Regulation of Hexokinase II Gene Expression by Glucose Flux in Skeletal Muscle
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...
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Published in | The Journal of biological chemistry Vol. 271; no. 25; pp. 14959 - 14963 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Biochemistry and Molecular Biology
21.06.1996
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Subjects | |
Online Access | Get full text |
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Summary: | 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, 28â36). 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 2â4-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 insulinopenia, 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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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 |
ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.271.25.14959 |