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

This Article Full Text Full Text (PDF) All Versions of this Article: 563/2/471    most recent jphysiol.2004.080333v1 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 Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Puljak, L. Articles by Kilic, G. Search for Related Content PubMed PubMed Citation Articles by Puljak, L. Articles by Kilic, G.

¹ Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO 80523, USA
² Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA
³ Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8887, USA

The initial response of liver cells to insulin is mediated through exocytosis of Cl^– channel-containing vesicles and a subsequent opening of plasma membrane Cl^– channels. Intracellular accumulation of fatty acids leads to profound defects in metabolism, and is closely associated with insulin resistance. It is not known whether the activity of Cl^– channels is altered in insulin resistance and by which mechanisms. We studied the effects of fatty acid accumulation on Cl^– channel opening in a model liver cell line. Overnight treatment with amiodarone increased the fat content by 2-fold, and the rates of gluconeogenesis by 5-fold. The ability of insulin to suppress gluconeogenesis was markedly reduced indicating that amiodarone treatment induces insulin resistance. Western blot analysis showed that these cells express the same number of insulin receptors as control cells. However, insulin failed to activate exocytosis and Cl^– channel opening. These inhibitory effects were mimicked in control cells by exposures to arachidonic acid (15 µM). Further studies demonstrated that fatty acids stimulate the PKC activity, and inhibition of PKC partially restored exocytosis and Cl^– channel opening in insulin-resistant cells. Accordingly, activation of PKC with PMA in control cells potently inhibited the insulin responses. These results suggest that stimulation of PKC activity in insulin resistance contributes to the inhibition of cellular responses to insulin in liver cells.

(Received 30 November 2004; accepted after revision 7 January 2005; first published online 13 January 2005)
Corresponding author G. Kilic: Department of Internal Medicine, University of Texas South-western Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8887, USA. Email: gordan.kilic{at}utsouthwestern.edu