells ( J:138005 )

• mature T cells are absent in mutant animals

increased macrophage cell number ( J:138005 )

• percentage of granulocytes is elevated

increased monocyte cell number ( J:138005 )

• percentage of granulocytes is elevated

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:138005 )

N • spontaneously hyperglycemic mice are restored to euglycemia after receiving islet transplants at a dose of 4000 islet equivalents (IEQ) and remain euglycemic for the length of observation; at levels of 2000 and 3000 IEQ, mice display a drop in blood sugar, but eventually return to hyperglycemic status

abnormal glucose homeostasis ( J:138005 )

• glucose regulation is impaired as early as 3 weeks of age in nearly all mice

hyperglycemia ( J:138005 )

• male mice show greater susceptibility to develop hyperglycemia than females

Genotype
MGI:3817776

cx24

• Allelic Composition: Ins2^Akita/Ins2^Akita; Prf1^tm1Sdz/Prf1^tm1Sdz; Rag1^tm1Mom/Rag1^tm1Mom
• Genetic Background: NOD.Cg-Rag1^tm1Mom Ins2^Akita Prf1^tm1Sdz

mortality/aging

postnatal lethality, complete penetrance ( J:138005 )

• mice die prior to weaning

Genotype
MGI:5504442

ot25

• Allelic Composition: Ins2^Akita/?
• Genetic Background: involves: C57BL/6NSlc

growth/size/body

decreased body fat mass ( J:130021 )

♂ • whole body fat mass is reduced at 8 and 3 weeks of age, however whole body lean mass is no different from wild-type

heart left ventricle hypertrophy ( J:130021 )

♂ • ventricular hypertrophy

decreased body weight ( J:130021 )

♂

adipose tissue

decreased body fat mass ( J:130021 )

♂ • whole body fat mass is reduced at 8 and 3 weeks of age, however whole body lean mass is no different from wild-type

decreased adipocyte glucose uptake ( J:130021 )

♂ • insulin-stimulated glucose uptake in brown adipose tissue is reduced during hyperinsulinemic-euglycemic clamps

increased adipocyte glucose uptake ( J:130021 )

♂ • insulin-stimulated glucose uptake in white adipose tissue is increased more than 3-fold during hyperinsulinemic-euglycemic clamps

behavior/neurological

increased food intake ( J:130021 )

♂ • daily food intake is increased twofold

decreased locomotor activity ( J:130021 )

♂ • mutants are less active during a 24 hour cycle

homeostasis/metabolism

decreased circulating triglyceride level ( J:130021 )

♂ • following an overnight fast and phloridzin treatment to lower plasma glucose levels, basal plasma triglyceride levels are reduced by 40%

♂ • however, the insulin clamp has no effect on plasma triglyceride levels in mutants compared to wild-type mice in which there is a 50% reduction

increased energy expenditure ( J:130021 )

♂ • mutants show increased energy expenditure during a 24 hour cycle

increased carbon dioxide production ( J:130021 )

♂ • both rate of oxygen consumption and carbon dioxide production are increased by about 40%

increased oxygen consumption ( J:130021 )

♂ • both rate of oxygen consumption and carbon dioxide production are increased by about 40%

decreased respiratory quotient ( J:130021 )

♂ • respiratory exchange ratio is reduced, indicating increased lipid oxidation

abnormal glucose homeostasis ( J:130021 )

♂ • during hyperinsulinemic-euglycemic clamps, mutants show a 40% reduction in insulin-stimulated whole body glucose turnover

♂ • basal hepatic glucose production is increased

♂ • hepatic glucose production remains elevated during the insulin clamp unlike in wild-type mice which show a decrease

♂ • during hyperinsulinemic-euglycemic clamps, insulin-stimulated whole body glycolysis and glycogen plus lipid synthesis are reduced by 40-50%

hyperglycemia ( J:130021 )

♂ • mutants develop overnight-fasted hyperglycemia

decreased circulating insulin level ( J:130021 )

♂ • fed insulin levels are reduced

insulin resistance ( J:130021 )

♂ • nonobese mutants develop insulin resistance in skeletal muscle, liver, and brown adipose tissue, as indicated by an approximate 80% reduction in glucose infusion rate during hyperinsulinemic-euglycemic clamps

♂ • chronic treatment with phloridzin to chronically lower circulating glucose levels normalizes peripheral insulin action but does not normalize hepatic insulin action

decreased liver triglyceride level ( J:130021 )

♂ • intrahepatic triglyceride levels are reduced during hyperinsulinemic-euglycemic clamps

decreased skeletal muscle triglyceride level ( J:130021 )

♂ • during hyperinsulinemic-euglycemic clamps, intramuscular triglyceride levels are reduced by almost 90%

cardiovascular system

abnormal heart morphology ( J:130021 )

♂ • cardiac remodeling

thick interventricular septum ( J:130021 )

♂

abnormal heart left ventricle morphology ( J:130021 )

♂ • left ventricular posterior wall thickness is increased

heart left ventricle hypertrophy ( J:130021 )

♂ • ventricular hypertrophy

abnormal cardiac muscle contractility ( J:130021 )

♂ • ventricular fractional shortening and ejection fraction are altered in mutants

♂ • chronic treatment with phloridzin to chronically lower circulating glucose levels normalizes cardiac function

liver/biliary system

decreased liver triglyceride level ( J:130021 )

♂ • intrahepatic triglyceride levels are reduced during hyperinsulinemic-euglycemic clamps

muscle

heart left ventricle hypertrophy ( J:130021 )

♂ • ventricular hypertrophy

abnormal cardiac muscle contractility ( J:130021 )

♂ • ventricular fractional shortening and ejection fraction are altered in mutants

♂ • chronic treatment with phloridzin to chronically lower circulating glucose levels normalizes cardiac function

decreased skeletal muscle cell glucose uptake ( J:130021 )

♂ • during hyperinsulinemic-euglycemic clamps, skeletal muscle glucose uptake is reduced by about 30%

♂ • chronic treatment with phloridzin to chronically lower circulating glucose levels improves muscle glucose metabolism

decreased skeletal muscle triglyceride level ( J:130021 )

♂ • during hyperinsulinemic-euglycemic clamps, intramuscular triglyceride levels are reduced by almost 90%

cellular

decreased adipocyte glucose uptake ( J:130021 )

♂ • insulin-stimulated glucose uptake in brown adipose tissue is reduced during hyperinsulinemic-euglycemic clamps

increased adipocyte glucose uptake ( J:130021 )

♂ • insulin-stimulated glucose uptake in white adipose tissue is increased more than 3-fold during hyperinsulinemic-euglycemic clamps

decreased skeletal muscle cell glucose uptake ( J:130021 )

♂ • during hyperinsulinemic-euglycemic clamps, skeletal muscle glucose uptake is reduced by about 30%

♂ • chronic treatment with phloridzin to chronically lower circulating glucose levels improves muscle glucose metabolism

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:130021