Overview

Also Known As: BKS db

This strain is used to model phases I to III of diabetes type II and obesity. Mice homozygous for the diabetes spontaneous mutation (Lepr^db) manifest morbid obesity, chronic hyperglycemia, pancreatic beta cell atrophy and become hypoinsulinemic. Obesity starts at 3 to 4 weeks of age. Elevated plasma insulin begins at 10 to 14 days and elevated blood sugar at 4 to 8 weeks. Homozygous mice are polyphagic, polydipsic, and polyuric. The severity of disease on BKS background leads to uncontrolled rise in blood sugar, severe depletion of insulin-producing beta-cells of the pancreatic islets, peripheral neuropathy, myocardial disease and death by 10 months of age. Exogenous insulin fails to control blood glucose levels and gluconeogenic enzyme activity increases. Wound healing is delayed, and metabolic efficiency is increased.

Genetic overview

Genetic Background	Generation
000662 C57BLKS/J	Contact Technical Support (2018-07-27 00:00:00)

Dock7^m

Allele Type	Gene Symbol	Gene Name
Spontaneous	Dock7	dedicator of cytokinesis 7

Lepr^db

Allele Type	Gene Symbol	Gene Name
Spontaneous	Lepr	leptin receptor

View Genetics

Research Applications

Diabetes and Obesity Research
Internal/Organ Research
Dermatology Research
Immunology, Inflammation and Autoimmunity Research
Reproductive Biology Research
Mouse/Human Gene Homologs
Metabolism Research
Endocrine Deficiency Research

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Base Price

Starting at:

$99.79 Domestic price for female 4-week

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Details

Important Note

This strain is maintained with Dock7^m and Lepr^db in repulsion. Although these genes are tightly linked, there is a small possibility of recombination. The heterozygotes we distribute are presumed to be non-recombinant, but are untested.

Detailed Description

Mice homozygous for the diabetes spontaneous mutation (Lepr^db) become identifiably obese around three to four weeks of age. Elevations of plasma insulin begin at 10 to 14 days of age and of blood sugar at four to eight weeks. Homozygous mutant mice are polyphagic, polydipsic, and polyuric. The course of the disease is markedly influenced by genetic background. A number of features are observed on the C57BLKS background, including an uncontrolled rise in blood sugar, severe depletion of the insulin-producing beta-cells of the pancreatic islets, and death by 10 months of age. Exogenous insulin fails to control blood glucose levels and gluconeogenic enzyme activity increases. Peripheral neuropathy and myocardial disease are seen in C57BLKS-Lepr^db homozygotes. Wound healing is delayed, and metabolic efficiency is increased. Female homozygotes exhibit decreased uterine and ovarian weights, decreased ovarian hormone production and hypercytolipidemia in follicular granulosa and endometrial epithelial tissue layers (Garris et al., 2004, Garris et al., 2004).

Although normal in body weight, blood glucose, and plasma insulin, heterozygotes (Lepr^db/+) also have increased metabolic efficiency and can survive a prolonged fast longer than controls. Experiments involving destruction of the ventromedial nucleus of the hypothalamus suggest that Lepr^db may cause a defect in the hypothalamus. Steroid sulfotransferase enzymes, aberrantly expressed in diabetic mice, interact with the Lepr^db mutation as modifiers of gender differences in obesity-induced diabetes susceptibility. Because of the sterility of Lepr^db homozygotes, the misty (Dock7^m) mutation has been incorporated into stocks for maintenance of the diabetes mutation. The repulsion double heterozygote (Dock7^m +/+ Lepr^db) facilitates identification of heterozygotes for breeding, while the coupling double heterozygote, (Dock7^m Lepr^db/+ +) allows identification of homozygotes before the phenotype becomes severe.

The recessive misty mutation causes a mild dilution of coat color and on certain backgrounds a white tail tip often accompanied by a belly spot. Melanocytes from Dock7^m/Dock7^m mice have a highly dendritic shape, show deficient proliferation in culture and have much more melanin content. Fewer melanoblasts are found in primary cultures from Dock7^m/Dock7^m mice than from wildtype controls. Between two and five weeks of age, Dock7^m/Dock7^m mice are smaller than controls. At 35 days of age they are shorter, weigh 15% less on average, and have less inguinal adipose mass than controls. Misty homozygotes completely lack brown fat. Although platelet count, seratonin content and ATP content are normal, Dock7^m/Dock7^m homozygotes have an increased bleed time and reduced platelet ADP levels.(Woolley 1941 and 1945; Truett et al. 1998; Sviderskaya et al. 1998.)

Control Suggestions

Dock7^m +/+ Lepr^db (Heterozygote from the colony)
Dock7^m +/Dock7^m + from the colony
000662 C57BLKS/J

Additional Information

Considerations for Choosing Controls

Selected References

Gueorguiev M; Goth ML; Korbonits M. 2001. Leptin and puberty: a review. Pituitary 4(1-2):79-86PubMed: 11824512 MGI: J:109856
Kampfer H; Paulukat J; Muhl H; Wetzler C; Pfeilschifter J; Frank S. 2000. Lack of interferon-gamma production despite the presence of interleukin-18 during cutaneous wound healing. Mol Med 6(12):1016-27PubMed: 11474118 MGI: J:109870
Fantuzzi G; Faggioni R. 2000. Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol 68(4):437-46PubMed: 11037963 MGI: J:109886
Yoon JW; Leiter EH; Coleman DL; Kim MK; Pak CY; McArthur RG; Roncari DA. 1988. Genetic control of organ-reactive autoantibody production in mice by obesity (ob) diabetes (db) genes. Diabetes 37(9):1287-93PubMed: 3044893 MGI: J:109940
Dardenne M; Savino W; Bach JF. 1984. Autoimmune mice develop antibodies to thymic hormone: production of anti-thymulin monoclonal autoantibodies from diabetic (db/db) and B/W mice. J Immunol 133(2):740-3PubMed: 6539799 MGI: J:109953
Mandel MA; Mahmoud AA. 1978. Impairment of cell-mediated immunity in mutation diabetic mice (db/db). J Immunol 120(4):1375-7PubMed: 347001 MGI: J:109964
Leiter EH; Chapman HD. 1994. Obesity-induced diabetes (diabesity) in C57BL/KsJ mice produces aberrant trans-regulation of sex steroid sulfotransferase genes. J Clin Invest 93(5):2007-13PubMed: 8182132 MGI: J:17991
Serreze DV; Leiter EH; Kuff EL; Jardieu P; Ishizaka K. 1988. Molecular mimicry between insulin and retroviral antigen p73. Development of cross-reactive autoantibodies in sera of NOD and C57BL/KsJ db/db mice. Diabetes 37(3):351-8PubMed: 3286334 MGI: J:27625
Chen H; Charlat O; Tartaglia LA; Woolf EA; Weng X; Ellis SJ; Lakey ND; Culpepper J; Moore KJ; Breitbart RE; Duyk GM; Tepper RI; Morgenstern JP. 1996. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84(3):491-5PubMed: 8608603 MGI: J:31324
Lee GH; Proenca R; Montez JM; Carroll KM; Darvishzadeh JG; Lee JI; Friedman JM. 1996. Abnormal splicing of the leptin receptor in diabetic mice. Nature 379(6566):632-5PubMed: 8628397 MGI: J:31327
Chua SC Jr; Chung WK; Wu-Peng XS; Zhang Y; Liu SM; Tartaglia L; Leibel RL. 1996. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor [see comments] Science 271(5251):994-6PubMed: 8584938 MGI: J:31419
Hummel KP; Dickie MM; Coleman DL. 1966. Diabetes, a new mutation in the mouse. Science 153(740):1127-8PubMed: 5918576 MGI: J:5010

View All References

Genetics

Dock7^m

Allele Symbol: Dock7^m

Allele Name	misty
Allele Type	Spontaneous
Allele Synonym(s)	misty; Dock7^m
Gene Symbol and Name	Dock7, dedicator of cytokinesis 7
Gene Synonym(s)	Gm430; ZIR2; RIKEN cDNA 3110056M06 gene; gene model 430, (NCBI); m; 3110056M06Rik; m; misty; 3110056M06Rik; mKIAA1771; LOC242555; EIEE23
Strain of Origin	DBA/J
Chromosome	4
Molecular Note	Crosses between mice homozygous for misty and for moonlight, which mapped to overlapping critical regions on Chr 4, demonstrated failure of the two mutations to complement one another. Once moonlight had been identified as a mutation of Dock7 (Dock7^mnlt), sequence analysis of this gene from misty mice revealed a retrotransposon LTR insertion following nucleotide 2045 (numbering from the A of the transcription initiation codon) that interrupts exon 18 and shifts the reading frame after codon 682 so that ten incorrect amino acids are incorporated into the protein before its premature termination.

Lepr^db

Allele Symbol: Lepr^db

Allele Name	diabetes
Allele Type	Spontaneous
Allele Synonym(s)	Lepr^db; diabetes
Gene Symbol and Name	Lepr, leptin receptor
Gene Synonym(s)	diabetes; OB-R; OB-RGRP; obese-like; obl; OBR; CD295; LEP-R; Leprb; LEPRD; LEPROT; obl; Modb1; leptin receptor gene-related protein; obese-like; db; Fa; Obr
Strain of Origin	C57BLKS/J
Chromosome	4
General Note	Phenotypic Similarity to Human Syndrome: Gestational Diabetes J:219658
Molecular Note	A G-to-T transversion in this allele created a donor splice site that causes abnormal splicing and a 106 nt insertion in the transcript, leading to premature termination of the long cellular domain of the Ob-Rb splice form and loss of its signal transducing function.

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Models with phenotypic similarity to human diseases where etiology is unknown or involving genes where ortholog is unknown.

platelet storage pool deficiency

Research Areas By Genotype

This mouse can be used to support research in many areas including:

Diabetes and Obesity Research
- Hyperglycemia
- Type 2 Diabetes (NIDDM)
Internal/Organ Research
- Wound Healing
  - delayed/impaired

Genotype: Dock7^m related

Dermatology Research
- Color and White Spotting Defects

Genotype: Lepr^db related

Immunology, Inflammation and Autoimmunity Research
- Immunodeficiency Associated with Other Defects
Internal/Organ Research
- Adipose Defects
Reproductive Biology Research
- Fertility Defects
Mouse/Human Gene Homologs
- obesity, morbid, with hypogonadism (rare)
Diabetes and Obesity Research
- Obesity With Diabetes
- Impaired Wound Healing
- Hyperinsulinemia
- Insulin Resistance
Metabolism Research
Endocrine Deficiency Research
- Adipose Defects
- Hypothalamus/Pituitary Defects
- Pancreas Defects

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Dock7^m/Dock7^m
involves: DBA/J

integument phenotype

diluted coat color
- coat color is not as diluted as that of homozygous dilute (Myo5a^d) or homozygous leaden (Mlph^ln) mice
- individual hairs have more cortical pigment than found in homozygous dilute or homozygous leaden mice

variable body spotting
- white tail tip with or without a white belly spot

pigmentation phenotype

diluted coat color
- coat color is not as diluted as that of homozygous dilute (Myo5a^d) or homozygous leaden (Mlph^ln) mice
- individual hairs have more cortical pigment than found in homozygous dilute or homozygous leaden mice

variable body spotting
- white tail tip with or without a white belly spot

Genotype: Dock7^m/Dock7^m
B6.D(Cg)-Dock7

adipose tissue phenotype

abnormal brown adipose tissue mass
- appears to be completely absent in neonatal mice

decreased white adipose tissue amount
- mice have 21% less inguinal adipose mass

growth/size/body region phenotype

decreased body length
- mutants are 8% shorter

decreased body weight
- mutants weigh 15% less

hematopoietic system phenotype

decreased platelet ADP level
- Normal - however, the platelet count, and platelet serotonin and ATP levels are normal
- platelet ADP levels are low

homeostasis/metabolism phenotype

increased bleeding time

Genotype: Lepr^db/Lepr^db
FVB.BKS-Lepr

endocrine/exocrine gland phenotype

increased pancreatic beta cell number
- obese mice show massive expansion of beta cells (744 insulin +ve cells/islet cross-section in obese vs 165 +ve cells in lean mice); there are 4.5-fold more cells per islet cross-section in obese mice

pancreatic islet hyperplasia
- some islets in obese mice have more than 1000 cells per cross section; such islets are absent in lean mice

renal/urinary system phenotype

abnormal renal glomerulus morphology
- at 7 months of age, obese mice show an increased mesangial matrix in most glomeruli compared to lean controls, resembling diabetic nephropathy; some small glomeruli have separated from the capsule with nearly obliterated microtubules

growth/size/body region phenotype

obese
- mice of both sexes are obese

homeostasis/metabolism phenotype

abnormal circulating glucose level
- Background Sensitivity - after a 2-day fast on refeeding with carbohydrate-free diet, female obese mice show a rise in glucose

hyperglycemia
- fasting mice are hyperglycemic at 3 months of age, while obese B6.BKS-Lepr^db fasted mice are euglycemic
- levels increase from 5 to 7 months in obese females to ~500 ng/ml, significantly higher than the males (~40 ng/ml) or obese B6.BKS-Lepr^db females (~50 ng/ml)
- Background Sensitivity - obese mice have a prolonged period of hyperglycemia compared to obese B6.BKS-Lepr^db mice where glucose levels rarely exceed 250 mg/dl

impaired glucose tolerance
- Background Sensitivity - at 7 months of age obese males are severely glucose intolerant with glucose levels of >400 mg/dl 90 minutes after glucose load compared to obese B6.BKS-Lepr^db mice clear glucose load by 90 min
- Background Sensitivity - obese mice show a rapid increase of blood glucose above 400 mg/dl with diminished rate of glucose clearance

increased circulating insulin level
- Background Sensitivity - /ml)
- Background Sensitivity - at 3 months of age, females show a trend toward higher insulin levels compared to obese B6.BKS-Lepr^db females; at 5-7 months insulin levels (~500 ng/ml) are ~10-fold higher than levels in obese female obese B6.BKS-Lepr^db mice (~50 ng/ml)

insulin resistance
- at 7 months of age, 3U/kg of insulin does not alter circulating glucose levels, while in B6.BKS-Lepr mice, glucose decreases by 50% by 40 minutes; 12U/kg insulin does not cause a decrease in glucose in obese female mice on the FVB background
- at a dose of 3U/kg 6-week old mice show a diminished response to insulin
- circulating insulin levels in the fed state show that obese mice have exteme insulin resistance

Genotype: Lepr^db/Lepr^db
B6.Cg-Dock7 +/+ Lepr/J

behavior/neurological phenotype

polyphagia

reduced male mating frequency

hematopoietic system phenotype

abnormal leukocyte morphology

decreased leukocyte cell number
- decrease blood leukocyte numbers

increased neutrophil cell number
- increased numbers in bronchoalveolar lavage

homeostasis/metabolism phenotype

abnormal chemokine level
- elevated levels of eotaxin, keratinocyte cytokine, and monocyte chemotactic protein-1 (also elevated in serum) in bronchoalveolar lavage fluid

abnormal circulating cholesterol level

abnormal circulating lipid level
- HDL cholesterol and glucose levels increase concurrently
- Background Sensitivity - plasma lipid levels are similar at 3.5 and 14 months of age on the C57BL/6J background unlike on a C57BL/KsJ background

abnormal glucose homeostasis

abnormal hormone level
- female mice exhibit an increase in hypothalamic gonadotrophin releasing hormone compared to in wild-type mice

abnormal interleukin level
- elevated levels of IL-6 in bronchoalveolar lavage fluid

decreased adiponectin level
- decreased in serum

hyperglycemia

increased circulating cholesterol level
- fasting plasma total cholesterol concentration is increased 2 fold over controls

increased circulating glucose level

increased circulating HDL cholesterol level

increased circulating insulin level

increased circulating interleukin-6 level
- elevated levels of IL-6 in serum

increased circulating LDL cholesterol level

increased circulating leptin level

increased circulating triglyceride level
- triglyceride levels are elevated 1.5- to 2-fold

increased circulating VLDL cholesterol level

cardiovascular system phenotype

abnormal myocardial fiber morphology
- exhibit myocyte hypertrophy

heart left ventricle hypertrophy
- increase in left ventricle wall thickness and mass is seen by 6 months of age but not at 2 months of age
- induced weight loss via leptin infusion, but not via caloric restriction, partially resolves the hypertrophy

immune system phenotype

abnormal chemokine level
- elevated levels of eotaxin, keratinocyte cytokine, and monocyte chemotactic protein-1 (also elevated in serum) in bronchoalveolar lavage fluid

abnormal interleukin level
- elevated levels of IL-6 in bronchoalveolar lavage fluid

abnormal leukocyte morphology

decreased leukocyte cell number
- decrease blood leukocyte numbers

increased circulating interleukin-6 level
- elevated levels of IL-6 in serum

increased neutrophil cell number
- increased numbers in bronchoalveolar lavage

lung inflammation
- elevated levels of eotaxin, Il6, keratinocyte cytokine, monocyte chemotactic protein-1, and neutrophiles in bronchoalveolar lavage as a result of ozone exposure
- elevated pulmonary levels of Il1beta mRNA 24 hours after ozone exposure
- elevated pulmonary levels of TNF mRNA 24 hours after ozone exposure but to a lesser extent than in controls
- ozone induces a nonsignificant elevation of TNFR2 levels
- ozone induces significantly elevated levels of TNFR1

muscle phenotype

abnormal myocardial fiber morphology
- exhibit myocyte hypertrophy

heart left ventricle hypertrophy
- increase in left ventricle wall thickness and mass is seen by 6 months of age but not at 2 months of age
- induced weight loss via leptin infusion, but not via caloric restriction, partially resolves the hypertrophy

neoplasm

increased metastatic potential
- increased metastasis to the lung of both melanoma cell lines and lung cancer cell lines initially injected in the tail vein

nervous system phenotype

abnormal hypothalamus physiology

reproductive system phenotype

abnormal female reproductive system morphology
- atrophy of the reproductive organs

absent estrous cycle
- mice exhibit diestrous vaginal acyclicity or occasional metestrous acyclicity

absent estrus
- females never show signs of vaginal oestrous

anovulation

constricted vagina orifice

female infertility
- all females fail to reproduce

small uterus

respiratory system phenotype

abnormal functional residual capacity
- pressure volume curves shifted to the right
- reduced

abnormal lung compliance
- responsiveness to methacholine and serotonin is much greater than controls
- total lung resistance increases much more in response to ozone than in control mice

abnormal respiratory mechanics
- end-expiratory pause increases considerably less than in controls after ozone exposure

decreased pulmonary ventilation
- ventilation volumes decline with ozone exposure but to a lesser degree than for controls

lung inflammation
- elevated levels of eotaxin, Il6, keratinocyte cytokine, monocyte chemotactic protein-1, and neutrophiles in bronchoalveolar lavage as a result of ozone exposure
- elevated pulmonary levels of Il1beta mRNA 24 hours after ozone exposure
- elevated pulmonary levels of TNF mRNA 24 hours after ozone exposure but to a lesser extent than in controls
- ozone induces a nonsignificant elevation of TNFR2 levels
- ozone induces significantly elevated levels of TNFR1

growth/size/body region phenotype

decreased body length
- snout to anus length is decreased by about 5% compared to wild-type mice

obese
- body weight is 10% and 20% more in males and females, respectively, compared to Leprr^tm1Mgmj homozygotes
- body weight is 2- to 3-fold more than in wild-type mice by 10 weeks of age
- develop progressive obesity
- increase in body weight becomes apparent at 4-6 weeks of age

Genotype: Lepr^db/Lepr⁺
B6.Cg-Dock7 +/+ Lepr/J

growth/size/body region phenotype

increased body weight
- slight but significant increase in body weight compared to wild-type mice

mortality/aging

extended life span
- increased survival when totally deprived of food than wild-type controls
- Background Sensitivity - survival when deprived of food is not as long as when in a C57BLKsS background

Genotype: Lepr^db/Lepr^db
involves: 129S2/SvPas * C57BL/6 * C57BLKS/J

renal/urinary system phenotype

abnormal kidney morphology
- total kidney collagen is increased in females by 96%

abnormal renal glomerulus morphology
- any genotype
- glomerular extracellular matrix (ECM) area in females is increased by 31% compared to wild-type female controls and female single Serpine1-deficient animals; however, when expressed as fractional glomerular ECM area, little difference is observed between any genotype

Genotype: Lepr^db/Lepr^db
involves: C57BL/6 * C57BLKS/J

adipose tissue phenotype

increased percent body fat/body weight

homeostasis/metabolism phenotype

abnormal oxygen consumption
- oxygen consumption normalized to lean mass is increased compared to wild-type controls but oxygen consumption normalized to metabolic size is decreased compared to wild-type controls

hyperglycemia

impaired adaptive thermogenesis
- thermoregulation in response to cold exposure is severely impaired compared to wild-type controls

impaired glucose tolerance

increased circulating glucose level

increased circulating insulin level

increased circulating leptin level

insulin resistance

limbs/digits/tail phenotype

short femur

reproductive system phenotype

abnormal female reproductive system morphology

absent estrous cycle

absent estrus

female infertility

skeleton phenotype

short femur

behavior/neurological phenotype

abnormal eating behavior

hypoactivity
- decreased activity in both the light and dark cycle

polyphagia

growth/size/body region phenotype

decreased body length

decreased lean body mass

increased body weight

obese
- early onset obesity starting from 4 weeks of age

Genotype: Lepr^db/Lepr^db
B6.BKS(D)-Lepr/J

behavior/neurological phenotype

abnormal behavior
- faster in food finding trials relative to controls

hypoactivity
- during the dark phase

homeostasis/metabolism phenotype

abnormal response/metabolism to endogenous compounds
- mice treated with leptin fail to exhibit a decrease in food intake unlike similarly treated wild-type mice

decreased body temperature

decreased carbon dioxide production

decreased oxygen consumption

impaired glucose tolerance

insulin resistance

renal/urinary system phenotype

glomerulosclerosis
- homozygotes develop significant glomerulosclerosis by 18 weeks of age

The following phenotype relates to a compound genotype created using this strain

Genotype: Lepr^db/Lepr^db
involves: C57BLKS/J

adipose tissue phenotype

abnormal adipose tissue morphology
- increase in adipose tissue weight in both males and females

increased total body fat amount
- increase in total fat content

reproductive system phenotype

abnormal endometrium morphology
- basal membrane of epithelial cells displays a folded contour at locations where lipid accumulates
- increased volume and density of lipid inclusion vacuoles
- tissue norepinephrin levels elevated by 4 weeks of age and remain elevated

abnormal uterus morphology

decreased uterus weight
- 1/3 normal tissue weight by 12 weeks
- decreased relative to controls by 4 weeks of age

vision/eye phenotype

abnormal intraocular pressure
- modest but significant elevation of intraocular pressure

behavior/neurological phenotype

abnormal conditioned taste aversion behavior
- aversion response is more strongly generalized from saccharin to sucrose
- lower aversion threshold for sucrose than in controls
- recovery from conditioned taste aversion is more rapid than in controls

polydipsia

polyphagia

cellular phenotype

abnormal aerobic respiration
- carbohydrate oxidation becomes reduced
- elevation of fatty acids in perfused hearts causes an increase in fatty acid oxidation combined with a reduction in glucose oxidation rates
- palmitate oxidation is elevated

abnormal respiratory electron transport chain
- state 3 respiration is elevated in cardiac mitochondria incubated with palmitoyl-carnitine but not with pyruvate

endocrine/exocrine gland phenotype

abnormal pancreatic beta cell morphology
- individual beta cell size is increased

abnormal pancreatic beta cell physiology
- beta cells exhibit DNA damage unlike control cells

abnormal pancreatic islet morphology
- islet mass and density are significantly increased compared to wild-type mice

growth/size/body region phenotype

decreased body length
- mutants are about 5% shorter than controls

increased body weight
- by four weeks of age
- overweight by 4 weeks of age

obese

hematopoietic system phenotype

increased glycosylated hemoglobin level
- significant increase in the percentage of plasma glycosylated hemoglobin

homeostasis/metabolism phenotype

abnormal glucose homeostasis
- diabetic phenotype appears earlier in males than in females

abnormal vascular wound healing
- reduced neointimal area relative to controls 4 weeks after femoral artery injury
- vascular smooth muscle proliferation significantly reduced

altered response to myocardial infarction
- homozygotes subjected to 45 min of ischemia display an increase in diastolic dimensions, significant dilatation of left ventricular end-systolic dimensions, a 30% reduction in fractional shortening, and an increase in cardiac hypertrophy, 28 days postreperfusion, indicating decreased tolerance to myocardial infarction

decreased body temperature

decreased circulating glucose level
- mice treated with adenovirus expressing Adipor1 (1.5-fold increase in liver expression), show decreased plasma glucose compared to wild-type
- mice treated with an adenovirus expressing Adipor2 (5-fold increase in liver expression), show decreased plasma glucose compared to wild-type

decreased circulating insulin level
- mice treated with an adenovirus expressing Adipor 2 show improved glucose resistance and decreased plasma insulin level

hyperglycemia
- at 12 weeks
- by 8 weeks
- diabetes is improved after treatment with an adenovirus expressing Adipor1 or Adipor2

hyperlipidemia

impaired adaptive thermogenesis
- mutants become hypothermic after a 12 hour fast
- mutants housed at 4 degrees C for 3.5 hours cannot maintain their body temperature like wild-type and drop about 1 degree in body temperature every 30 min until they reach 34 degrees C, at which point they stabilize this temperature, indicating decreased sympathetic activity
- sympathetic activity

impaired glucose tolerance

increased circulating cholesterol level

increased circulating corticosterone level

increased circulating free fatty acid level

increased circulating glucose level
- plasma fasting glucose is increased

increased circulating insulin level
- fasting insulin is increased
- hyperinsulinemia by 8 weeks

increased circulating leptin level

increased circulating triglyceride level

increased glycosylated hemoglobin level
- significant increase in the percentage of plasma glycosylated hemoglobin

increased urine protein level
- in females when compared to female controls
- levels of protein in urine similar in males and females but levels in males lower than in male controls

insulin resistance
- mice treated with an adenovirus expressing Adipor1 or Adipor 2 show improved insulin resistance

immune system phenotype

increased susceptibility to autoimmune diabetes
- T cells from homozygous mice but not those from heterozygous mice suppressed the beta cell response to glucose + theophylline

liver/biliary system phenotype

increased liver weight

cardiovascular system phenotype

abnormal blood circulation
- reduced aortic flow

abnormal cardiovascular system physiology
- at low fatty acid supply, hearts consume 86% more oxygen (MV_O2) for noncontractile purposes compared with control hearts and a further increase in fatty acid supply has no effect on the already elevated unloaded MV_O2, indicating reduced cardiac efficiency in unloaded hearts

abnormal myocardium layer morphology
- myocardial triacylglycerol content 2X that of controls at 10-18 weeks of age

abnormal vascular wound healing
- reduced neointimal area relative to controls 4 weeks after femoral artery injury
- vascular smooth muscle proliferation significantly reduced

altered response to myocardial infarction
- homozygotes subjected to 45 min of ischemia display an increase in diastolic dimensions, significant dilatation of left ventricular end-systolic dimensions, a 30% reduction in fractional shortening, and an increase in cardiac hypertrophy, 28 days postreperfusion, indicating decreased tolerance to myocardial infarction

cardiac ischemia
- reduced recovery of mechanical function after 13 minutes of ischemia and reperfusion

decreased cardiac muscle contractility
- hearts show a significant increase in the slope of the MV_O2-PVA (pressure volume area) regression line after elevation of fatty acids, suggesting a reduction in contractile efficiency

decreased cardiac output
- cardiac output is reduced in fatty acid perfused hearts

decreased heart rate
- intrinsic heart rates are reduced at all workloads

decreased systemic arterial blood pressure

decreased systemic arterial systolic blood pressure
- decreased peak systolic pressure
- decreased peak systolic pressure X cardiac output
- decreased peak systolic pressure X heart rate

increased left ventricle diastolic pressure
- hearts show a significant increase in the slope of the MV_O2-PVA (pressure volume area) regression line after elevation of fatty acids, suggesting a reduction in contractile efficiency

increased vasoconstriction
- hypercontractility corrollated with the levels of obesity, hyperglycemia, and hyperinsulinemia
- hypercontractility of smooth muscle in aortic strips due to either phenylephrine or serotonin
- maximal contractions increase with age rather than decrease as in controls

mortality/aging

increased sensitivity to induced morbidity/mortality
- homozygotes subjected to 30 and 45 min of left coronary artery occlusion show survival rates of 58% and 44%, respectively, at 28 days after reperfusion, compared to 100% and 88% in controls
- homozygotes subjected to 30, 45, and 60 min of left coronary artery ischemia-reperfusion exhibit survival rates of 71%, 53%, and 18%, respectively, at 24 h after reperfusion, much lower than in controls

muscle phenotype

abnormal myocardium layer morphology
- myocardial triacylglycerol content 2X that of controls at 10-18 weeks of age

decreased cardiac muscle contractility
- hearts show a significant increase in the slope of the MV_O2-PVA (pressure volume area) regression line after elevation of fatty acids, suggesting a reduction in contractile efficiency

increased vasoconstriction
- hypercontractility corrollated with the levels of obesity, hyperglycemia, and hyperinsulinemia
- hypercontractility of smooth muscle in aortic strips due to either phenylephrine or serotonin
- maximal contractions increase with age rather than decrease as in controls

nervous system phenotype

abnormal hypothalamus physiology
- hypothalamic uptake of norepinephrine is decreased in males

renal/urinary system phenotype

abnormal kidney calyx morphology
- calyceal dilation eventually develops

abnormal kidney papilla morphology
- eventually becomes flattened

abnormal renal glomerulus morphology
- basement membrane becomes thickened with age

increased kidney weight

increased urine protein level
- in females when compared to female controls
- levels of protein in urine similar in males and females but levels in males lower than in male controls

polyuria

renal glomerular immunoglobulin deposits

renal glomerular protein deposits
- large quantites of immunoglobulin and complement are found in the mesangium

Genotype: Lepr^db/Lepr^db
C57BLKS/J-Lepr

behavior/neurological phenotype

polyphagia

cardiovascular system phenotype

abnormal cardiovascular system physiology

decreased cardiac output

decreased heart rate

liver/biliary system phenotype

increased liver weight

renal/urinary system phenotype

increased kidney weight

growth/size/body region phenotype

obese

homeostasis/metabolism phenotype

decreased body temperature

hyperglycemia

hyperlipidemia

increased circulating cholesterol level

increased circulating free fatty acid level

increased circulating insulin level

increased circulating leptin level

increased circulating triglyceride level

Genotype: Lepr^db/Lepr^db
BKS.Cg-Dock7 +/+ Lepr/J

behavior/neurological phenotype

abnormal food intake
- food intake is about 60% of control level

abnormal learning/memory/conditioning

abnormal locomotor circadian rhythm
- daily locomotor activity rhythmicity severely diminished at 13-14 weeks, 75% fail to show significant rhythmicity
- daily locomotor pattern becomes attenuated in 6-8 week old mice but rhythmicity is retained
- daily locomotor rhythmicity restored by feeding restriction during dark phase

abnormal spatial learning
- longer swimming distances than control mice in a Morris water maze test

abnormal spatial reference memory
- cross the original platform location less frequently than do controls in a Morris water maze test

cellular phenotype

abnormal axon extension
- axonal growth cone extension fails to occur for neurons treated in culture with 100ng/ml of leptin

endocrine/exocrine gland phenotype

increased glucagon secretion
- increased secreation of glucagon by pancreatic cells in culture

growth/size/body region phenotype

increased body weight

obese
- become progressively obese starting at 5 weeks of age
- weight reaches 2.5X that of control mice by 3 months of age

weight loss
- body weight drops after 6 days on feeding restriction during the dark phase

homeostasis/metabolism phenotype

abnormal circulating cholesterol level

abnormal circulating glucose level

abnormal circulating lipid level
- Background Sensitivity - but have significantly higher plasma triglyceride levels
- Background Sensitivity - plasma lipid levels differ between young and old mutants unlike on the C57BL/6J background where levels are similar at both ages; 14-month old mice have lower triglycerides, HDL cholesterol and combined VLDL + LDL cholesterol levels than 14-week old mice, but have significantly higher plasma triglyceride levels

albuminuria
- moderate albuminuria is observed at 26 weeks of age

decreased circulating glucose level
- affect of BDNF on blood glucose becomes progressively less as mice age
- brain derived neurotrophic factor (BDNF) causes a drop in blood glucose relative to controls 8 weeks after treatment
- glucose levels are reduced at all times tested when mice are placed on feeding restriction during the dark phase
- neurotrophin 3 also causes a drop in blood glucose but the glucose levels return to normal by 24 hours after treatment

decreased circulating insulin level
- BDNF causes a 50% reduction in plasma insulin relative to controls
- morning insulin levels lowered when feeding is restricted during the dark phase

decreased circulating triglyceride level
- triglyceride levels are reduced at all times tested when mice are placed on feeding restriction during the dark phase

decreased prostaglandin level
- in diabetic wounds, PGE2 level is consistently less than 50% of wild-type wounds at all times

decreased urine albumin level
- )
- mutants treated with sRAGE do not show the increased albumin excretion seen in untreated mutants (0.11 ug albumin/ug creatinine vs 0.20 ug albumin/ ug creatinine); levels are not significantly different from control animals (0.08 ug albumin/ ug creatinine)

delayed wound healing
- T26A, a prostaglandin transporter inhibitor, topically applied to wounds shortened wound closure to 16 days in mutants, similar to untreated controls; T26A increased re-epithelialization, neovascularization, and blood flow in wounds
- wound healing is impaired, with an average wound closure time of 22 days, 7 days longer than in controls

hyperglycemia
- fasting blood glucose level is significantly higher than control at 26 weeks of age

improved glucose tolerance
- BDNF treatment causes a lower blood glucose level response in a glucose tolerance test

increased circulating cholesterol level
- fasting plasma total cholesterol concentration is increased 2 fold over controls

increased circulating glucose level
- blood glucose shows a progressive increase from 5 through 33 weeks

increased circulating HDL cholesterol level

increased circulating LDL cholesterol level

increased circulating triglyceride level
- triglyceride levels are elevated 1.5- to 2-fold

increased circulating VLDL cholesterol level

increased glucagon secretion
- increased secreation of glucagon by pancreatic cells in culture

muscle phenotype

abnormal myocardial fiber morphology
- dense bodies present in places normally occupied by mitochondria
- disrupted sarcomeres sometimes
- presence of many lipid droplets

nervous system phenotype

abnormal axon extension
- axonal growth cone extension fails to occur for neurons treated in culture with 100ng/ml of leptin

abnormal axon morphology
- non significant shift toward smaller fiber diameter at 15 weeks of age
- shift of unmyelinated fibers to smaller diameters
- significantly shifted to smaller diameter fibers by 25 weeks in ventral roots, dorsal roots, sural nerve
- small numbers of very large unmyelinated fibers (up to 1.6 micrometers)
- smaller diameter nerve fibers in peroneal, phrenic and vagus nerves at 25 weeks but not significant

abnormal CNS synaptic transmission

abnormal myelin sheath morphology
- number of myelin lamellae relative to nerve diameter is increased

abnormal nerve conduction
- insulin treatment results in improved conductance but only for the duration of treatment and control levels of conductance are never restored
- motor nerve conductance significantly lower than controls from 7 weeks of age onward
- no conductance improvement is seen in mice over 23 weeks in age due to insulin treatment
- velocity returns to and is maintained at prediabetic levels by 15 weeks of age whereas control mice show a continuous increase in velocity

abnormal nervous system morphology

absent long term depression
- CA1 hippocampal slices indicate no long term depression on recordings of excitatory post-synaptic potentials

decreased motor neuron number
- myelinated fiber density increases in most nerves (not the peroneal and phrenic nerves)
- myelinated fibers reduced in numbers at 25 weeks in the sural nerve
- unmyelinated fiber density increase in the sural, peroneal, and vagus nerves
- unmyelinated fibers reduced in numbers at 25 weeks in the vagus nerve

reduced long term potentiation
- CA1 hippocampal slices indicate brief post tetanic potentiation but no long term potentiation on recordings of excitatory post-synaptic potentials

renal/urinary system phenotype

albuminuria
- moderate albuminuria is observed at 26 weeks of age

decreased urine albumin level
- )
- mutants treated with sRAGE do not show the increased albumin excretion seen in untreated mutants (0.11 ug albumin/ug creatinine vs 0.20 ug albumin/ ug creatinine); levels are not significantly different from control animals (0.08 ug albumin/ ug creatinine)

expanded mesangial matrix
- moderate mesangial expansion is observed in glomeruli at 26 weeks

increased creatinine clearance
- ght)
- male mutants treated with sRAGE to achieve RAGE blockade display increased creatinine clearance (~5.1 ml/hour/100 x g body weight) compared to PBS-treated mutants (~3 ml/hour/100 x g body weight), approaching wild-type levels (6.7 ml/hour/100 x g body weight)

vision/eye phenotype

abnormal eye electrophysiology
- delays in oscillatory potentials 1, 2, 3 although only the delay in "OP1" is significant
- prolonged latency of the b-wave in the retina

cardiovascular system phenotype

abnormal myocardial fiber morphology
- dense bodies present in places normally occupied by mitochondria
- disrupted sarcomeres sometimes
- presence of many lipid droplets

abnormal vascular development
- dense bodies found in the smooth muscle of intramyocardial arteries

Genotype: Lepr^db/Lepr^db
BKS.Cg-Dock7 +/+ Lepr/OlaHsd

digestive/alimentary phenotype

abnormal digestive system physiology
- transepithelial resistance in the epithelium is reduced, indictive of a disrupted mucosal barrier function

abnormal intestinal epithelium morphology
- reduced levels of occludin in intestinal sections
- zonula occludens 1 has a discontinuous distribution

immune system phenotype

abnormal acute inflammation
- higher levels of endotoxin are found in portal blood (entotoxemia)

abnormal chemokine secretion
- increased release of monocyte chemo attractant protein by hepatic stellate cells

increased interleukin-6 secretion
- increased release by hepatic stellate cells

increased susceptibility to endotoxin shock
- increased succeptibility of hepatic stellate cells to LPS

liver inflammation

liver/biliary system phenotype

liver inflammation

Genotype: Lepr^db/Lepr⁺
involves: C57BLKS/J

adipose tissue phenotype

increased total body fat amount
- 20% greater adipose tissue mass during pregnancy than in controls

homeostasis/metabolism phenotype

abnormal circulating insulin level
- 2.2X increase in fasting insulin during pregnancy compared to a 3X increase in controls
- leptin treatment results in a 14% reduction in insulin levels compared to a 45% reduction in controls

abnormal glucose homeostasis

abnormal hormone level
- elevated placental leptin levels in pregnant females

decreased circulating insulin level
- pregnant dams exhibit lower fasting insulin levels than wild-type mothers

impaired glucose tolerance
- 45-55% higher glucose levels after a glucose challenge but dramatically improved by leptin treatment and glucose levels reduced 33 and 30% in glucose tolerance tests at 30 and 60 minute time points
- both male and female heterozygous offspring have impaired glucose tolerance irrespective of maternal environment (heterozygous or wild-type mothers)
- females exhibit impaired glucose tolerance during pregnancy
- glucose levels 41% higher in a glucose tolerance test at 30 and at 60 minute time points
- profound glucose intolerance during pregnancy

increased circulating glucose level
- fasting glucose levels elevated 25% during pregnancy

increased circulating leptin level
- heterozygous offspring exhibit an increase in leptin levels at 6 months of age
- mothers exhibit higher circulating leptin levels than wild-type mothers

behavior/neurological phenotype

increased food intake
- food intake 11% greater than controls during pregnancy
- leptin treatment suppresses food intake to near control levels

cellular phenotype

maternal effect
- offspring born from heterozygous mothers with gestational diabetes have lower fasting insulin levels and worse glucose tolerance than offspring born from wild-type mothers
- wild-type males born to heterozygous mothers are heavier than wild-type mice born to wild-type mothers, but postnatal weight gain of female offspring is not affected by the maternal environment

embryo phenotype

enlarged placenta
- placentas from heterozygous fetuses are larger than those of wild-type fetuses, irrespective of maternal genotype

growth/size/body region phenotype

increased birth weight
- heterozygous fetuses carried by wild-type dams exhibit a 5% higher birth weight than wild-type littermates
- heterozygous fetuses from heterozygous mothers are 3% bigger than wild-type littermates
- Normal - however, wild-type pups from heterozygous mothers are no bigger than wild-type fetuses carried by wild-type mothers

increased body weight
- heterozygous pregnant dams are heavier than wild-type mothers at E18.5
- male and female heterozygous offspring from both normal and complicated pregnancies, are heavier than wild-type littermates at 3 and 6 months of age

increased susceptibility to weight gain
- 33% greater maternal weight gain
- birth weights significantly heavier than controls and unaffected by maternal leptin treatment unlike controls where maternal leptin treatment causes a decrease in birth weights
- maternal body weight at term 24% greater than controls

Genotype: Dock7^m/Dock7⁺ Lepr^db/Lepr⁺
BKS.Cg-Dock7 +/+ Lepr/J

mortality/aging

extended life span
- increased survival when totally deprived of food than wild-type controls
- Background Sensitivity - survival when deprived of food is longer rhan when in a C57BL/6 background

Genotype: Dock7^m/Dock7^m
BKS.Cg-Dock7 +/+ Lepr/BomTac

mammalian phenotype

behavior/neurological phenotype
- Normal - e; anxiety-like behavior in a light-dark transfer test; and preference for social familiarity/novelty
- Normal - homozygous mutant and wild type control (C57BL/6J) mice exhibit similar locomotor activity; response in the tail-suspension test for depressive behavior; learning as measured by habituation of object exploration; working memory as measured using the Y maze; anxiety-like behavior in a light-dark transfer test; and preference for social familiarity/novelty

Genotype: Lepr^db/Lepr^db
BKS.Cg-Dock7 +/+ Lepr/Jcl

adipose tissue phenotype

abnormal epididymal fat pad morphology
- the epididymal fat pad exhibits macrophage infiltration unlike in wild-type mice

cellular phenotype

increased pancreatic islet cell apoptosis
- pancreatic islet cell apoptosis is increased compared to in heterozygous mice

endocrine/exocrine gland phenotype

abnormal pancreas physiology
- at 8 weeks, pancreatic islet cell proliferation is increased compared to in heterozygous mice
- Normal - however, pancreatic islet cell proliferation by 16 weeks is normal

increased pancreatic beta cell mass

increased pancreatic islet cell apoptosis
- pancreatic islet cell apoptosis is increased compared to in heterozygous mice

homeostasis/metabolism phenotype

hyperglycemia

increased circulating insulin level

Phenotype Information

Phenotype details on BKS.Cg-Dock7^m +/+ Lepr^db/J

References

Gueorguiev M; Goth ML; Korbonits M. 2001. Leptin and puberty: a review. Pituitary 4(1-2):79-86PubMed: 11824512 MGI: J:109856
Kampfer H; Paulukat J; Muhl H; Wetzler C; Pfeilschifter J; Frank S. 2000. Lack of interferon-gamma production despite the presence of interleukin-18 during cutaneous wound healing. Mol Med 6(12):1016-27PubMed: 11474118 MGI: J:109870
Fantuzzi G; Faggioni R. 2000. Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol 68(4):437-46PubMed: 11037963 MGI: J:109886
Yoon JW; Leiter EH; Coleman DL; Kim MK; Pak CY; McArthur RG; Roncari DA. 1988. Genetic control of organ-reactive autoantibody production in mice by obesity (ob) diabetes (db) genes. Diabetes 37(9):1287-93PubMed: 3044893 MGI: J:109940
Dardenne M; Savino W; Bach JF. 1984. Autoimmune mice develop antibodies to thymic hormone: production of anti-thymulin monoclonal autoantibodies from diabetic (db/db) and B/W mice. J Immunol 133(2):740-3PubMed: 6539799 MGI: J:109953
Mandel MA; Mahmoud AA. 1978. Impairment of cell-mediated immunity in mutation diabetic mice (db/db). J Immunol 120(4):1375-7PubMed: 347001 MGI: J:109964
Leiter EH; Chapman HD. 1994. Obesity-induced diabetes (diabesity) in C57BL/KsJ mice produces aberrant trans-regulation of sex steroid sulfotransferase genes. J Clin Invest 93(5):2007-13PubMed: 8182132 MGI: J:17991
Serreze DV; Leiter EH; Kuff EL; Jardieu P; Ishizaka K. 1988. Molecular mimicry between insulin and retroviral antigen p73. Development of cross-reactive autoantibodies in sera of NOD and C57BL/KsJ db/db mice. Diabetes 37(3):351-8PubMed: 3286334 MGI: J:27625
Chen H; Charlat O; Tartaglia LA; Woolf EA; Weng X; Ellis SJ; Lakey ND; Culpepper J; Moore KJ; Breitbart RE; Duyk GM; Tepper RI; Morgenstern JP. 1996. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84(3):491-5PubMed: 8608603 MGI: J:31324
Lee GH; Proenca R; Montez JM; Carroll KM; Darvishzadeh JG; Lee JI; Friedman JM. 1996. Abnormal splicing of the leptin receptor in diabetic mice. Nature 379(6566):632-5PubMed: 8628397 MGI: J:31327
Chua SC Jr; Chung WK; Wu-Peng XS; Zhang Y; Liu SM; Tartaglia L; Leibel RL. 1996. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor [see comments] Science 271(5251):994-6PubMed: 8584938 MGI: J:31419
Hummel KP; Dickie MM; Coleman DL. 1966. Diabetes, a new mutation in the mouse. Science 153(740):1127-8PubMed: 5918576 MGI: J:5010

Additional References

Bahary N; Leibel RL; Joseph L; Friedman JM. 1990. Molecular mapping of the mouse db mutation. Proc Natl Acad Sci U S A 87(21):8642-6PubMed: 1978328 MGI: J:10819
Fiedorek FT Jr; Kay ES. 1994. Mapping of PCR-based markers for mouse chromosome 4 on a backcross penetrant for the misty (m) mutation. Mamm Genome 5(8):479-85PubMed: 7949731 MGI: J:20039
Werner S; Breeden M; Hubner G; Greenhalgh DG; Longaker MT. 1994. Induction of keratinocyte growth factor expression is reduced and delayed during wound healing in the genetically diabetic mouse. J Invest Dermatol 103(4):469-73PubMed: 7930669 MGI: J:20802
Cohen MP; Sharma K; Jin Y; Hud E; Wu VY; Tomaszewski J; Ziyadeh FN. 1995. Prevention of diabetic nephropathy in db/db mice with glycated albumin antagonists. A novel treatment strategy. J Clin Invest 95(5):2338-45PubMed: 7738197 MGI: J:24919
Aichler M; Borgmann D; Krumsiek J; Buck A; MacDonald PE; Fox JEM; Lyon J; Light PE; Keipert S; Jastroch M; Feuchtinger A; Mueller NS; Sun N; Palmer A; Alexandrov T; Hrabe de Angelis M; Neschen S; Tschop MH; Walch A. 2017. N-acyl Taurines and Acylcarnitines Cause an Imbalance in Insulin Synthesis and Secretion Provoking beta Cell Dysfunction in Type 2 Diabetes. Cell Metab 25(6):1334-1347.e4PubMed: 28591636 MGI: J:251858
Leiter EH; Chapman HD; Coleman DL. 1989. The influence of genetic background on the expression of mutations at the diabetes locus in the mouse. V. Interaction between the db gene and hepatic sex steroid sulfotransferases correlates with gender-dependent susceptibility to hyperglycemia. Endocrinology 124(2):912-22PubMed: 2912706 MGI: J:26013
Moellmann J; Klinkhammer BM; Onstein J; Stohr R; Jankowski V; Jankowski J; Lebherz C; Tacke F; Marx N; Boor P; Lehrke M. 2018. Glucagon-Like Peptide 1 and Its Cleavage Products Are Renoprotective in Murine Diabetic Nephropathy. Diabetes 67(11):2410-2419PubMed: 30104246 MGI: J:266068
Barinaga M. 1996. Researchers nail down leptin receptor [news; comment] Science 271(5251):913PubMed: 8584929 MGI: J:31488
Garris DR. 1988. Reproductive tract and pancreatic norepinephrine levels in pre- and overt-diabetic C57BL/KsJ mice: relationship to body weight, blood glucose, serum insulin, and reproductive dysfunction. Proc Soc Exp Biol Med 189(1):79-83PubMed: 3054905 MGI: J:35691
Sviderskaya EV; Novak EK; Swank RT; Bennett DC. 1998. The murine misty mutation: phenotypic effects on melanocytes, platelets and brown fat. Genetics 148(1):381-90PubMed: 9475748 MGI: J:45425
Truett GE; Tempelman RJ; Walker JA; Wilson JK. 1998. Misty (m) affects growth traits. Am J Physiol 275(1 Pt 2):R29-32PubMed: 9688956 MGI: J:48831
Coleman DL; Hummel KP. 1973. The influence of genetic background on the expression of the obese (Ob) gene in the mouse. Diabetologia 9(4):287-93PubMed: 4588246 MGI: J:5400
Herberg L; Coleman DL. 1977. Laboratory animals exhibiting obesity and diabetes syndromes. Metabolism 26(1):59-99PubMed: 834144 MGI: J:5759
Coleman DL. 1978. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 14(3):141-8PubMed: 350680 MGI: J:5986
Coleman DL. 1979. Obesity genes: beneficial effects in heterozygous mice. Science 203(4381):663-5PubMed: 760211 MGI: J:6081
Giacomelli F; Wiener J. 1979. Primary myocardial disease in the diabetic mouse. An ultrastructural study. Lab Invest 40(4):460-73PubMed: 431046 MGI: J:6115
Johnson LM; Sidman RL. 1979. A reproductive endocrine profile in the diabetes (db) mutant mouse. Biol Reprod 20(3):552-9PubMed: 378276 MGI: J:6157
Trayhurn P. 1979. Thermoregulation in the diabetic-obese (db/db) mouse. The role of non-shivering thermogenesis in energy balance. Pflugers Arch 380(3):227-32PubMed: 573463 MGI: J:6202
Leiter EH; Coleman DL; Eppig JJ. 1979. Endocrine pancreatic cells of postnatal diabetes (db) mice in cell culture. In Vitro 15(7):507-21PubMed: 393618 MGI: J:6264
Robertson DM; Sima AA. 1980. Diabetic neuropathy in the mutant mouse [C57BL/ks(db/db)]: a morphometric study. Diabetes 29(1):60-7PubMed: 6991317 MGI: J:6323
Kawai K; Sugimoto K; Nakashima K; Miura H; Ninomiya Y. 2000. Leptin as a modulator of sweet taste sensitivities in mice Proc Natl Acad Sci U S A 97(20):11044-9PubMed: 10995460 MGI: J:64744
Memon RA; Tecott LH; Nonogaki K; Beigneux A; Moser AH; Grunfeld C; Feingold KR. 2000. Up-regulation of peroxisome proliferator-activated receptors (PPAR-alpha) and PPAR-gamma messenger ribonucleic acid expression in the liver in murine obesity: troglitazone induces expression of PPAR-gamma-responsive adipose tissue-specific genes in the liver of obese diabetic mice [In Process Citation] Endocrinology 141(11):4021-31PubMed: 11089532 MGI: J:65569
Di Marzo V; Goparaju SK; Wang L; Liu J; Batkai S; Jarai Z; Fezza F; Miura GI; Palmiter RD; Sugiura T; Kunos G. 2001. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410(6830):822-5PubMed: 11298451 MGI: J:68834
Won Hong S; Isono M; Chen S; Iglesias-De La Cruz MC; Han DC; Ziyadeh FN. 2001. Increased glomerular and tubular expression of transforming growth factor-beta1, its type II receptor, and activation of the Smad signaling pathway in the db/db mouse. Am J Pathol 158(5):1653-63PubMed: 11337363 MGI: J:69101
Debray-Sachs M; Sai P; Boitard C; Assan R; Hamburger J. 1983. Anti-pancreatic immunity in genetically diabetic mice. Clin Exp Immunol 51(1):1-7PubMed: 6339122 MGI: J:7005
Harris RB; Mitchell TD; Yan X; Simpson JS; Redmann SM Jr. 2001. Metabolic responses to leptin in obese db/db mice are strain dependent. Am J Physiol Regul Integr Comp Physiol 281(1):R115-32PubMed: 11404285 MGI: J:70291
Gilbertson DG; Duff ME; West JW; Kelly JD; Sheppard PO; Hofstrand PD; Gao Z; Shoemaker K; Bukowski TR; Moore M; Feldhaus AL; Humes JM; Palmer TE; Hart CE. 2001. Platelet-derived Growth Factor C (PDGF-C), a Novel Growth Factor That Binds to PDGF alpha and beta Receptor. J Biol Chem 276(29):27406-14PubMed: 11297552 MGI: J:70550
Norido F; Canella R; Zanoni R; Gorio A. 1984. Development of diabetic neuropathy in the C57BL/Ks (db/db) mouse and its treatment with gangliosides. Exp Neurol 83(2):221-32PubMed: 6692864 MGI: J:7294
Shao J; Yamashita H; Qiao L; Draznin B; Friedman JE. 2002. Phosphatidylinositol 3-kinase redistribution is associated with skeletal muscle insulin resistance in gestational diabetes mellitus. Diabetes 51(1):19-29PubMed: 11756318 MGI: J:73759
Jacobi J; Jang JJ; Sundram U; Dayoub H; Fajardo LF; Cooke JP. 2002. Nicotine accelerates angiogenesis and wound healing in genetically diabetic mice. Am J Pathol 161(1):97-104PubMed: 12107094 MGI: J:77831
Semeniuk LM; Kryski AJ; Severson DL. 2002. Echocardiographic assessment of cardiac function in diabetic db/db and transgenic db/db-hGLUT4 mice. Am J Physiol Heart Circ Physiol 283(3):H976-82PubMed: 12181126 MGI: J:78898
Manodori AB; Kuypers FA. 2002. Altered red cell turnover in diabetic mice. J Lab Clin Med 140(3):161-5PubMed: 12271273 MGI: J:79265
Teixeira SR; Tappenden KA; Erdman JW Jr. 2003. Altering dietary protein type and quantity reduces urinary albumin excretion without affecting plasma glucose concentrations in BKS.cg-m +Lepr db/+Lepr db (db/db) mice. J Nutr 133(3):673-8PubMed: 12612136 MGI: J:82219
Wendt TM; Tanji N; Guo J; Kislinger TR; Qu W; Lu Y; Bucciarelli LG; Rong LL; Moser B; Markowitz GS; Stein G; Bierhaus A; Liliensiek B; Arnold B; Nawroth PP; Stern DM; D'Agati VD; Schmidt AM. 2003. RAGE Drives the Development of Glomerulosclerosis and Implicates Podocyte Activation in the Pathogenesis of Diabetic Nephropathy. Am J Pathol 162(4):1123-37PubMed: 12651605 MGI: J:82491
Wang YX; Lee CH; Tiep S; Yu RT; Ham J; Kang H; Evans RM. 2003. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell 113(2):159-70PubMed: 12705865 MGI: J:83119
Peppa M; Brem H; Ehrlich P; Zhang JG; Cai W; Li Z; Croitoru A; Thung S; Vlassara H. 2003. Adverse effects of dietary glycotoxins on wound healing in genetically diabetic mice. Diabetes 52(11):2805-13PubMed: 14578300 MGI: J:86304
Schmidt RE; Dorsey DA; Beaudet LN; Frederick KE; Parvin CA; Plurad SB; Levisetti MG. 2003. Non-obese diabetic mice rapidly develop dramatic sympathetic neuritic dystrophy: a new experimental model of diabetic autonomic neuropathy. Am J Pathol 163(5):2077-91PubMed: 14578206 MGI: J:86318
He H; Liu R; Desta T; Leone C; Gerstenfeld LC; Graves DT. 2004. Diabetes causes decreased osteoclastogenesis, reduced bone formation, and enhanced apoptosis of osteoblastic cells in bacteria stimulated bone loss. Endocrinology 145(1):447-52PubMed: 14525917 MGI: J:87439
Bouchard G; Johnson D; Carver T; Paigen B; Carey MC. 2002. Cholesterol gallstone formation in overweight mice establishes that obesity per se is not linked directly to cholelithiasis risk. J Lipid Res 43(7):1105-13PubMed: 12091495 MGI: J:88773
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Additional - Dock7^m related

Additional - Lepr^db related

Technical Support

Contact Technical Support

Genotyping Protocols
- Restriction Enzyme Digest: Lepr^db
- End Point Analysis: Lepr^db
- End Point Analysis: Dock7^m-Probe
- QPCR: Dock7^m qPCR
- Genotyping resources and troubleshooting
Dietary Information
- LabDiet® 5K52 formulation (6% fat)
Breeding Considerations

This strain is a good breeder.

Since both males and females homozygous for Lepr^db are sterile, the closely linked coat color mutation, m, has been incorporated into stocks for maintenance of the db mutation. Breeding is performed by mating repulsion double heterozygotes, Dock7^m +/+ Lepr^db, which presumably yield 1/4 diabetics (black, obese at weaning) for studies , 1/2 wild-type repulsion double heterozygotes (black, lean) for futher breeding, and 1/4 misty mice (grey, lean) that can be discarded. The risk of recombination between the Dock7^m and Lepr^db loci is only about 2%, recognizable in pups as young as 3 days old by absence of pigment in paws and tip of tail. Dietary restrictions can prolong life and carbohydrate-free, protein-enriched defined diets can diminish the significantly the severity of the disease.

Wean-aged mice may show signs of barbering that include whisker picking. Affected mice typically regrow whiskers within two weeks after weaning.
- Additional Breeding and Husbandry Support
Appearance
- Lepr^db: black, fat
  Related Genotype: a/a + Lepr^db/+ Lepr^db
  
  Dock7^m Lepr^db: black, lean
  Related Genotype: a/a Dock7^m +/+ Lepr^db
  
  Dock7^m: misty (grey), lean
  Related Genotype: a/a Dock7^m +/Dock7^m +
Citation
When using the BKS.Cg-Dock7^m +/+ Lepr^db/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #000642 in your Materials and Methods section.

Animal Health Reports

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Pricing & Availability

Readily Available

Domestic
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Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service	Genotype	Price
	Heterozygous or wildtype for m, Heterozygous or wildtype for Lepr<db>

We will fulfill your order by providing at least two carriers for each strain ordered. The total number, sex, and genotypes provided will vary, although typically 8 or more animals are provided. Please check genotypes which will be recovered. While the genotypes of all animals produced will be communicated to you prior to scheduling shipment, the genotypes of animals provided may not reflect the mating scheme and genotypes described in the strain description. Animals are typically ready to ship in 11-14 weeks. If a second recovery is required to produce the minimum number of animals, then delivery time would increase to approximately 25 weeks. If we fail to produce animals of the correct genotype, you will not be charged. We cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

Cryorecovery to establish a Dedicated Supply for greater quantities of mice. Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation.

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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JAX® Mice, Products & Services Conditions of Use

"MICE" means mouse strains, their progeny derived by inbreeding or crossbreeding, unmodified derivatives from mouse strains or their progeny supplied by The Jackson Laboratory ("JACKSON"). "PRODUCT(S)" means biological materials supplied by JACKSON, and their derivatives. "SERVICES" means projects conducted by JACKSON for other parties that may include but are not limited to the use of MICE or PRODUCTS. "RECIPIENT" means each recipient of MICE, PRODUCTS, or SERVICES provided by JACKSON including each institution, its employees and other researchers under its control. MICE or PRODUCTS shall not be: (i) used for any purpose other than internal research, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services. Acceptance of MICE, PRODUCTS or SERVICES from JACKSON shall be deemed as agreement by RECIPIENT to these conditions, and departure from these conditions requires JACKSON’s prior written authorization.

No Warranty

MICE, PRODUCTS AND SERVICES ARE PROVIDED "AS IS". JACKSON EXTENDS NO WARRANTIES OF ANY KIND, EITHER EXPRESS, IMPLIED, OR STATUTORY, WITH RESPECT TO MICE, PRODUCTS OR SERVICES, INCLUDING ANY IMPLIED WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, OR ANY WARRANTY OF NON-INFRINGEMENT OF ANY PATENT, TRADEMARK, OR OTHER INTELLECTUAL PROPERTY RIGHTS.

Credit for PRODUCTS or SERVICES

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of, PRODUCTS or SERVICES, JACKSON will, at its option, provide credit or replacement for the PRODUCT received or the SERVICES provided; JACKSON makes no other representations and this shall be the exclusive remedy of the purchaser. Please note specific policy for live mice.

Animal Care and Use for SERVICES

Consistent with the requirement for a written understanding regarding animal care and use, the JACKSON Animal Care and Use Committee will review the animal care and use protocol(s) associated with any SERVICES to be performed at JACKSON, and JACKSON shall have ultimate responsibility and authority for the care of animals while on site or in JACKSON custody.

No Liability

In no event shall JACKSON, its trustees, directors, officers, employees, and affiliates be liable for any causes of action or damages, including any direct, indirect, special, or consequential damages, arising out of the provision of MICE, PRODUCTS, or SERVICES, including economic damage or injury to property and lost profits, and including any damage arising from acts or negligence on the part of JACKSON, its agents or employees. Unless prohibited by law, in purchasing or receiving MICE, PRODUCTS, or SERVICES from JACKSON, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges JACKSON from all such causes of action or damages, and further agrees to defend and indemnify JACKSON from any costs or damages arising out of any third party claims.

MICE, PRODUCTS or SERVICES are to be used in a safe manner and in accordance with all applicable governmental rules and regulations.

The foregoing represents the General Terms and Conditions applicable to JACKSON’s MICE, PRODUCTS or SERVICES. In addition, special terms and conditions of sale of certain MICE, PRODUCTS, or SERVICES may be set forth separately in JACKSON web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, PRODUCTS and SERVICES by JACKSON, and by its licensees and distributors.

Acceptance of delivery of MICE, PRODUCTS or SERVICES shall be deemed agreement to these terms and conditions. No purchase order or other document transmitted by purchaser or recipient that may modify the terms and conditions hereof, shall be in any way binding on JACKSON, and instead the terms and conditions set forth herein, including any special terms and conditions set forth separately, shall govern the sale of MICE, PRODUCTS or SERVICES by JACKSON.

Also Known As: BKS db

Genetic overview

Research Applications

Base Price

Important Note

Detailed Description

Control Suggestions

Additional Information

Selected References

Dock7m

Allele Symbol: Dock7m

Leprdb

Allele Symbol: Leprdb

Disease Terms

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Models with phenotypic similarity to human diseases where etiology is unknown or involving genes where ortholog is unknown.

Research Areas By Genotype

This mouse can be used to support research in many areas including:

Genotype: Dock7m related

Genotype: Leprdb related

Mammalian Phenotype Terms by Genotype

Genotype: Dock7m/Dock7minvolves: DBA/J

integument phenotype

pigmentation phenotype

Genotype: Dock7m/Dock7mB6.D(Cg)-Dock7

adipose tissue phenotype

growth/size/body region phenotype

hematopoietic system phenotype

homeostasis/metabolism phenotype

Genotype: Leprdb/LeprdbFVB.BKS-Lepr

endocrine/exocrine gland phenotype

renal/urinary system phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

Genotype: Leprdb/LeprdbB6.Cg-Dock7 +/+ Lepr/J

behavior/neurological phenotype

hematopoietic system phenotype

homeostasis/metabolism phenotype

cardiovascular system phenotype

immune system phenotype

muscle phenotype

neoplasm

nervous system phenotype

reproductive system phenotype

respiratory system phenotype

growth/size/body region phenotype

Genotype: Leprdb/Lepr+B6.Cg-Dock7 +/+ Lepr/J

growth/size/body region phenotype

mortality/aging

Genotype: Leprdb/Leprdbinvolves: 129S2/SvPas * C57BL/6 * C57BLKS/J

renal/urinary system phenotype

Genotype: Leprdb/Leprdbinvolves: C57BL/6 * C57BLKS/J

adipose tissue phenotype

homeostasis/metabolism phenotype

limbs/digits/tail phenotype

reproductive system phenotype

skeleton phenotype

behavior/neurological phenotype

growth/size/body region phenotype

Genotype: Leprdb/LeprdbB6.BKS(D)-Lepr/J

behavior/neurological phenotype

homeostasis/metabolism phenotype

renal/urinary system phenotype

Genotype: Leprdb/Leprdbinvolves: C57BLKS/J

adipose tissue phenotype

reproductive system phenotype

vision/eye phenotype

behavior/neurological phenotype

cellular phenotype

endocrine/exocrine gland phenotype

growth/size/body region phenotype

hematopoietic system phenotype

homeostasis/metabolism phenotype

immune system phenotype

liver/biliary system phenotype

cardiovascular system phenotype

mortality/aging

muscle phenotype

nervous system phenotype

renal/urinary system phenotype

Dock7^m

Allele Symbol: Dock7^m

Lepr^db

Allele Symbol: Lepr^db

Genotype: Dock7^m related

Genotype: Lepr^db related

Genotype: Dock7^m/Dock7^m
involves: DBA/J

Genotype: Dock7^m/Dock7^m
B6.D(Cg)-Dock7

Genotype: Lepr^db/Lepr^db
FVB.BKS-Lepr

Genotype: Lepr^db/Lepr^db
B6.Cg-Dock7 +/+ Lepr/J

Genotype: Lepr^db/Lepr⁺
B6.Cg-Dock7 +/+ Lepr/J

Genotype: Lepr^db/Lepr^db
involves: 129S2/SvPas * C57BL/6 * C57BLKS/J

Genotype: Lepr^db/Lepr^db
involves: C57BL/6 * C57BLKS/J

Genotype: Lepr^db/Lepr^db
B6.BKS(D)-Lepr/J

Genotype: Lepr^db/Lepr^db
involves: C57BLKS/J

Genotype: Lepr^db/Lepr^db
C57BLKS/J-Lepr

Genotype: Lepr^db/Lepr^db
BKS.Cg-Dock7 +/+ Lepr/J

Genotype: Lepr^db/Lepr^db
BKS.Cg-Dock7 +/+ Lepr/OlaHsd

Genotype: Lepr^db/Lepr⁺
involves: C57BLKS/J

Genotype: Dock7^m/Dock7⁺ Lepr^db/Lepr⁺
BKS.Cg-Dock7 +/+ Lepr/J

Genotype: Dock7^m/Dock7^m
BKS.Cg-Dock7 +/+ Lepr/BomTac

Genotype: Lepr^db/Lepr^db
BKS.Cg-Dock7 +/+ Lepr/Jcl

Additional - Dock7^m related

Additional - Lepr^db related