TY - JOUR
T1 - Regulation of hexokinase II gene expression by glucose flux in skeletal muscle
AU - Tsao, Tsu Shuen
AU - Burcelin, Rémy
AU - Charron, Maureen J.
PY - 1996
Y1 - 1996
N2 - The in vivo studies of transcriptional regulation by glucose, in general, have yielded ambiguous interpretations due to the closed loop relationship between insulin and glucose. Insulin cannot be held as a constant since elevated glucose levels will elicit a corresponding rise in insulin and current animal models of insulinopenia are associated with a plethora of counter-regulatory hormone responses. One potential solution to increase intracellular glucose flux without a further increase in insulin was achieved by transgenic overexpression of the insulin-sensitive glucose transporter, GLUT4, in specific skeletal muscles (previously described in Tsao, T.-S., Burcelin, R., Katz, E. B., Huang, L., and Charron, M. J. (1996) Diabetes 45, 28-36). Using these MLC-GLUT4 transgenic mice as a model, we investigated the effects of increased glucose flux on hexokinase II (HK II) gene expression in skeletal muscle. Under conditions where blood glucose levels were normal and insulin levels decreased by 36%, HK II mRNA level was reduced in non-GLUT4- overexpressing tissues (i.e. heart and adipose tissue) of 2-4-month-old male MLC-GLUT4 transgenic mice. This reduction in HK II mRNA was prevented in skeletal muscle, where overexpression of GLUT4 caused a 2.5-fold increase in basal and insulin-stimulated glucose uptake. The levels of HK II mRNA in heart, muscle, and adipose tissue are paralleled by HK II enzymatic activity. In conclusion: 1) due to relative mild insulin-openia, HK II expression is decreased in non-GLUT4-overexpressing tissues of MLC-GLUT4 mice compared to age/sex-matched controls, and 2) GLUT4-mediated increase in cellular glucose flux can prevent the decrease in HK II expression (in GLUT4-overexpressing tissues) as a result of relative mild insulinopenia. Indeed, during the process of aging, the return of circulating insulin levels of MLC-GLUT4 mice to normal levels is associated with the normalization of HK II expression in all tissues of MLC-GLUT4 and age/sex-matched control mice. We propose that: 1) glucose flux has an amplifying effect on the ability of insulin to stimulate skeletal muscle HK II gene expression and 2) insulin-dependent glucose flux may be a potential mechanism by which HK II gene expression is regulated by sensitivity to insulin.
AB - The in vivo studies of transcriptional regulation by glucose, in general, have yielded ambiguous interpretations due to the closed loop relationship between insulin and glucose. Insulin cannot be held as a constant since elevated glucose levels will elicit a corresponding rise in insulin and current animal models of insulinopenia are associated with a plethora of counter-regulatory hormone responses. One potential solution to increase intracellular glucose flux without a further increase in insulin was achieved by transgenic overexpression of the insulin-sensitive glucose transporter, GLUT4, in specific skeletal muscles (previously described in Tsao, T.-S., Burcelin, R., Katz, E. B., Huang, L., and Charron, M. J. (1996) Diabetes 45, 28-36). Using these MLC-GLUT4 transgenic mice as a model, we investigated the effects of increased glucose flux on hexokinase II (HK II) gene expression in skeletal muscle. Under conditions where blood glucose levels were normal and insulin levels decreased by 36%, HK II mRNA level was reduced in non-GLUT4- overexpressing tissues (i.e. heart and adipose tissue) of 2-4-month-old male MLC-GLUT4 transgenic mice. This reduction in HK II mRNA was prevented in skeletal muscle, where overexpression of GLUT4 caused a 2.5-fold increase in basal and insulin-stimulated glucose uptake. The levels of HK II mRNA in heart, muscle, and adipose tissue are paralleled by HK II enzymatic activity. In conclusion: 1) due to relative mild insulin-openia, HK II expression is decreased in non-GLUT4-overexpressing tissues of MLC-GLUT4 mice compared to age/sex-matched controls, and 2) GLUT4-mediated increase in cellular glucose flux can prevent the decrease in HK II expression (in GLUT4-overexpressing tissues) as a result of relative mild insulinopenia. Indeed, during the process of aging, the return of circulating insulin levels of MLC-GLUT4 mice to normal levels is associated with the normalization of HK II expression in all tissues of MLC-GLUT4 and age/sex-matched control mice. We propose that: 1) glucose flux has an amplifying effect on the ability of insulin to stimulate skeletal muscle HK II gene expression and 2) insulin-dependent glucose flux may be a potential mechanism by which HK II gene expression is regulated by sensitivity to insulin.
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U2 - 10.1074/jbc.271.25.14959
DO - 10.1074/jbc.271.25.14959
M3 - Article
C2 - 8663067
AN - SCOPUS:17544372397
SN - 0021-9258
VL - 271
SP - 14959
EP - 14963
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 25
ER -