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Dissociation between Fat-Induced in Vivo Insulin Resistance and Proximal Insulin Signaling in Skeletal Muscle in Men at Risk for Type 2 Diabetes

Department of Endocrinology and Clinical Research Unit (H.S., C.B.J., S.M., A.A.V.), Hvidovre Hospital, University of Copenhagen, DK-2650 Hvidovre, Denmark; Department of Clinical Physiology (M.B., X.M.S., J.R.Z.), Karolinska Hospital, Karolinska Institutet, SE 17177 Stockholm, Sweden; and Steno Diabetes Center (A.A.V.), 2820 Gentofte, Denmark

Address all correspondence and requests for reprints to: Heidi Storgaard, Steno Diabetes Center, Niels Steensensvej 2, 2820 Gentofte, Denmark. E-mail: heis{at}steno.dk or hstorgaard{at}dadlnet.dk.

The effect of short- (2 h) and long-term (24 h) low-grade Intralipid infusion on whole-body insulin action, cellular glucose metabolism, and proximal components of the insulin signal transduction cascade was studied in seven obese male glucose intolerant first degree relatives of type 2 diabetic patients [impaired glucose tolerance (IGT) relatives] and eight matched control subjects.

Indirect calorimetry and excision of vastus lateralis skeletal muscle biopsies were performed before and during hyperinsulinemic euglycemic clamps combined with 3[³H]glucose. Clamps were performed after 0, 2, or 24 h Intralipid infusion (0.4 ml·kg^-1·min^-1).

Insulin-stimulated glucose disposal decreased approximately 25% after short- and long-term fat infusion in both IGT relatives and controls. Glucose oxidation decreased and lipid oxidation increased after both short- and long-term fat infusion in both groups. Insulin-stimulated glucose oxidation was higher after long-term as compared with short-term fat infusion in control subjects. Short- or long-term infusion did not affect the absolute values of basal or insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation, tyrosine-associated phosphoinositide 3-kinase (PI 3-kinase) activity, insulin receptor substrate-1-associated PI 3-kinase activity, or Akt serine phosphorylation in IGT relatives or matched controls. In fact, a paradoxical increase in both basal and insulin-stimulated PI 3-kinase activity was noted in the total study population after both short- and long-term fat infusion.

Short- and long-term low-grade Intralipid infusion-induced (or enhanced) whole-body insulin resistance and impaired glucose metabolism in IGT relatives and matched control subjects. The fat-induced metabolic changes were not explained by impairment of the proximal insulin signaling transduction in skeletal muscle.

This work was supported by grants from the Novo-Nordisk Foundation; Danish Research Council; Danish Diabetes Association; Association of Danish Female Doctors; Grosserer C. P. Frederiksens Foundation, Beckett Foundation; Direktør E. Danielsen and Wife’s Foundation; Eli Lilly’s Diabetes Research Foundation; Handelsgartner Ove V. B. Olsen’s and Edith B. Olsen’s Foundation; Ebba Celinders Foundation; Christian the 3rd Foundation; H:S Research Foundation; the Swedish Medical Research Council; and the Swedish Diabetes Association. H.S. was granted a research fellowship scholarship from the Faculty of Medicine, University of Copenhagen, Denmark.

Abbreviations: DTT, Dithiothreitol; ECL, enhanced chemiluminescence; EGP, endogenous glucose production; EGS, exogenous glucose storage; FFA, free fatty acid; GF, glycolytic flux; GOX, glucose oxidation; IGT, impaired glucose tolerance; IR, insulin receptor; IRS, IR substrate; IVGTT, intravenous glucose tolerance test; LIPOX, lipid oxidation; NOGM, nonoxidative glucose metabolism; OGTT, oral glucose tolerance test; PI 3-kinase, phosphoinositide 3-kinase; PVDF, polyvinylidene difluoride; Ra, glucose appearance rate; Rd, glucose disposal rate; SA, specific activity.

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