Plasma free fatty acids decrease insulin-stimulated skeletal muscle glucose uptake by suppressing glycolysis in conscious rats.
The effects of elevated plasma free fatty acid (FFA) levels on insulin -stimulated whole-body and skeletal muscle glucose transport, glucose uptake, glycolysis, and glycogen synthesis were studied in conscious rats during hyperinsulinemic-euglycemic clamps with (n = 26) or without (n = 23) Intralipid and heparin infusion. Whole-body and skeletal muscle glucose uptake, glycolysis, and glycogen synthesis were estimated using D-[3-3H]glucose and 2-[14C]deoxyglucose (study 1), and glucose transport activity was assessed by analyzing plasma kinetics of L-[14C]glucose and 3-O-[3H]-methylglucose (study 2). Plasma FFA levels decreased during the clamps without intralipid but increased above basal during the clamps with Intralipid infusion (P < 0.01 for both). Elevated plasma FFA levels decreased insulin-stimulated whole-body glucose uptake by approximately 15% and approximately 20% during physiological and maximal insulin clamps, respectively (P < 0.01). Similarly, insulin-stimulated glucose uptake was also decreased in individual skeletal muscles with Intralipid infusion (P < 0.05). The most profound effect of elevated plasma FFA levels was a 30-50% suppression of insulin-stimulated glycolysis in whole body and individual skeletal muscles in both clamps. In contrast, physiological insulin-stimulated glycogen synthesis was increased with elevated plasma FFA levels in whole body and individual skeletal muscles (P < 0.05). Glucose-6-phosphate (G-6-P) levels were increased in soleus and extensor digitorum longus (EDL) muscles with Intralipid infusion in both clamps (P < 0.05). Intralipid infusion did not alter the time profiles of plasma L-glucose and 3-O-methylglucose after an intravenous injection during maximal insulin clamps, and compartmental analysis indicated no significant effect of elevated FFA levels on glucose transport activity in insulin-sensitive tissues (P > 0.05). Thus, elevated plasma FFA decreased insulin-stimulated glucose uptake in skeletal muscle by suppressing glycolysis and increasing G-6-P levels. These findings suggest that the classic glucose-fatty acid cycle was the predominant mechanism underlying the inhibitory effect of FFA on skeletal muscle glucose uptake.
Kim
J K
JK
Department of Physiology and Biophysics, University of Southern California School of Medicine, Los Angeles, 90033, USA.
Wi
J K
JK
Youn
J H
JH
D019325:3-O-Methylglucose; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism*; D002250:Carbon Radioisotopes; D003847:Deoxyglucose / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D006003:Glycogen / Q000096:biosynthesis; D006019:Glycolysis / Q000187:drug effects; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008433:Mathematics; D008757:Methylglucosides / Q000378:metabolism; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014316:Tritium
D001786:Blood Glucose; D002250:Carbon Radioisotopes; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D008757:Methylglucosides; D014316:Tritium; D019325:3-O-Methylglucose; D006003:Glycogen; D003847:Deoxyglucose; D005947:Glucose