Mouse Genome Informatics
ht
    Slc2a4tm1Mch/Slc2a4+
involves: 129/Sv * C57BL/6J * CD-1 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
homeostasis/metabolism
N
• surprisingly, male heterozygotes display normal fed glucagon, free fatty acid and lactate levels relative to wild-type males (J:43650)
• at 4-5-months, heterozygotes display normal fed plasma glucose concentrations relative to wild-type (J:43935)
• 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)
• 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
• 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
• 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)
• 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
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
• at 8-12 months, hypertrophic hearts of male heterozygotes with hyperglycemia and hyperinsulinemia exhibit diffuse necrosis
• at 8-12 months, male heterozygotes with hyperglycemia and hyperinsulinemia display features of diabetic cardiomyopathy
• 8 of 10 heterozygotes exhibit hypertrophic cardiomyocytes
• at 8-12 months, hypertrophic hearts of male heterozygotes with hyperglycemia and hyperinsulinemia show focal signs of individual cell necrosis typified by calcification
• at 10-12 months, male heterozygotes with hyperglycemia and hyperinsulinemia exhibit significantly increased peak arterial blood pressure in the presence of normal ventricular performance
• at 8-12 months, hypertrophic hearts of male heterozygotes with hyperglycemia and hyperinsulinemia display thicker vascular walls and inflammatory cell infiltration

adipose tissue
• 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
• at 8-12 months, 6 of 8 male heterozygotes with hyperglycemia and hyperinsulinemia display liver micro- or macrosteatosis; macrosteatosis involves 30-50% of the hepatic lobule
• surprisingly, heterozygotes with hepatic steatosis continue to exhibit a normal serum lipid content

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

cellular
• 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
OMIM IDRef(s)
Diabetes Mellitus, Noninsulin-Dependent; NIDDM 125853 J:43650