Phenotypes associated with this allele

• Allele Symbol: Slc2a4^tm1Mch
• Allele Name: targeted mutation 1, Maureen J Charron
• Allele ID: MGI:2149725
• Summary: 7 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Slc2a4^tm1Mch/Slc2a4^tm1Mch	involves: 129/Sv * C57BL/6 * C57BL/6J * CD-1 * SJL	MGI:2175012
hm2	Slc2a4^tm1Mch/Slc2a4^tm1Mch	involves: 129/Sv * C57BL/6 * C57BL/6J * SJL	MGI:3586339
hm3	Slc2a4^tm1Mch/Slc2a4^tm1Mch	involves: 129/Sv * C57BL/6J * SJL	MGI:3625090
hm4	Slc2a4^tm1Mch/Slc2a4^tm1Mch	involves: C57BL/6 * CBA	MGI:3586496
ht5	Slc2a4^tm1Mch/Slc2a4^+	involves: 129/Sv * C57BL/6 * SJL	MGI:3811337
ht6	Slc2a4^tm1Mch/Slc2a4^+	involves: 129/Sv * C57BL/6J * CD-1 * SJL	MGI:3586490
cx7	Pdx1^tm2Cvw/Pdx1^+ Slc2a4^tm1Mch/Slc2a4^+	involves: 129/Sv * Black Swiss * C57BL/6 * SJL	MGI:3811338

Genotype
MGI:2175012

hm1

• Allelic Composition: Slc2a4^tm1Mch/Slc2a4^tm1Mch
• Genetic Background: involves: 129/Sv * C57BL/6 * C57BL/6J * CD-1 * SJL

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

mortality/aging

premature death ( J:49328 )

• most homozygotes die at 5-7 months of age, probably as a result of cardiac dysfunction related to hypertrophy

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:49328 )

N • at 2-4 months, both male and female homozygotes are able to clear glucose as effectively as wild-type mice in oral glucose tolerance tests

N • at this age, homozygotes display normal fasting and fed glucagon levels relative to wild-type mice

abnormal circulating glucose level ( J:49328 )

• at 2-4 months, homozygous males, but not females, show a 34% reduction in fasting glycemia relative to wild-type mice

• at 2-4 months, homozygous males, but not females, show a 20% increase in fed glycemia relative to wild-type mice

• homozygotes exhibit a sexually dimorphic response in the absence of overt diabetes

increased circulating insulin level ( J:49328 )

• at 2-4 months, both male and female homozygotes show a 5-6-fold increase in fed insulin concentrations relative to wild-type mice; in contrast, fasting insulin levels remain unchanged

decreased circulating ketone body level ( J:49328 )

• in the fasted state, both male and female homozygotes show a ~9-fold reduction in serum beta-hydroxybutyrate concentrations relative to wild-type mice

decreased circulating free fatty acids level ( J:49328 )

• at 2-4 months, male and female homozygotes show a 10-20% reduction in serum free fatty levels in the fasted state and a 23-45% reduction in the fed state relative to wild-type mice

insulin resistance ( J:49328 )

• both male and female homozygotes show decreased insulin sensitivity during insulin sensitivity tests

cardiovascular system

increased heart weight ( J:49328 )

• at necropsy, homozygotes have heart weight to body weight ratios 2.3 to 2.5 times those of age-matched wild-type and 1.4 to 1.5 times those of weight-matched wild-type mice

cardiac hypertrophy ( J:49328 )

• at necropsy, 2-4-month-old male and female homozygotes exhibit significant cardiac hypertrophy

adipose tissue

decreased total body fat amount ( J:49328 )

• at 3 months, most male and female homozygotes show a significant reduction in internal fat deposits

decreased gonadal fat pad weight ( J:49328 )

• at 3.5 months, female homozygotes display no ovarian fat pad

growth/size/body

increased heart weight ( J:49328 )

• at necropsy, homozygotes have heart weight to body weight ratios 2.3 to 2.5 times those of age-matched wild-type and 1.4 to 1.5 times those of weight-matched wild-type mice

cardiac hypertrophy ( J:49328 )

• at necropsy, 2-4-month-old male and female homozygotes exhibit significant cardiac hypertrophy

postnatal growth retardation ( J:49328 )

muscle

abnormal muscle physiology ( J:49328 )

• in skeletal muscles, male and female homozygotes show a 30-58% reduction in fasted lactate levels and a 47-70% reduction in fed lactate levels relative to wild-type mice

Genotype
MGI:3586339

hm2

• Allelic Composition: Slc2a4^tm1Mch/Slc2a4^tm1Mch
• Genetic Background: involves: 129/Sv * C57BL/6 * C57BL/6J * SJL

muscle

decreased skeletal muscle glycogen level ( J:75600 )

• dorsal flexors, consisting of the tibialis anterior and extensor digitorum longus muscles, of male homozygotes show a 34% reduction in resting glycogen content relative to wild-type flexors

abnormal skeletal muscle fiber type ratio ( J:75600 )

• mutant dorsal flexor muscles exhibit a decline in the relative number of type IIB (fast-glycolytic) fibers and an increase in the relative number of type IIA (fast-oxidative) fibers

decreased skeletal muscle mass ( J:75600 )

• in homozygotes, dorsal flexor mass is significantly lower than that of wild-type dorsal flexors

impaired skeletal muscle contractility ( J:75600 )

• homozygotes display impaired mechanical performance of the dorsal flexors during shortening contractions

• peak power output is significantly reduced when normalized to muscle mass; decreased contractile performance may be related to low glycogen content in muscle before contraction

increased muscle fatigability ( J:75600 )

• the dorsal flexor complex of homozygotes displays increased susceptibility to fatigue, which may be related to the reduced muscle carbohydrate store

• the work output, both specific and relative, is significantly reduced during the steady-state phase of a fatigue protocol, suggesting a decrease in exercise capacity

homeostasis/metabolism

decreased skeletal muscle glycogen level ( J:75600 )

• dorsal flexors, consisting of the tibialis anterior and extensor digitorum longus muscles, of male homozygotes show a 34% reduction in resting glycogen content relative to wild-type flexors

growth/size/body

cardiac hypertrophy ( J:75600 )

• in contrast to reduced dorsal flexor mass, mutant cardiac mass shows a 1.4-fold increase relative to wild-type cardiac mass

decreased body mass index ( J:75600 )

• homozygotes exhibit a significantly reduced body mass relative to wild-type mice

cardiovascular system

cardiac hypertrophy ( J:75600 )

• in contrast to reduced dorsal flexor mass, mutant cardiac mass shows a 1.4-fold increase relative to wild-type cardiac mass

Genotype
MGI:3625090

hm3

• Allelic Composition: Slc2a4^tm1Mch/Slc2a4^tm1Mch
• Genetic Background: involves: 129/Sv * C57BL/6J * SJL

cardiovascular system

cardiac hypertrophy ( J:107849 )

• observe a unique cardiac hypertrophy characterized by vascular sclerosis, interstitial fibrosis, and concentric hypertrophy, however blood pressure is normal, hearts do not respond to isoproterenol, and glucose uptake and the myosin protein profile are normal

• 2.5-fold increase in the heart weight-to-body weight ratio

• myocyte hypertrophy in all four chambers

thick ventricular wall ( J:107849 )

• 1.5-fold increase in left ventricular free wall thickness

cardiac interstitial fibrosis ( J:107849 )

• throughout the ventricles

growth/size/body

cardiac hypertrophy ( J:107849 )

• observe a unique cardiac hypertrophy characterized by vascular sclerosis, interstitial fibrosis, and concentric hypertrophy, however blood pressure is normal, hearts do not respond to isoproterenol, and glucose uptake and the myosin protein profile are normal

• 2.5-fold increase in the heart weight-to-body weight ratio

• myocyte hypertrophy in all four chambers

cellular

cardiac interstitial fibrosis ( J:107849 )

• throughout the ventricles

Genotype
MGI:3586496

hm4

• Allelic Composition: Slc2a4^tm1Mch/Slc2a4^tm1Mch
• Genetic Background: involves: C57BL/6 * CBA

homeostasis/metabolism

abnormal glucose homeostasis ( J:69914 )

• mutant adipocytes, cardiac and skeletal muscles show abnormal subcellular distribution and impaired insulin-stimulated translocation of leucyl/cystinyl aminopeptidase (LNPEP; an insulin-regulated membrane aminopeptidase sharing the same trafficking route with SLC2A4) from an intracellular compartment to the plasma membrane

• as a result, LNPEP is redistributed to the plasma membrane under basal conditions and no translocation of the enzyme is observed in response to insulin

Genotype
MGI:3811337

ht5

• Allelic Composition: Slc2a4^tm1Mch/Slc2a4⁺
• Genetic Background: involves: 129/Sv * C57BL/6 * SJL

endocrine/exocrine glands

pancreatic islet hyperplasia ( J:97234 )

• islet cell hyperplasia becomes prominent by 40 weeks of age and persists until late in life

• islet mass increases 6- to 8-fold by 21 months of age

• this increase is due only to an increase in beta-cell mass

increased insulin secretion ( J:97234 )

• insulin levels are significantly higher for an hour after glucose administration

• however, the glucose-to-insulin ratio is similar to wild-type

homeostasis/metabolism

increased insulin secretion ( J:97234 )

• insulin levels are significantly higher for an hour after glucose administration

• however, the glucose-to-insulin ratio is similar to wild-type

impaired glucose tolerance ( J:97234 )

• mice have elevated blood glucose levels for at least 2 hours after glucose administration averaging around 350 mg/dl

Genotype
MGI:3586490

ht6

• Allelic Composition: Slc2a4^tm1Mch/Slc2a4⁺
• Genetic Background: involves: 129/Sv * C57BL/6J * CD-1 * SJL

growth/size/body

cardiac hypertrophy ( J:43650 )

• at 8-12 months, male heterozygotes with hyperglycemia and hyperinsulinemia display features of diabetic cardiomyopathy

• 8 of 10 heterozygotes exhibit hypertrophic cardiomyocytes

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:43650 , J:43935 )

N • surprisingly, male heterozygotes display normal fed glucagon, free fatty acid and lactate levels relative to wild-type males (J:43650)

N • at 4-5-months, heterozygotes display normal fed plasma glucose concentrations relative to wild-type (J:43935)

N • at 4-5-months, normoglycemic heterozygotes of normal growth and body composition show no significant changes in plasma free fatty acid levels relative to wild-type mice (J:43935)

abnormal glucose homeostasis ( J:43935 )

• in clamp studies, 4-5-month-old conscious normoglycemic heterozygotes with a 50% increase in fasting insulinemia show a ~55% reduction in the rates of glucose infusion, glucose disappearance, glycolysis, and muscle glucose uptake relative to wild-type mice

• notably, heterozygotes show normal hepatic glucose metabolism i.e. normal intrahepatic distribution of liver glucose fluxes through glucose cycling, gluconeogenesis, and glycogenolysis

hyperglycemia ( J:43650 )

• male heterozygotes display normal fasting glucose levels relative to wild-type mice

• in the fed state, male heterozygotes fall into three subgroups: (i) normal glycemia with normal insulin levels, (ii) normal glycemia with hyperinsulinemia, and (iii) hyperglycemia with hyperinsulinemia

• at 2-4 months, most fed males show normal glycemia and insulinemia with only 14% being overtly hyperglycemic

• at 5-7 months and 8-10 months, 62% and 50% of males, respectively, display fed hyperinsulinemia and hyperglycemia characteristic of NIDDM; ~28-38% of these heterozygotes exhibit normal glycemia with hyperinsulinemia, whereas 11-13% continue to display normal glycemia and insulinemia

increased circulating insulin level ( J:43650 , J:43935 )

• male heterozygotes display normal fasting insulin levels but develop fed hyperinsulinemia followed by fed hyperglycemia at varying ages (J:43650)

• hyperinsulinemia persists until death, in the absence of pancreatic failure (J:43650)

• after an ~6 h fast, 4-5-month-old heterozygotes show an ~50% increase in plasma insulin levels (post-absorptive hyperinsulinemia); as a result, basal rates of hepatic glucose production and plasma glucose concentration are moderately reduced (J:43935)

abnormal glycogen homeostasis ( J:43935 )

• in clamp studies, 4-5-month-old conscious normoglycemic heterozygotes show a ~55% reduction in the rates of glycogen synthesis as a result of decreased stimulation of glucose transport and phosphorylation

• in heterozygotes, insulin-mediated activation of muscle glycogen synthase is comparable to that of wild-type

insulin resistance ( J:43650 , J:43935 )

• in vitro, skeletal muscles of 5-7 month-old males displaying normal glycemia with fed insulinemia show insulin resistance characteristic of NIDDM (J:43650)

• upon insulin stimulation, glucose uptake in the soleus (oxidative, slow-twitch) and EDL (glycolytic, fast-twitch) muscles of hyperinsulinemic males is reduced by 38% and 34%, respectively (J:43650)

• at 4-5-months, conscious normoglycemic heterozygotes with a 50% increase in fasting insulinemia exhibit severe peripheral but not hepatic insulin resistance (J:43935)

cardiovascular system

myocardium necrosis ( J:43650 )

• at 8-12 months, hypertrophic hearts of male heterozygotes with hyperglycemia and hyperinsulinemia exhibit diffuse necrosis

cardiac hypertrophy ( J:43650 )

• at 8-12 months, male heterozygotes with hyperglycemia and hyperinsulinemia display features of diabetic cardiomyopathy

• 8 of 10 heterozygotes exhibit hypertrophic cardiomyocytes

dystrophic cardiac calcinosis ( J:43650 )

• at 8-12 months, hypertrophic hearts of male heterozygotes with hyperglycemia and hyperinsulinemia show focal signs of individual cell necrosis typified by calcification

hypertension ( J:43650 )

• at 10-12 months, male heterozygotes with hyperglycemia and hyperinsulinemia exhibit significantly increased peak arterial blood pressure in the presence of normal ventricular performance

heart inflammation ( J:43650 )

• at 8-12 months, hypertrophic hearts of male heterozygotes with hyperglycemia and hyperinsulinemia display thicker vascular walls and inflammatory cell infiltration

adipose tissue

increased fat cell size ( J:43650 )

• at 8-10 months, male heterozygotes with hyperglycemia and hyperinsulinemia display normal body weights and epididymal fat pad weights; however, adipocyte cell size is increased by 35% in the absence of overt obesity

liver/biliary system

hepatic steatosis ( J:43650 )

• at 8-12 months, 6 of 8 male heterozygotes with hyperglycemia and hyperinsulinemia display liver micro- or macrosteatosis

• surprisingly, heterozygotes with hepatic steatosis continue to exhibit a normal serum lipid content

macrovesicular hepatic steatosis ( J:43650 )

• macrosteatosis involves 30-50% of the hepatic lobule

muscle

myocardium necrosis ( J:43650 )

• at 8-12 months, hypertrophic hearts of male heterozygotes with hyperglycemia and hyperinsulinemia exhibit diffuse necrosis

decreased muscle cell glucose uptake ( J:43935 )

• in clamp studies, 4-5-month-old conscious normoglycemic heterozygotes with a 50% increase in fasting insulinemia show a ~55% reduction in the rate of muscle glucose uptake relative to wild-type mice

decreased skeletal muscle cell glucose uptake ( J:43650 )

• upon insulin stimulation, glucose uptake in the soleus (oxidative, slow-twitch) and EDL (glycolytic, fast-twitch) muscles of hyperinsulinemic males is reduced by 38% and 34%, respectively

immune system

heart inflammation ( J:43650 )

• at 8-12 months, hypertrophic hearts of male heterozygotes with hyperglycemia and hyperinsulinemia display thicker vascular walls and inflammatory cell infiltration

cellular

decreased muscle cell glucose uptake ( J:43935 )

• in clamp studies, 4-5-month-old conscious normoglycemic heterozygotes with a 50% increase in fasting insulinemia show a ~55% reduction in the rate of muscle glucose uptake relative to wild-type mice

decreased skeletal muscle cell glucose uptake ( J:43650 )

• upon insulin stimulation, glucose uptake in the soleus (oxidative, slow-twitch) and EDL (glycolytic, fast-twitch) muscles of hyperinsulinemic males is reduced by 38% and 34%, respectively

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:43650

Genotype
MGI:3811338

cx7

• Allelic Composition: Pdx1^tm2Cvw/Pdx1⁺; Slc2a4^tm1Mch/Slc2a4⁺
• Genetic Background: involves: 129/Sv * Black Swiss * C57BL/6 * SJL

endocrine/exocrine glands

pancreatic islet hyperplasia ( J:97234 )

• islet cell hyperplasia becomes prominent by 40 weeks of age and persists until late in life

• islet mass increases 6- to 8-fold by 21 months of age

• this increase is due only to an increase in beta-cell mass

decreased insulin secretion ( J:97234 )

• insulin levels are lower than wild-type for at least 2 hours after administration of glucose

• insulin-to-glucose ratios are at least three times lower than controls 15 minutes into glucose tolerance tests

• insulin secretion is also significantly decreased during in situ pancreas infusion with either 5.6 mM glucose or 20mM arginine

• there is less insulin per mg of pancreatic protein in mice 31 to 47 weeks in age

homeostasis/metabolism

decreased insulin secretion ( J:97234 )

• insulin levels are lower than wild-type for at least 2 hours after administration of glucose

• insulin-to-glucose ratios are at least three times lower than controls 15 minutes into glucose tolerance tests

• insulin secretion is also significantly decreased during in situ pancreas infusion with either 5.6 mM glucose or 20mM arginine

• there is less insulin per mg of pancreatic protein in mice 31 to 47 weeks in age

increased circulating glucose level ( J:97234 )

• fasting glucose levels rise with age so that by 48 weeks of age half of these mice have a blood glucose level higher than 150mg/dl

• mean glucose levels are significantly higher than controls by 32 weeks of age

decreased circulating insulin level ( J:97234 )

• insulin levels are reduced with age

impaired glucose tolerance ( J:97234 )

• mice have extremely elevated blood glucose levels for at least 2 hours after glucose administration averaging around 475 mg/dl