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J Clin Invest. 1993 July; 92(1): 91–98.
PMCID: PMC293539

Interaction between glucose and free fatty acid metabolism in human skeletal muscle.


The mechanism by which FFA metabolism inhibits intracellular insulin-mediated muscle glucose metabolism in normal humans is unknown. We used the leg balance technique with muscle biopsies to determine how experimental maintenance of FFA during hyperinsulinemia alters muscle glucose uptake, oxidation, glycolysis, storage, pyruvate dehydrogenase (PDH), or glycogen synthase (GS). 10 healthy volunteers had two euglycemic insulin clamp experiments. On one occasion, FFA were maintained by lipid emulsion infusion; on the other, FFA were allowed to fall. Leg FFA uptake was monitored with [9,10-3H]-palmitate. Maintenance of FFA during hyperinsulinemia decreased muscle glucose uptake (1.57 +/- 0.31 vs 2.44 +/- 0.39 mumol/min per 100 ml tissue, P < 0.01), leg respiratory quotient (0.86 +/- 0.02 vs 0.93 +/- 0.02, P < 0.05), contribution of glucose to leg oxygen consumption (53 +/- 6 vs 76 +/- 8%, P < 0.05), and PDH activity (0.328 +/- 0.053 vs 0.662 +/- 0.176 nmol/min per mg, P < 0.05). Leg lactate balance was increased. The greatest effect of FFA replacement was reduced muscle glucose storage (0.36 +/- 0.20 vs 1.24 +/- 0.25 mumol/min per 100 ml, P < 0.01), accompanied by decreased GS fractional velocity (0.129 +/- 0.26 vs 0.169 +/- 0.033, P < 0.01). These results confirm in human skeletal muscle the existence of competition between glucose and FFA as oxidative fuels, mediated by suppression of PDH. Maintenance of FFA levels during hyperinsulinemia most strikingly inhibited leg muscle glucose storage, accompanied by decreased GS activity.

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  • RANDLE PJ, GARLAND PB, HALES CN, NEWSHOLME EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963 Apr 13;1(7285):785–789. [PubMed]
  • Randle PJ, Newsholme EA, Garland PB. Regulation of glucose uptake by muscle. 8. Effects of fatty acids, ketone bodies and pyruvate, and of alloxan-diabetes and starvation, on the uptake and metabolic fate of glucose in rat heart and diaphragm muscles. Biochem J. 1964 Dec;93(3):652–665. [PubMed]
  • Randle PJ. Fuel selection in animals. Biochem Soc Trans. 1986 Oct;14(5):799–806. [PubMed]
  • Randle PJ, Kerbey AL, Espinal J. Mechanisms decreasing glucose oxidation in diabetes and starvation: role of lipid fuels and hormones. Diabetes Metab Rev. 1988 Nov;4(7):623–638. [PubMed]
  • Felber JP, Ferrannini E, Golay A, Meyer HU, Theibaud D, Curchod B, Maeder E, Jequier E, DeFronzo RA. Role of lipid oxidation in pathogenesis of insulin resistance of obesity and type II diabetes. Diabetes. 1987 Nov;36(11):1341–1350. [PubMed]
  • Vaag A, Skött P, Damsbo P, Gall MA, Richter EA, Beck-Nielsen H. Effect of the antilipolytic nicotinic acid analogue acipimox on whole-body and skeletal muscle glucose metabolism in patients with non-insulin-dependent diabetes mellitus. J Clin Invest. 1991 Oct;88(4):1282–1290. [PMC free article] [PubMed]
  • Bevilacqua S, Buzzigoli G, Bonadonna R, Brandi LS, Oleggini M, Boni C, Geloni M, Ferrannini E. Operation of Randle's cycle in patients with NIDDM. Diabetes. 1990 Mar;39(3):383–389. [PubMed]
  • Thiébaud D, DeFronzo RA, Jacot E, Golay A, Acheson K, Maeder E, Jéquier E, Felber JP. Effect of long chain triglyceride infusion on glucose metabolism in man. Metabolism. 1982 Nov;31(11):1128–1136. [PubMed]
  • Ferrannini E, Barrett EJ, Bevilacqua S, DeFronzo RA. Effect of fatty acids on glucose production and utilization in man. J Clin Invest. 1983 Nov;72(5):1737–1747. [PMC free article] [PubMed]
  • Wolfe BM, Klein S, Peters EJ, Schmidt BF, Wolfe RR. Effect of elevated free fatty acids on glucose oxidation in normal humans. Metabolism. 1988 Apr;37(4):323–329. [PubMed]
  • Walker M, Fulcher GR, Catalano C, Petranyi G, Orskov H, Alberti KG. Physiological levels of plasma non-esterified fatty acids impair forearm glucose uptake in normal man. Clin Sci (Lond) 1990 Aug;79(2):167–174. [PubMed]
  • Walker M, Fulcher GR, Sum CF, Orskov H, Alberti KG. Effect of glycemia and nonesterified fatty acids on forearm glucose uptake in normal humans. Am J Physiol. 1991 Sep;261(3 Pt 1):E304–E311. [PubMed]
  • Groop LC, Bonadonna RC, Shank M, Petrides AS, DeFronzo RA. Role of free fatty acids and insulin in determining free fatty acid and lipid oxidation in man. J Clin Invest. 1991 Jan;87(1):83–89. [PMC free article] [PubMed]
  • Boden G, Jadali F, White J, Liang Y, Mozzoli M, Chen X, Coleman E, Smith C. Effects of fat on insulin-stimulated carbohydrate metabolism in normal men. J Clin Invest. 1991 Sep;88(3):960–966. [PMC free article] [PubMed]
  • Johnson AB, Argyraki M, Thow JC, Cooper BG, Fulcher G, Taylor R. Effect of increased free fatty acid supply on glucose metabolism and skeletal muscle glycogen synthase activity in normal man. Clin Sci (Lond) 1992 Feb;82(2):219–226. [PubMed]
  • Kelley DE, Reilly JP, Veneman T, Mandarino LJ. Effects of insulin on skeletal muscle glucose storage, oxidation, and glycolysis in humans. Am J Physiol. 1990 Jun;258(6 Pt 1):E923–E929. [PubMed]
  • Mandarino LJ, Wright KS, Verity LS, Nichols J, Bell JM, Kolterman OG, Beck-Nielsen H. Effects of insulin infusion on human skeletal muscle pyruvate dehydrogenase, phosphofructokinase, and glycogen synthase. Evidence for their role in oxidative and nonoxidative glucose metabolism. J Clin Invest. 1987 Sep;80(3):655–663. [PMC free article] [PubMed]
  • Karl IE, Pagliara AS, Kipnis DM. A microfluorometric enzymatic assay for the determination of alanine and pyruvate in plasma and tissues. J Lab Clin Med. 1972 Sep;80(3):434–441. [PubMed]
  • Douglas AR, Jones NL, Reed JW. Calculation of whole blood CO2 content. J Appl Physiol (1985) 1988 Jul;65(1):473–477. [PubMed]
  • Herbert V, Lau KS, Gottlieb CW, Bleicher SJ. Coated charcoal immunoassay of insulin. J Clin Endocrinol Metab. 1965 Oct;25(10):1375–1384. [PubMed]
  • Miles JM, Ellman MG, McClean KL, Jensen MD. Validation of a new method for determination of free fatty acid turnover. Am J Physiol. 1987 Mar;252(3 Pt 1):E431–E438. [PubMed]
  • Simoneau JA, Lortie G, Boulay MR, Thibault MC, Bouchard C. Repeatability of fibre type and enzyme activity measurements in human skeletal muscle. Clin Physiol. 1986 Aug;6(4):347–356. [PubMed]
  • Simoneau JA, Bouchard C. Human variation in skeletal muscle fiber-type proportion and enzyme activities. Am J Physiol. 1989 Oct;257(4 Pt 1):E567–E572. [PubMed]
  • Frayn KN. Calculation of substrate oxidation rates in vivo from gaseous exchange. J Appl Physiol Respir Environ Exerc Physiol. 1983 Aug;55(2):628–634. [PubMed]
  • Gelfand RA, Barrett EJ. Effect of physiologic hyperinsulinemia on skeletal muscle protein synthesis and breakdown in man. J Clin Invest. 1987 Jul;80(1):1–6. [PMC free article] [PubMed]
  • Consoli A, Nurjahan N, Gerich JE, Mandarino LJ. Skeletal muscle is a major site of lactate uptake and release during hyperinsulinemia. Metabolism. 1992 Feb;41(2):176–179. [PubMed]
  • Bogardus C, Lillioja S, Stone K, Mott D. Correlation between muscle glycogen synthase activity and in vivo insulin action in man. J Clin Invest. 1984 Apr;73(4):1185–1190. [PMC free article] [PubMed]
  • Argyraki M, Wright PD, Venables CW, Proud G, Taylor R. In vitro study of human skeletal muscle strips: effect of nonesterified fatty acid supply on glucose storage. Metabolism. 1989 Dec;38(12):1183–1187. [PubMed]
  • Wititsuwannakul D, Kim KH. Mechanism of palmityl coenzyme A inhibition of liver glycogen synthase. J Biol Chem. 1977 Nov 10;252(21):7812–7817. [PubMed]
  • Grundleger ML, Thenen SW. Decreased insulin binding, glucose transport, and glucose metabolism in soleus muscle of rats fed a high fat diet. Diabetes. 1982 Mar;31(3):232–237. [PubMed]
  • Hargreaves M, Kiens B, Richter EA. Effect of increased plasma free fatty acid concentrations on muscle metabolism in exercising men. J Appl Physiol (1985) 1991 Jan;70(1):194–201. [PubMed]
  • Laakso M, Edelman SV, Brechtel G, Baron AD. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. J Clin Invest. 1990 Jun;85(6):1844–1852. [PMC free article] [PubMed]
  • Kelley DE, Mokan M, Mandarino LJ. Intracellular defects in glucose metabolism in obese patients with NIDDM. Diabetes. 1992 Jun;41(6):698–706. [PubMed]

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