adipose tissue phenotype

• increased total body fat amount
  • female homozygotes store twice as much body fat as age-matched wild-type females
  (MGI Ref ID J:64791)

growth/size/body region phenotype

• decreased body weight
  • homozygotes exhibit a small reduction in body weight that persists during weaning and into adulthood
  (MGI Ref ID J:46134)
  • at 5 weeks, male homozygotes weigh ~18% less than wild-type males
  (MGI Ref ID J:74303)

• weight loss
  • mice gained weight until about 9 weeks, and began to decline
  (MGI Ref ID J:135659)

• decreased birth body size
  • homozygous neonates are 10% smaller than heterozygous or wild-type littermates
  (MGI Ref ID J:46134)

• obese
  • female homozygotes weigh 20% more than wild-type females and are obese despite elevated leptin levels
  (MGI Ref ID J:64791)

homeostasis/metabolism phenotype

• abnormal glucose homeostasis
  • however, insulin-stimulated, phosphotyrosine-associated PI 3-kinase response after exercise is slightly higher than the insulin-stimulated response alone
  (MGI Ref ID J:74303)
  • immediately after treadmill exercise, male homozygotes show an attenuated increase in insulin-stimulated, phosphotyrosine-associated PI 3-kinase activity relative to wild-type males
  (MGI Ref ID J:74303)
  • homozygous males are more severely affected than age-matched females with respect to abnormal glucose homeostasis
  (MGI Ref ID J:64791)

• increased circulating insulin level
  • both fasting and fed insulin levels were higher than in wild-type mice
  (MGI Ref ID J:135659)
  • despite fasting hyperinsulinemia, homozygotes respond with a nearly 2-fold increase in insulin levels 60 minutes after glucose loading
  (MGI Ref ID J:46134)
  • at >6 weeks, homozygotes display a 3-fold increase in fasting insulin levels relative to wild-type mice
  (MGI Ref ID J:46134)

• decreased circulating luteinizing hormone level
  • surprisingly, female homozygotes display low plasma luteinizing hormone levels relative to wild-type females in both dioestrous and oestrous states
  (MGI Ref ID J:64791)

• decreased skeletal muscle glycogen level
  • after treadmill exercise, homozygotes display significantly lower muscle glycogen levels than wild-type mice
  (MGI Ref ID J:74303)
  • at rest, fasted homozygotes tend to have reduced muscle glycogen levels relative to wild-type mice
  (MGI Ref ID J:74303)

• hyperglycemia
  • developed a progressive increase with severe hyperglycemia
  (MGI Ref ID J:135659)
  • 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
  (MGI Ref ID J:46134)
  • fasting glucose levels were higher than in wild-type mice
  (MGI Ref ID J:135659)
  • homozygotes show increased levels of randomly fed sugars at postnatal day 3, and fasting hyperglycemia between 3 and 6 weeks of age
  (MGI Ref ID J:46134)
  • seen at about 10 weeks of age
  (MGI Ref ID J:96047)
  • developed in males between 4 and 6 weeks of age, which progressed to overt diabetes during the next 5-6 weeks until they died
  (MGI Ref ID J:94000)

• impaired glucose tolerance
  • at 6-8 weeks, homozygotes display significant glucose intolerance (>95% penetrance) during an intraperitoneal glucose-tolerance test
  (MGI Ref ID J:46134)
  • 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
  (MGI Ref ID J:64791)
  • by 6 weeks, male homozygotes are severely glucose intolerant
  (MGI Ref ID J:64791)

• abnormal circulating insulin level
  • elevated serum insulin levels at 6 weeks (before diabetes developed) and decreased insulin levels at 8 weeks with the onset of diabetes
  (MGI Ref ID J:94000)

• decreased circulating prolactin level
  • female homozygotes display low plasma prolactin levels relative to wild-type females
  (MGI Ref ID J:64791)

• abnormal circulating hormone level
  (MGI Ref ID J:64791)

• abnormal circulating glucose level
  • plasma insulin concentrations are similar between wild-type and mutant mice at rest and remain unchanged after exercise
  (MGI Ref ID J:74303)
  • treadmill exercise reduces blood glucose by ~20% in fasted wild-type mice but has no effect on blood glucose in fasted homozygotes
  (MGI Ref ID J:74303)

• abnormal energy homeostasis
  • females homozygotes show hypothalamic resistance to leptin, suggesting defects in homeostatic mechanisms involved in leptin sensing and/or signaling
  (MGI Ref ID J:64791)

• decreased circulating estradiol level
  • female homozygotes display reduced plasma estradiol levels relative to wild-type females in both dioestrous and oestrous states
  (MGI Ref ID J:64791)

• decreased circulating testosterone level
  • female homozygotes display reduced plasma testosterone levels relative to wild-type females in both dioestrous and oestrous states
  (MGI Ref ID J:64791)

• increased circulating leptin level
  • 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
  (MGI Ref ID J:64791)
  • at 8 weeks, circulating leptin levels are increased by >5-fold relative to wild-type levels
  (MGI Ref ID J:64791)

• insulin resistance
  • homozygotes exhibit profound insulin resistance in both skeletal muscle and liver
  (MGI Ref ID J:46134)
  • insulin resistant compared to wild-type
  (MGI Ref ID J:135659)

• decreased circulating progesterone level
  • female homozygotes display reduced plasma progesterone levels relative to wild-type females in both dioestrous and oestrous states
  (MGI Ref ID J:64791)

• abnormal lipid homeostasis
  • dyslipidemia
  (MGI Ref ID J:96047)

behavior/neurological phenotype

• polyphagia
  • female homozygotes consume 30% more chow relative to wild-type females
  (MGI Ref ID J:64791)

• abnormal mating frequency
  • only 18.2% of female homozygotes vs 100% of wild-type display copulation plugs, suggesting abnormal oestrous cycle and sexual behavior
  (MGI Ref ID J:64791)

• polydipsia
  (MGI Ref ID J:46134)

cellular phenotype

• decreased oocyte number
  • at E18.5, mutant ovaries contain decreased numbers of primary oocytes relative to wild-type ovaries
  (MGI Ref ID J:64791)

mortality/aging

• premature death
  • female mutants exhibit a similar disease progression but rarely die
  (MGI Ref ID J:46134)
  • death due to diabetes
  (MGI Ref ID J:94000)
  • male mutants die prematurely from dehydration and hyperosomolar coma
  (MGI Ref ID J:46134)

endocrine/exocrine gland phenotype

• abnormal ovarian follicle morphology
  • at 6 weeks, mutant ovaries contain very few surface follicles and show thickening of the cortex relative to wild-type
  (MGI Ref ID J:64791)

• small ovary
  • at 6 weeks, female homozygotes show normal development of the external genitalia and reproductive tract; however, mutant ovaries are small relative to wild-type
  (MGI Ref ID J:64791)

• decreased pancreatic beta cell number
  • at 8 weeks, islet area reduced by threefold due to 50% fewer beta cells
  (MGI Ref ID J:94000)

• small pituitary intermediate lobe
  • the size of the intermediate lobe is reduced more than that of other lobes
  (MGI Ref ID J:74303)

• abnormal pancreatic beta cell morphology
  • individual beta cell size is decreased
  (MGI Ref ID J:96047)

• decreased pancreatic beta cell mass
  • at 4 weeks, homozygotes show a significant reduction in pancreatic beta-cell mass indicating failure of compensatory islet hyperplasia
  (MGI Ref ID J:46134)
  • reduced beta cell mass compared to wild-type
  (MGI Ref ID J:135659)
  • no significant difference in non-beta endocrine-cell mass is observed
  (MGI Ref ID J:46134)
  • decreased beta cell proliferation and increased beta cell accounts for reduction in beta cell mass
  (MGI Ref ID J:135659)

• small pancreatic islets
  • islet mass and density are significantly decreased compared to wild-type mice
  (MGI Ref ID J:96047)

• decreased gonadotroph cell number
  • mutant pituitaries contain ~40% less gonadotrophs than wild-type pituitaries
  (MGI Ref ID J:64791)

• absent corpus luteum
  • mutant ovaries show an almost complete absence of corpora lutea
  (MGI Ref ID J:64791)

• small pituitary gland
  • mutant pituitaries are ~30% smaller
  (MGI Ref ID J:64791)

• impaired ovarian folliculogenesis
  • adult mutant ovaries contain reduced numbers of primary follicles with few growing follicles reaching an antral phase of development
  (MGI Ref ID J:64791)

muscle phenotype

• decreased skeletal muscle glycogen level
  • after treadmill exercise, homozygotes display significantly lower muscle glycogen levels than wild-type mice
  (MGI Ref ID J:74303)
  • at rest, fasted homozygotes tend to have reduced muscle glycogen levels relative to wild-type mice
  (MGI Ref ID J:74303)

nervous system phenotype

• small pituitary intermediate lobe
  • the size of the intermediate lobe is reduced more than that of other lobes
  (MGI Ref ID J:74303)

• decreased gonadotroph cell number
  • mutant pituitaries contain ~40% less gonadotrophs than wild-type pituitaries
  (MGI Ref ID J:64791)

• small pituitary gland
  • mutant pituitaries are ~30% smaller
  (MGI Ref ID J:64791)

renal/urinary system phenotype

• polyuria
  • homozygotes display polyuria without ketosis
  (MGI Ref ID J:46134)

reproductive system phenotype

• reduced male fertility
  • male homozygotes exhibit reduced fertility; males are adequate breeders only if mated prior to the onset of severe diabetes
  (MGI Ref ID J:64791)

• impaired ovarian folliculogenesis
  • adult mutant ovaries contain reduced numbers of primary follicles with few growing follicles reaching an antral phase of development
  (MGI Ref ID J:64791)

• absent estrous cycle
  • 61% of female homozygotes fail to cycle and remain in an inactive or dioestrous state
  (MGI Ref ID J:64791)

• female infertility
  • 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
  (MGI Ref ID J:64791)
  • when bred with homozygous mutant males, 0% of homozygous virgin females become pregnant during an 8-week period
  (MGI Ref ID J:64791)

• small ovary
  • at 6 weeks, female homozygotes show normal development of the external genitalia and reproductive tract; however, mutant ovaries are small relative to wild-type
  (MGI Ref ID J:64791)

• absent corpus luteum
  • mutant ovaries show an almost complete absence of corpora lutea
  (MGI Ref ID J:64791)

• reduced female fertility
  • when bred with wild-type males, only 9% of homozygous virgin females (4?6-week-old) become pregnant during an 8-week period
  (MGI Ref ID J:64791)

• abnormal ovulation
  • Normal - however, uterine tissues of mutant females respond normally to exogenous sex steroids
  (MGI Ref ID J:64791)
  • female homozygotes are resistant to exogenous gonadotropin stimulation
  (MGI Ref ID J:64791)

• abnormal ovarian follicle morphology
  • at 6 weeks, mutant ovaries contain very few surface follicles and show thickening of the cortex relative to wild-type
  (MGI Ref ID J:64791)

• abnormal oogenesis
  (MGI Ref ID J:64791)

• anovulation
  • female homozygotes show features of anovulation, such as thickening of the ovarian stroma and absence of corpora lutea
  (MGI Ref ID J:64791)

• decreased oocyte number
  • at E18.5, mutant ovaries contain decreased numbers of primary oocytes relative to wild-type ovaries
  (MGI Ref ID J:64791)