Mouse Genome Informatics
hm
    Irs2tm1Mfw/Irs2tm1Mfw
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
mortality/aging
• 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)

homeostasis/metabolism
• female homozygotes display reduced plasma testosterone levels relative to wild-type females in both dioestrous and oestrous states (J:64791)
• female homozygotes display reduced plasma estradiol levels relative to wild-type females in both dioestrous and oestrous states (J:64791)
• surprisingly, female homozygotes display low plasma luteinizing hormone levels relative to wild-type females in both dioestrous and oestrous states (J:64791)
• female homozygotes display low plasma prolactin levels relative to wild-type females (J:64791)
• elevated serum insulin levels at 6 weeks (before diabetes developed) and decreased insulin levels at 8 weeks with the onset of diabetes
• 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)
• 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 (J:64791)
• at 8 weeks, circulating leptin levels are increased by >5-fold relative to wild-type levels (J:64791)
• female homozygotes display reduced plasma progesterone levels relative to wild-type females in both dioestrous and oestrous states (J:64791)
• females homozygotes show hypothalamic resistance to leptin, suggesting defects in homeostatic mechanisms involved in leptin sensing and/or signaling (J:64791)
• homozygous males are more severely affected than age-matched females with respect to abnormal glucose homeostasis (J:64791)
• 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)
• 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
• 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)
• 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)
• 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)
• 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
• homozygotes exhibit profound insulin resistance in both skeletal muscle and liver (J:46134)
• insulin resistant compared to wild-type (J:135659)
• dyslipidemia

behavior/neurological
• female homozygotes consume 30% more chow relative to wild-type females (J:64791)
• only 18.2% of female homozygotes vs 100% of wild-type display copulation plugs, suggesting abnormal oestrous cycle and sexual behavior (J:64791)

renal/urinary system
• homozygotes display polyuria without ketosis

endocrine/exocrine glands
• mutant pituitaries contain ~40% less gonadotrophs than wild-type pituitaries
• mutant pituitaries are ~30% smaller
• the size of the intermediate lobe is reduced more than that of other lobes
• individual beta cell size is decreased
• 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)
• at 8 weeks, islet area reduced by threefold due to 50% fewer beta cells
• islet mass and density are significantly decreased compared to wild-type mice
• mutant ovaries show an almost complete absence of corpora lutea (J:64791)
• at 6 weeks, mutant ovaries contain very few surface follicles and show thickening of the cortex relative to wild-type (J:64791)
• adult mutant ovaries contain reduced numbers of primary follicles with few growing follicles reaching an antral phase of development (J:64791)
• at 6 weeks, female homozygotes show normal development of the external genitalia and reproductive tract; however, mutant ovaries are small relative to wild-type (J:64791)

growth/size/body
• female homozygotes store twice as much body fat as age-matched wild-type females (J:64791)
• homozygous neonates are 10% smaller than heterozygous or wild-type littermates
• homozygotes exhibit a small reduction in body weight that persists during weaning and into adulthood (J:46134)
• at 5 weeks, male homozygotes weigh ~18% less than wild-type males (J:74303)
• mice gained weight until about 9 weeks, and began to decline
• female homozygotes weigh 20% more than wild-type females and are obese despite elevated leptin levels (J:64791)

nervous system
• mutant pituitaries contain ~40% less gonadotrophs than wild-type pituitaries
• mutant pituitaries are ~30% smaller
• the size of the intermediate lobe is reduced more than that of other lobes

reproductive system
• mutant ovaries show an almost complete absence of corpora lutea (J:64791)
• at 6 weeks, mutant ovaries contain very few surface follicles and show thickening of the cortex relative to wild-type (J:64791)
• adult mutant ovaries contain reduced numbers of primary follicles with few growing follicles reaching an antral phase of development (J:64791)
• at 6 weeks, female homozygotes show normal development of the external genitalia and reproductive tract; however, mutant ovaries are small relative to wild-type (J:64791)
• at E18.5, mutant ovaries contain decreased numbers of primary oocytes relative to wild-type ovaries (J:64791)
• female homozygotes are resistant to exogenous gonadotropin stimulation (J:64791)
• however, uterine tissues of mutant females respond normally to exogenous sex steroids (J:64791)
• female homozygotes show features of anovulation, such as thickening of the ovarian stroma and absence of corpora lutea (J:64791)
• 61% of female homozygotes fail to cycle and remain in an inactive or dioestrous state (J:64791)
• when bred with homozygous mutant males, 0% of homozygous virgin females become pregnant during an 8-week period (J:64791)
• 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 (J:64791)
• when bred with wild-type males, only 9% of homozygous virgin females (4?6-week-old) become pregnant during an 8-week period (J:64791)
• male homozygotes exhibit reduced fertility; males are adequate breeders only if mated prior to the onset of severe diabetes (J:64791)

adipose tissue
• female homozygotes store twice as much body fat as age-matched wild-type females (J:64791)

Mouse Models of Human Disease
OMIM IDRef(s)
Diabetes Mellitus, Noninsulin-Dependent; NIDDM 125853 J:46134