Abstract To investigate the sites of the free fatty acid (FFA) effects to increase basal hepatic glucose production and to impair hepatic insulin action, we performed 2-h and 7-h Intralipid + heparin (IH) and saline infusions in the basal fasting state and during hyperinsulinemic clamps in overnight-fasted rats. We measured endogenous glucose production (EGP), total glucose output (TGO, the flux through glucose-6-phosphatase), glucose cycling (GC, index of flux through glucokinase = TGO − EGP), hepatic glucose 6-phosphate (G-6- P ) content, and hepatic glucose-6-phosphatase and glucokinase activities. Plasma FFA levels were elevated about threefold by IH. In the basal state, IH increased TGO, in vivo glucose-6-phosphatase activity (TGO/G-6- P ), and EGP ( P < 0.001). During the clamp compared with the basal experiments, 2-h insulin infusion increased GC and in vivo glucokinase activity (GC/TGO; P < 0.05) and suppressed EGP ( P < 0.05) but failed to significantly affect TGO and in vivo glucose-6-phosphatase activity. IH decreased the ability of insulin to increase GC and in vivo glucokinase activity ( P < 0.01), and at 7 h, it also decreased the ability of insulin to suppress EGP ( P < 0.001). G-6- P content was comparable in all groups. In vivo glucose-6-phosphatase and glucokinase activities did not correspond to their in vitro activities as determined in liver tissue, suggesting that stable changes in enzyme activity were not responsible for the FFA effects. The data suggest that, in overnight-fasted rats, FFA increased basal EGP and induced hepatic insulin resistance at different sites. 1 ) FFA increased basal EGP through an increase in TGO and in vivo glucose-6-phosphatase activity, presumably due to a stimulatory allosteric effect of fatty acyl-CoA on glucose-6-phosphatase. 2 ) FFA induced hepatic insulin resistance (decreased the ability of insulin to suppress EGP) through an impairment of insulin's ability to increase GC and in vivo glucokinase activity, presumably due to an inhibitory allosteric effect of fatty acyl-CoA on glucokinase and/or an impairment in glucokinase translocation. glucose-6-phosphatase glucokinase total glucose output glucose cycling Footnotes T. K. T. Lam was supported by a Canadian Institute of Health Research Doctoral Award and a Banting and Best Diabetes Centre/Novo Nordisk Studentship. This study was funded by a research grant to A. Giacca from the Canadian Diabetes Association. Part of this work was presented at the 61st Annual Meeting and Scientific Sessions of the American Diabetes Association, June 22–26, 2001, in Philadelphia, PA. Address for reprint requests and other correspondence: A. Giacca, Univ. of Toronto, Dept. of Physiology, Medical Science Bldg., 1 King's College Circle, Rm. 3363, Toronto, ON M5S 1A8, Canada (E-mail: email@example.com ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 10.1152/ajpendo.00332.2002 Copyright © 2003 the American Physiological Society
AJP - Endocrinology and Metabolism – The American Physiological Society
Published: Feb 1, 2003
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