Phenotypes Associated with This Genotype

Genotype
MGI:3586490

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

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

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:43650 , J:43935 )

• 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)

• 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 (J:43935)

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

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:43650 , J:43935 )

• 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)

• 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 (J:43935)

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