Dissociation between fat-induced in vivo insulin resistance and proximal insulin signaling in skeletal muscle in men at risk for type 2 diabetes

J Clin Endocrinol Metab. 2004 Mar;89(3):1301-11. doi: 10.1210/jc.2003-031243.

Abstract

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[(3)H]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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Glucose / metabolism
  • C-Peptide / blood
  • Calorimetry, Indirect
  • Diabetes Mellitus, Type 2 / epidemiology
  • Diabetes Mellitus, Type 2 / metabolism*
  • Fat Emulsions, Intravenous / administration & dosage
  • Fat Emulsions, Intravenous / pharmacokinetics
  • Fatty Acids, Nonesterified / blood*
  • Glucose Clamp Technique
  • Humans
  • Insulin / blood*
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance*
  • Middle Aged
  • Muscle, Skeletal / metabolism*
  • Oxidation-Reduction
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Risk Factors
  • Signal Transduction / physiology*
  • Triglycerides / blood

Substances

  • Blood Glucose
  • C-Peptide
  • Fat Emulsions, Intravenous
  • Fatty Acids, Nonesterified
  • IRS1 protein, human
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • Triglycerides
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt