Transgenic mice expressing the human GLUT4/muscle-fat facilitative glucose transporter protein exhibit efficient glycemic control.
To examine the physiological role of the GLUT4/muscle-fat specific facilitative glucose transporter in regulating glucose homeostasis, we have generated transgenic mice expressing high levels of this protein in an appropriate tissue-specific manner. Examination of two independent founder lines demonstrated that high-level expression of GLUT4 protein resulted in a marked reduction of fasting glucose levels (approximately 70 mg/dl) compared to wild-type mice (approximately 130 mg/dl). Surprisingly, 30 min following an oral glucose challenge the GLUT4 transgenic mice had only a slight elevation in plasma glucose levels (approximately 90 mg/dl), whereas wild-type mice displayed a typical 2- to 3-fold increase (approximately 250-300 mg/dl). In parallel to the changes in plasma glucose, insulin levels were approximately 2-fold lower in the transgenic mice compared to the wild-type mice. Furthermore, isolated adipocytes from the GLUT4 transgenic mice had increased basal glucose uptake and subcellular fractionation indicated elevated levels of cell surface-associated GLUT4 protein. Consistent with these results, in situ immunocytochemical localization of GLUT4 protein in adipocytes and cardiac myocytes indicated a marked increase in plasma membrane-associated GLUT4 protein in the basal state. Taken together these data demonstrate that increased expression of the human GLUT4 gene in vivo results in a constitutively high level of cell surface GLUT4 protein expression and more efficient metabolic control over fluctuations in plasma glucose concentrations.
Liu
M L
ML
Department of Physiology and Biophysics, University of Iowa, Iowa City 52242.
Gibbs
E M
EM
McCoid
S C
SC
Milici
A J
AJ
Stukenbrok
H A
HA
McPherson
R K
RK
Treadway
J L
JL
Pessin
J E
JE
D017667:Adipocytes / Q000166:cytology; D000818:Animals; D001692:Biological Transport; D001786:Blood Glucose / Q000378:metabolism*; D002451:Cell Compartmentation; D002462:Cell Membrane / Q000378:metabolism; D048429:Cell Size; D005260:Female; D005455:Fluorescent Antibody Technique; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4; D006003:Glycogen / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008861:Microsomes / Q000378:metabolism; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009124:Muscle Proteins; D009132:Muscles / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism
D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495692:SLC2A4 protein, human; C495693:Slc2a4 protein, mouse; D006003:Glycogen