HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Online-Only Appendix All Versions of this Article: db07-0516v1 57/1/13    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lauritzen, H. P.M.M Articles by Galbo, H. Search for Related Content PubMed PubMed Citation Articles by Lauritzen, H. P.M.M Articles by Galbo, H. Social Bookmarking                What's this?

Denervation and high-fat diet reduce insulin-signalling in t-tubules in skeletal muscle of living mice

¹ Research Division, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA
²Copenhagen Muscle Research Centre, Department of Medical Physiology, The Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark
³Department of Rheumatology, Bispebjerg Hospital, DK-2400, Copenhagen NV, Denmark

Objective.: Insulin stimulates muscle glucose transport by translocation of GLUT4 to sarcolemma and t-tubules. Despite muscle glucose uptake plays a major role in insulin resistance and type II diabetes, the temporal and spatial changes in insulin signalling and GLUT4 translocation during these conditions are not well described.

Research Design and Methods.: We used time-lapse confocal imaging of GFP-ARNO (evaluation of PI3-K activation) and GLUT4-GFP transfected quadriceps muscle in living, anaesthetized mice, either muscle denervated or high-fat fed. T-tubules were visualized with dye Sulforhodamine B. In incubated muscle glucose transport was measured by 2-deoxy-D-[³H]-glucose uptake, and functional detubulation was carried out by osmotic shock. Muscle fibers were immunostained for insulin receptors.

Results.: Denervation and high-fat diet reduced insulin-mediated glucose transport. In denervated muscle insulin-stimulated PIP3 production was abolished in t-tubules, while PIP3 production at sarcolemma was increased 2.6-fold. Correspondingly, GLUT4-GFP translocation to t-tubules was abolished, while translocation to sarcolemma was increased 2.3-fold. In high-fat fed mice a 65% reduction in both insulin-induced t-tubular PIP3 production and GLUT4-GFP translocation was seen. Sarcolemma was less affected with reductions of 40 % in PIP3 production and 15 % in GLUT4-GFP translocation. Access to t-tubules was not compromised and insulin receptor distribution in sarcolemma and t-tubules was unaffected by denervation or high-fat feeding. Detubulation of normal muscle reduced basal and abolished insulin-induced glucose transport.

Conclusions.: Our findings demonstrate, for the first time, that impaired insulin signalling and GLUT4 translocation is compartmentalized in muscle and primarily localized to t-tubules and not sarcolemma during insulin resistance.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?