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Articles in PresS, published online ahead of print August 13, 2002
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00341.2002
Submitted on July 31, 2002
Accepted on August 12, 2002
1 Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom
2 Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom
* To whom correspondence should be addressed. E-mail: g.d.holman{at}bath.ac.uk.
Abnormalities in intracellular pH regulation have been proposed to be important in Type 2 diabetes and the associated cardiomyopathy and hypertension. We have therefore investigated the dependence of insulin-stimulated glucose transport on cytosolic pH in cardiomyocytes. Insulin treatment of cardiomyocytes resulted in a marked alkalinization of the cytoplasm as measured using carboxy-SNARF 1. The alkalinizing effect of insulin was blocked by treatment with either cariporide (which inhibits the Na+/H+ exchanger) or by bafilomycin A1 (which inhibits H+-ATPase activity). Following treatments with cariporide or bafilomycin A1, insulin stimulation of insulin receptor and IRS1 phosphorylation and Akt activity were normal. By contrast, glucose transport activity and the levels of functional GLUT4 at the plasma membrane (detected using an exofacial photolabel) were reduced by approximately 50%. Immunocytochemical analysis revealed insulin treatment caused a translocation of the GLUT4 from peri-nuclear structures and increased its co-localization with cell surface syntaxin4. However, neither cariporide nor bafilomycin A1 treatment reduced the translocation of immunodetectable GLUT4 to the sarcolemma region of the cell. It is therefore hypothesized that insulin-stimulated cytosol alkalinization facilitates the final stages of translocation and incorporation of fully functional GLUT4 at the surface-limiting membrane.
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