DIFFERENTIAL-EFFECTS OF ACUTE HYPERTRIGLYCERIDEMIA ON INSULIN ACTION AND INSULIN-RECEPTOR AUTOPHOSPHORYLATION

Experimentally induced hypertriglyceridemia (HTG) and high plasma free fatty acid (FFA) levels impair in vivo insulin action. To determine i f this is a consequence of impaired in vive insulin receptor autophosp horylation and related to defective receptor signaling, hyperinsulinem ic euglycemic clamps, indirect calorimetry, and skeletal muscle biopsi es were performed in nine healthy subjects. In vive insulin action was determined from the glucose infusion rate (GINF) and glucose oxidatio n (Glc(ox)) during 40 and 120 mU . m(-2). min(-1) clamps with (HTG cla mp) and without (control clamp) a triglyceride emulsion infusion. The percentage of receptors autophosphorylated in vivo was determined by I -125-labeled insulin tracer binding in skeletal muscle immunoprecipita tes of insulin receptors and phosphorylated receptors. Compared with t he control clamps, plasma triglycerides and FFA increased four- and tw ofold, whereas GINF and Glc(ox) decreased 15 and 35%, respectively, du ring the HTG clamps (all P < 0.05). However, the percentages of recept ors phosphorylated after the 40 and 120 mU . m(-2). min(-1) HTG clamps (9.2 +/- 1.5 and 21.1 +/- 2.6%, respectively) were similar to the con trol clamps (9.0 +/- 0.6 and 18.6 +/- 2.2%, respectively). These resul ts indicate that, if impaired insulin signal transduction is a mechani sm by which HTG and FFA impair insulin action, it occurs at a site dow nstream from insulin receptor autophosphorylation.