Fatty acid infusion selectively impairs insulin action on Akt1 and protein kinase C lambda /zeta but not on glycogen synthase kinase-3.
To determine the mechanism(s) for insulin resistance induced by fatty acids, we measured the ability of insulin to activate phosphoinositide 3-kinase (PI3K) and multiple distal pathways in rats. Following a 5-h infusion of lipid or glycerol (control), rats underwent a euglycemic hyperinsulinemic clamp. Insulin stimulated IRS-1-associated PI3K activity in muscle of glycerol-infused rats 2.4-fold but had no effect in lipid-infused rats. IRS-2- and phosphotyrosine-associated PI3K activity were increased 3.5- and 4.8-fold, respectively, by insulin in glycerol-infused rats but only 1.6- and 2.3-fold in lipid-infused rats. Insulin increased Akt1 activity 3.9-fold in glycerol-infused rats, and this was impaired 41% in lipid-infused rats. Insulin action on Akt2 and p70S6K were not impaired, whereas activation of protein kinase C lambda/zeta activity was reduced 47%. Insulin inhibited glycogen synthase kinase 3alpha (GSK-3alpha) activity by 30% and GSK-3beta activity by approximately 65% and increased protein phosphatase-1 activity by 40-47% in both glycerol- and lipid-infused rats. Insulin stimulated glycogen synthase activity 2.0-fold in glycerol-infused rats but only 1.4-fold in lipid-infused rats. Thus, 1) elevation of fatty acids differentially affects insulin action on pathways distal to PI3K, impairing activation of Akt1 and protein kinase C lambda/zeta and 2) insulin action on glycogen synthase can be regulated independent of effects on GSK-3 and protein phosphatase-1 activity in vivo.
Kim
Young-Bum
YB
Diabetes Unit, Division of Endocrinology and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Shulman
Gerald I
GI
Kahn
Barbara B
BB
D000818:Animals; D029681:Arabidopsis Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D005227:Fatty Acids / Q000494:pharmacology*; D005990:Glycerol / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D007328:Insulin / Q000494:pharmacology*; D007329:Insulin Antagonists / Q000494:pharmacology*; D007527:Isoenzymes; D020935:MAP Kinase Signaling System; D008297:Male; D009132:Muscles / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010940:Plant Proteins / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism*; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000378:metabolism*; D054645:Protein Phosphatase 1; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013997:Time Factors; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta
D029681:Arabidopsis Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D005227:Fatty Acids; D005990:Glycerol; D006006:Glycogen Synthase; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D007328:Insulin; D007329:Insulin Antagonists; D007527:Isoenzymes; D010749:Phosphoprotein Phosphatases; D010940:Plant Proteins; D015221:Potassium Channels; D020033:Protein Isoforms; D011493:Protein Kinase C; D054645:Protein Phosphatase 1; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta; C074500:AKT1 protein, Arabidopsis