Analysis Tools
cellular
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• at E18.5, mutant ovaries contain decreased numbers of primary oocytes relative to wild-type ovaries
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mortality/aging
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• male mutants die prematurely from dehydration and hyperosomolar coma
(J:46134)
• female mutants exhibit a similar disease progression but rarely die
(J:46134)
• death due to diabetes
(J:94000)
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homeostasis/metabolism
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• female homozygotes display reduced plasma testosterone levels relative to wild-type females in both dioestrous and oestrous states
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• female homozygotes display reduced plasma estradiol levels relative to wild-type females in both dioestrous and oestrous states
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• surprisingly, female homozygotes display low plasma luteinizing hormone levels relative to wild-type females in both dioestrous and oestrous states
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• female homozygotes display low plasma prolactin levels relative to wild-type females
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• elevated serum insulin levels at 6 weeks (before diabetes developed) and decreased insulin levels at 8 weeks with the onset of diabetes
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• at >6 weeks, homozygotes display a 3-fold increase in fasting insulin levels relative to wild-type mice
(J:46134)
• despite fasting hyperinsulinemia, homozygotes respond with a nearly 2-fold increase in insulin levels 60 minutes after glucose loading
(J:46134)
• both fasting and fed insulin levels were higher than in wild-type mice
(J:135659)
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• as early as 4 weeks (i.e. prior to the onset of abnormal glucose tolerance) female homozygotes show a 2.5-fold increase in circulating leptin levels
• at 8 weeks, circulating leptin levels are increased by >5-fold relative to wild-type levels
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• female homozygotes display reduced plasma progesterone levels relative to wild-type females in both dioestrous and oestrous states
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• females homozygotes show hypothalamic resistance to leptin, suggesting defects in homeostatic mechanisms involved in leptin sensing and/or signaling
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• homozygous males are more severely affected than age-matched females with respect to abnormal glucose homeostasis
(J:64791)
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• immediately after treadmill exercise, male homozygotes show an attenuated increase in insulin-stimulated, phosphotyrosine-associated PI 3-kinase activity relative to wild-type males
(J:74303)
• however, insulin-stimulated, phosphotyrosine-associated PI 3-kinase response after exercise is slightly higher than the insulin-stimulated response alone
(J:74303)
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• treadmill exercise reduces blood glucose by ~20% in fasted wild-type mice but has no effect on blood glucose in fasted homozygotes
• plasma insulin concentrations are similar between wild-type and mutant mice at rest and remain unchanged after exercise
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• homozygotes show increased levels of randomly fed sugars at postnatal day 3, and fasting hyperglycemia between 3 and 6 weeks of age
(J:46134)
• at 10 weeks, homozygotes exhibit overt diabetes with fasting glucose levels of 323 35 mg dl-1; if left untreated, the fasting sugar levels rise progressively to >400 mg dl-1 at 12-16 weeks of age
(J:46134)
• seen at about 10 weeks of age
(J:96047)
• developed a progressive increase with severe hyperglycemia
(J:135659)
• fasting glucose levels were higher than in wild-type mice
(J:135659)
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• developed in males between 4 and 6 weeks of age, which progressed to overt diabetes during the next 5-6 weeks until they died
(J:94000)
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• at 6-8 weeks, homozygotes display significant glucose intolerance (>95% penetrance) during an intraperitoneal glucose-tolerance test
(J:46134)
• by 6 weeks, male homozygotes are severely glucose intolerant
(J:64791)
• in contrast, age-matched female homozygotes show only slightly increased blood glucose levels and mildly impaired glucose tolerance, suggesting sexual dimorphism in the diabetic phenotype
(J:64791)
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• at rest, fasted homozygotes tend to have reduced muscle glycogen levels relative to wild-type mice
• after treadmill exercise, homozygotes display significantly lower muscle glycogen levels than wild-type mice
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• homozygotes exhibit profound insulin resistance in both skeletal muscle and liver
(J:46134)
• insulin resistant compared to wild-type
(J:135659)
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• dyslipidemia
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muscle
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• at rest, fasted homozygotes tend to have reduced muscle glycogen levels relative to wild-type mice
• after treadmill exercise, homozygotes display significantly lower muscle glycogen levels than wild-type mice
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behavior/neurological
polydipsia
(
J:46134
)
polyphagia
(
J:64791
)
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• female homozygotes consume 30% more chow relative to wild-type females
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• only 18.2% of female homozygotes vs 100% of wild-type display copulation plugs, suggesting abnormal oestrous cycle and sexual behavior
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renal/urinary system
endocrine/exocrine glands
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• individual beta cell size is decreased
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• at 4 weeks, homozygotes show a significant reduction in pancreatic beta-cell mass indicating failure of compensatory islet hyperplasia
(J:46134)
• no significant difference in non-beta endocrine-cell mass is observed
(J:46134)
• reduced beta cell mass compared to wild-type
(J:135659)
• decreased beta cell proliferation and increased beta cell accounts for reduction in beta cell mass
(J:135659)
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• at 8 weeks, islet area reduced by threefold due to 50% fewer beta cells
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• islet mass and density are significantly decreased compared to wild-type mice
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• mutant pituitaries contain ~40% less gonadotrophs than wild-type pituitaries
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• mutant pituitaries are ~30% smaller
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• the size of the intermediate lobe is reduced more than that of other lobes
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• mutant ovaries show an almost complete absence of corpora lutea
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• at 6 weeks, mutant ovaries contain very few surface follicles and show thickening of the cortex relative to wild-type
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• reduced numbers of primary follicles in adult ovaries
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• adult mutant ovaries contain reduced numbers of primary follicles with few growing follicles reaching an antral phase of development
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small ovary
(
J:64791
)
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• at 6 weeks, female homozygotes show normal development of the external genitalia and reproductive tract; however, mutant ovaries are small relative to wild-type
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growth/size/body
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• homozygous neonates are 10% smaller than heterozygous or wild-type littermates
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• homozygotes exhibit a small reduction in body weight that persists during weaning and into adulthood
(J:46134)
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• at 5 weeks, male homozygotes weigh ~18% less than wild-type males
(J:74303)
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weight loss
(
J:135659
)
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• mice gained weight until about 9 weeks, and began to decline
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• female homozygotes weigh 20% more than wild-type females and are obese despite elevated leptin levels
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nervous system
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• mutant pituitaries contain ~40% less gonadotrophs than wild-type pituitaries
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• mutant pituitaries are ~30% smaller
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• the size of the intermediate lobe is reduced more than that of other lobes
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reproductive system
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• at E18.5, mutant ovaries contain decreased numbers of primary oocytes relative to wild-type ovaries
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• mutant ovaries show an almost complete absence of corpora lutea
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• at 6 weeks, mutant ovaries contain very few surface follicles and show thickening of the cortex relative to wild-type
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• reduced numbers of primary follicles in adult ovaries
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• adult mutant ovaries contain reduced numbers of primary follicles with few growing follicles reaching an antral phase of development
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small ovary
(
J:64791
)
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• at 6 weeks, female homozygotes show normal development of the external genitalia and reproductive tract; however, mutant ovaries are small relative to wild-type
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anovulation
(
J:64791
)
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• female homozygotes show features of anovulation, such as thickening of the ovarian stroma and absence of corpora lutea
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• female homozygotes are resistant to exogenous gonadotropin stimulation
• however, uterine tissues of mutant females respond normally to exogenous sex steroids
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• 61% of female homozygotes fail to cycle and remain in an inactive or dioestrous state
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• when bred with homozygous mutant males, 0% of homozygous virgin females become pregnant during an 8-week period
• at <10 weeks, female homozygotes are relatively euglycemic and mildly insulin resistant, suggesting that female infertility is not a direct result of impaired glucose metabolism
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• when bred with wild-type males, only 9% of homozygous virgin females (4-6-week-old) become pregnant during an 8-week period
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• male homozygotes exhibit reduced fertility; males are adequate breeders only if mated prior to the onset of severe diabetes
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adipose tissue
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• female homozygotes store twice as much body fat as age-matched wild-type females
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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:46134 | |
