Saturated fatty acid-induced insulin resistance in rat adipocytes.
Palmitate has been shown to stimulate glucose transport, translocation of GLUT4 and insulin receptor autophosphorylation in isolated rat adipocytes (Biochem Biophys Res Commun 177:343-49, 1991). Here we further characterize the ability of short-term treatment with free fatty acids to stimulate glucose transport in isolated rat adipocytes and demonstrate that prolonged treatment induces insulin resistance. Treatment of adipocytes for 15 min with 1 mM myristate (14:0), palmitate (16:0), or stearate (18:0) stimulates glucose transport by 119 +/- 33, 89 +/- 29, and 114 +/- 30%, respectively. In contrast, oleate (cis 18:1), 1), elaidate (trans 18:1), and linoleate (cis 18:2) do not stimulate glucose transport. Palmitate stimulates glucose transport in a concentration-dependent manner, demonstrating saturation at 1 mM and half-maximal stimulation at 0.25-0.5 mM. Prolonged treatment (4 h) of rat adipocytes with 1 mM palmitate induces insulin resistance. After a 4-h preincubation with palmitate (1 mM), insulin stimulates glucose transport in rat adipocytes by 4.4-fold +/- 0.8, vs. 8.8-fold +/- 0.8 in controls (n = 3). Palmitate-induced resistant cells demonstrated a 40% inhibition in maximal insulin responsiveness with little change in insulin sensitivity. Insulin binding is only slightly decreased (8%) in palmitate-pretreated cells. These studies indicate that saturated fatty acids stimulate glucose transport acutely and on prolonged exposure induce insulin resistance via a post-insulin binding defect. The underlying molecular mechanisms of insulin resistance induced by prolonged treatment with saturated fatty acids may now be investigated using this unique cellular model.
Hunnicutt
J W
JW
Department of Pathology, University of Alabama at Birmingham 35294.
Hardy
R W
RW
Williford
J
J
McDonald
J M
JM
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D007333:Insulin Resistance; D007700:Kinetics; D008297:Male; D019308:Palmitic Acid; D010169:Palmitic Acids / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D005230:Fatty Acids, Nonesterified; D007328:Insulin; D010169:Palmitic Acids; D019308:Palmitic Acid; D003847:Deoxyglucose; D005947:Glucose