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Publication
Glucose kinetics and exercise tolerance in mice lacking the GLUT4 glucose
transporter.
Authors Fueger PT, Li CY, Ayala JE, Shearer J, Bracy DP, Charron MJ, Rottman JN,
Wasserman DH
Submitted By David Wasserman on 11/6/2007
Status Published
Journal The Journal of physiology
Year 2007
Date Published 7/15/2007
Volume : Pages 582 : 801 - 812
PubMed Reference 17495042
Abstract The absence of GLUT4 severely impairs basal glucose uptake in vivo, but does not
alter glucose homeostasis or circulating insulin. Glucose uptake in isolated
contracting skeletal muscle (MGU) is also impaired by the absence of GLUT4, and
onset of muscle fatigue is hastened. Whether the body can compensate and
preserve glucose homeostasis during exercise, as it does in the basal state, is
unknown. One aim was to test the effectiveness of glucoregulatory compensation
for the absence of GLUT4 in vivo. The absence of GLUT4 was also used to further
define the role of hexokinase (HK) II, which catalyses glucose phosphorylation
after it is transported in the cell. HK II increases MGU during exercise, as
well as exercise endurance. In the absence of GLUT4, HK II expression will not
affect MGU. A second aim was to test whether, in the absence of GLUT4, HK II
retains its ability to increase exercise endurance. Wild-type (WT), GLUT4 null
(GLUT4(-/-)), and GLUT4 null overexpressing HK II (GLUT4(-/-)HK(Tg)) mice were
studied using a catheterized mouse model that allows blood sampling and isotope
infusions during treadmill exercise. The impaired capacity of working muscle to
take up glucose in GLUT4(-/-) is partially offset by an exaggerated increase in
the glucagon: insulin ratio, increased liver glucose production, hyperglycaemia,
and a greater capillary density in order to increase the delivery of glucose to
the exercising muscle of GLUT4(-/-). Hearts of GLUT4(-/-) also exhibited a
compensatory increase in HK II expression and a paradoxical increase in glucose
uptake. Exercise tolerance was reduced in GLUT4(-/-) compared to WT. As
expected, MGU in GLUT4(-/-)HK(Tg) was the same as in GLUT4(-/-). However, HK II
overexpression retained its ability to increase exercise endurance. In
conclusion, unlike the basal state where glucose homeostasis is preserved,
hyperglycaemia results during exercise in GLUT4(-/-) due to a robust stimulation
of liver glucose release in the face of severe impairments in MGU. Finally,
studies in GLUT4(-/-)HK(Tg) show that HK II improves exercise tolerance,
independent of its effects on MGU.




Strains
StrainDevelopment StatusCreation MethodOptions
C57BL/6J-Slc2a4tm1Mch Tg(Hk2)Phenotyping ongoingtransgenic
View
B6.Cg-Slc2a4tm1Mch/+Not specified/Otherknockout
View




Genes
SymbolDescription
Hk2hexokinase 2
Slc2a4solute carrier family 2 (facilitated glucose transporter), member 4

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