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Am J Physiol Endocrinol Metab 283: E1299-E1307, 2002. First published August 13, 2002; doi:10.1152/ajpendo.00341.2002
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Vol. 283, Issue 6, E1299-E1307, December 2002

Insulin-stimulated cytosol alkalinization facilitates optimal activation of glucose transport in cardiomyocytes

Jing Yang1,*, Alison K. Gillingham1,*, Alois Hodel1, Françoise Koumanov1, Brian Woodward2, and Geoffrey D. Holman1

Departments of 1 Biology and Biochemistry and 2 Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, United Kingdom

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-semi-napthorhodofluor-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). After treatments with cariporide or bafilomycin A1, insulin stimulation of insulin receptor and insulin receptor substrate-1 phosphorylation and Akt activity were normal. In contrast, glucose transport activity and the levels of functional GLUT4 at the plasma membrane (detected using an exofacial photolabel) were reduced by ~50%. Immunocytochemical analysis revealed that insulin treatment caused a translocation of the GLUT4 from perinuclear structures and increased its co-localization with cell surface syntaxin 4. 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.

GLUT4 translocation; cytosolic pH; cariporide; bafilomycin A1

* These authors contributed equally to this work.




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