Dissociation between fat-induced in vivo insulin resistance and proximal insulin signaling in skeletal muscle in men at risk for type 2 diabetes.
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.
Storgaard
Heidi
H
Department of Endocrinology and Clinical Research Unit, Hvidovre Hospital, University of Copenhagen, DK-2650 Hvidovre, Denmark. hstorgaard@dadlnet.dk
Jensen
Christine B
CB
Björnholm
Marie
M
Song
Xiao Mei
XM
Madsbad
Sten
S
Zierath
Juleen R
JR
Vaag
Allan A
AA
D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D002153:Calorimetry, Indirect; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000378:metabolism*; D005217:Fat Emulsions, Intravenous / Q000008:administration & dosage / Q000493:pharmacokinetics; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000097:blood*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D010084:Oxidation-Reduction; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012307:Risk Factors; D015398:Signal Transduction / Q000502:physiology*; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D002096:C-Peptide; D005217:Fat Emulsions, Intravenous; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014280:Triglycerides; C526292:IRS1 protein, human; C494918:AKT1 protein, human