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. 1991 Sep;88(3):960–966. doi: 10.1172/JCI115399

Effects of fat on insulin-stimulated carbohydrate metabolism in normal men.

G Boden 1, F Jadali 1, J White 1, Y Liang 1, M Mozzoli 1, X Chen 1, E Coleman 1, C Smith 1
PMCID: PMC295496  PMID: 1885781

Abstract

We have examined the onset and duration of the inhibitory effect of an intravenous infusion of lipid/heparin on total body carbohydrate and fat oxidation (by indirect calorimetry) and on glucose disappearance (with 6,6 D2-glucose and gas chromatography-mass spectrometry) in healthy men during euglycemic hyperinsulinemia. Glycogen synthase activity and concentrations of acetyl-CoA, free CoA-SH, citrate, and glucose-6-phosphate were measured in muscle biopsies obtained before and after insulin/lipid and insulin/saline infusions. Lipid increased insulin-inhibited fat oxidation (+40%) and decreased insulin-stimulated carbohydrate oxidation (-63%) within 1 h. These changes were associated with an increase (+489%) in the muscle acetyl-CoA/free CoA-SH ratio. Glucose disappearance did not decrease until 2-4 h later (-55%). This decrease was associated with a decrease in muscle glycogen synthase fractional velocity (-82%). The muscle content of citrate and glucose-6-phosphate did not change. We concluded that, during hyperinsulinemia, lipid promptly replaced carbohydrate as fuel for oxidation in muscle and hours later inhibited glucose uptake, presumably by interfering with muscle glycogen formation.

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Selected References

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  1. Allred J. B., Guy D. G. Determination of coenzyme A and acetyl CoA in tissue extracts. Anal Biochem. 1969 May;29(2):293–299. doi: 10.1016/0003-2697(69)90312-1. [DOI] [PubMed] [Google Scholar]
  2. Beatty C. H., Bocek R. M. Interrelation of carbohydrate and palmitate metabolism in skeletal muscle. Am J Physiol. 1971 Jun;220(6):1928–1934. doi: 10.1152/ajplegacy.1971.220.6.1928. [DOI] [PubMed] [Google Scholar]
  3. Bevilacqua S., Bonadonna R., Buzzigoli G., Boni C., Ciociaro D., Maccari F., Giorico M. A., Ferrannini E. Acute elevation of free fatty acid levels leads to hepatic insulin resistance in obese subjects. Metabolism. 1987 May;36(5):502–506. doi: 10.1016/0026-0495(87)90051-5. [DOI] [PubMed] [Google Scholar]
  4. Bevilacqua S., Buzzigoli G., Bonadonna R., Brandi L. S., Oleggini M., Boni C., Geloni M., Ferrannini E. Operation of Randle's cycle in patients with NIDDM. Diabetes. 1990 Mar;39(3):383–389. doi: 10.2337/diab.39.3.383. [DOI] [PubMed] [Google Scholar]
  5. Björntorp P., Sjöström L. Carbohydrate storage in man: speculations and some quantitative considerations. Metabolism. 1978 Dec;27(12 Suppl 2):1853–1865. doi: 10.1016/s0026-0495(78)80004-3. [DOI] [PubMed] [Google Scholar]
  6. Boden G., Ray T. K., Smith R. H., Owen O. E. Carbohydrate oxidation and storage in obese non-insulin-dependent diabetic patients. Effects of improving glycemic control. Diabetes. 1983 Nov;32(11):982–987. doi: 10.2337/diab.32.11.982. [DOI] [PubMed] [Google Scholar]
  7. Bogardus C., Thuillez P., Ravussin E., Vasquez B., Narimiga M., Azhar S. Effect of muscle glycogen depletion on in vivo insulin action in man. J Clin Invest. 1983 Nov;72(5):1605–1610. doi: 10.1172/JCI111119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bonadonna R. C., Zych K., Boni C., Ferrannini E., DeFronzo R. A. Time dependence of the interaction between lipid and glucose in humans. Am J Physiol. 1989 Jul;257(1 Pt 1):E49–E56. doi: 10.1152/ajpendo.1989.257.1.E49. [DOI] [PubMed] [Google Scholar]
  9. Cassens R. G., Bocek R. M., Beatty C. H. Effect of octanoate on carbohydrate metabolism in red and white muscle of the rhesus monkey. Am J Physiol. 1969 Sep;217(3):715–719. doi: 10.1152/ajplegacy.1969.217.3.715. [DOI] [PubMed] [Google Scholar]
  10. DANFORTH W. H. GLYCOGEN SYNTHETASE ACTIVITY IN SKELETAL MUSCLE. INTERCONVERSION OF TWO FORMS AND CONTROL OF GLYCOGEN SYNTHESIS. J Biol Chem. 1965 Feb;240:588–593. [PubMed] [Google Scholar]
  11. DeFronzo R. A., Jacot E., Jequier E., Maeder E., Wahren J., Felber J. P. The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes. 1981 Dec;30(12):1000–1007. doi: 10.2337/diab.30.12.1000. [DOI] [PubMed] [Google Scholar]
  12. Felber J. P., Meyer H. U., Curchod B., Iselin H. U., Rousselle J., Maeder E., Pahud P., Jéquier E. Glucose storage and oxidation in different degrees of human obesity measured by continuous indirect calorimetry. Diabetologia. 1981;20(1):39–44. doi: 10.1007/BF00253814. [DOI] [PubMed] [Google Scholar]
  13. Felley C. P., Felley E. M., van Melle G. D., Frascarolo P., Jéquier E., Felber J. P. Impairment of glucose disposal by infusion of triglycerides in humans: role of glycemia. Am J Physiol. 1989 Jun;256(6 Pt 1):E747–E752. doi: 10.1152/ajpendo.1989.256.6.E747. [DOI] [PubMed] [Google Scholar]
  14. Ferrannini E., Barrett E. J., Bevilacqua S., DeFronzo R. A. Effect of fatty acids on glucose production and utilization in man. J Clin Invest. 1983 Nov;72(5):1737–1747. doi: 10.1172/JCI111133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Goodman M. N., Berger M., Ruderman N. B. Glucose metabolism in rat skeletal muscle at rest. Effect of starvation, diabetes, ketone bodies and free fatty acids. Diabetes. 1974 Nov;23(11):881–888. doi: 10.2337/diab.23.11.881. [DOI] [PubMed] [Google Scholar]
  16. Gómez F., Jéquier E., Chabot V., Büber V., Felber J. P. Carbohydrate and lipid oxidation in normal human subjects: its influence on glucose tolerance and insulin response to glucose. Metabolism. 1972 May;21(5):381–391. doi: 10.1016/0026-0495(72)90051-0. [DOI] [PubMed] [Google Scholar]
  17. HALES C. N., RANDLE P. J. Effects of low-carbohydrate diet and diabetes mellitus on plasma concentrations of glucose, non-esterified fatty acid, and insulin during oral glucose-tolerance tests. Lancet. 1963 Apr 13;1(7285):790–794. doi: 10.1016/s0140-6736(63)91501-0. [DOI] [PubMed] [Google Scholar]
  18. Hagg S. A., Taylor S. I., Ruberman N. B. Glucose metabolism in perfused skeletal muscle. Pyruvate dehydrogenase activity in starvation, diabetes and exercise. Biochem J. 1976 Aug 15;158(2):203–210. doi: 10.1042/bj1580203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hissin P. J., Karnieli E., Simpson I. A., Salans L. B., Cushman S. W. A possible mechanism of insulin resistance in the rat adipose cell with high-fat/low-carbohydrate feeding. Depletion of intracellular glucose transport systems. Diabetes. 1982 Jul;31(7):589–592. doi: 10.2337/diab.31.7.589. [DOI] [PubMed] [Google Scholar]
  20. Kochan R. G., Lamb D. R., Lutz S. A., Perrill C. V., Reimann E. M., Schlender K. K. Glycogen synthase activation in human skeletal muscle: effects of diet and exercise. Am J Physiol. 1979 Jun;236(6):E660–E666. doi: 10.1152/ajpendo.1979.236.6.E660. [DOI] [PubMed] [Google Scholar]
  21. LELOIR L. F., OLAVARRIA J. M., GOLDEMBERG S. H., CARMINATTI H. Biosynthesis of glycogen from uridine diphosphate glucose. Arch Biochem Biophys. 1959 Apr;81(2):508–520. doi: 10.1016/0003-9861(59)90232-2. [DOI] [PubMed] [Google Scholar]
  22. Lee K. U., Lee H. K., Koh C. S., Min H. K. Artificial induction of intravascular lipolysis by lipid-heparin infusion leads to insulin resistance in man. Diabetologia. 1988 May;31(5):285–290. doi: 10.1007/BF00277409. [DOI] [PubMed] [Google Scholar]
  23. Liang Y., Matschinsky F. M. Content of CoA-esters in perifused rat islets stimulated by glucose and other fuels. Diabetes. 1991 Mar;40(3):327–333. doi: 10.2337/diab.40.3.327. [DOI] [PubMed] [Google Scholar]
  24. Lillioja S., Bogardus C., Mott D. M., Kennedy A. L., Knowler W. C., Howard B. V. Relationship between insulin-mediated glucose disposal and lipid metabolism in man. J Clin Invest. 1985 Apr;75(4):1106–1115. doi: 10.1172/JCI111804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. MARSH W. H., FINGERHUT B., MILLER H. AUTOMATED AND MANUAL DIRECT METHODS FOR THE DETERMINATION OF BLOOD UREA. Clin Chem. 1965 Jun;11:624–627. [PubMed] [Google Scholar]
  26. Meyer H. U., Curchod B., Maeder E., Pahud P., Jequier E., Felber J. P. Modifications of glucose storage and oxidation in nonobese diabetics, measured by continuous indirect calorimetry. Diabetes. 1980 Sep;29(9):752–756. doi: 10.2337/diab.29.9.752. [DOI] [PubMed] [Google Scholar]
  27. Molina J. M., Baron A. D., Edelman S. V., Brechtel G., Wallace P., Olefsky J. M. Use of a variable tracer infusion method to determine glucose turnover in humans. Am J Physiol. 1990 Jan;258(1 Pt 1):E16–E23. doi: 10.1152/ajpendo.1990.258.1.E16. [DOI] [PubMed] [Google Scholar]
  28. Owen O. E., Trapp V. E., Reichard G. A., Jr, Mozzoli M. A., Smith R., Boden G. Effects of therapy on the nature and quantity of fuels oxidized during diabetic ketoacidosis. Diabetes. 1980 May;29(5):365–372. doi: 10.2337/diab.29.5.365. [DOI] [PubMed] [Google Scholar]
  29. Pascoe W. S., Storlien L. H. Inducement by fat feeding of basal hyperglycemia in rats with abnormal beta-cell function. Model for study of etiology and pathogenesis of NIDDM. Diabetes. 1990 Feb;39(2):226–233. doi: 10.2337/diab.39.2.226. [DOI] [PubMed] [Google Scholar]
  30. RANDLE P. J., GARLAND P. B., HALES C. N., NEWSHOLME E. A. 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. doi: 10.1016/s0140-6736(63)91500-9. [DOI] [PubMed] [Google Scholar]
  31. Randle P. J., Garland P. B., Newsholme E. A., Hales C. N. The glucose fatty acid cycle in obesity and maturity onset diabetes mellitus. Ann N Y Acad Sci. 1965 Oct 8;131(1):324–333. doi: 10.1111/j.1749-6632.1965.tb34800.x. [DOI] [PubMed] [Google Scholar]
  32. Rennie M. J., Holloszy J. O. Inhibition of glucose uptake and glycogenolysis by availability of oleate in well-oxygenated perfused skeletal muscle. Biochem J. 1977 Nov 15;168(2):161–170. doi: 10.1042/bj1680161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Richter E. A., Hansen S. A., Hansen B. F. Mechanisms limiting glycogen storage in muscle during prolonged insulin stimulation. Am J Physiol. 1988 Nov;255(5 Pt 1):E621–E628. doi: 10.1152/ajpendo.1988.255.5.E621. [DOI] [PubMed] [Google Scholar]
  34. STEELE R., WALL J. S., DE BODO R. C., ALTSZULER N. Measurement of size and turnover rate of body glucose pool by the isotope dilution method. Am J Physiol. 1956 Sep;187(1):15–24. doi: 10.1152/ajplegacy.1956.187.1.15. [DOI] [PubMed] [Google Scholar]
  35. Schonfeld G., Kipnis D. M. Effects of fatty acids on carbohydrate and fatty acid metabolism of rat diaphragm. Am J Physiol. 1968 Aug;215(2):513–522. doi: 10.1152/ajplegacy.1968.215.2.513. [DOI] [PubMed] [Google Scholar]
  36. Shulman G. I., Rothman D. L., Jue T., Stein P., DeFronzo R. A., Shulman R. G. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N Engl J Med. 1990 Jan 25;322(4):223–228. doi: 10.1056/NEJM199001253220403. [DOI] [PubMed] [Google Scholar]
  37. Smith C. M., Narrow C. M., Kendrick Z. V., Steffen C. The effect of pantothenate deficiency in mice on their metabolic response to fast and exercise. Metabolism. 1987 Feb;36(2):115–121. doi: 10.1016/0026-0495(87)90003-5. [DOI] [PubMed] [Google Scholar]
  38. Soeldner J. S., Slone D. Critical variables in the radioimmunoassay of serum insulin using the double antibody technic. Diabetes. 1965 Dec;14(12):771–779. doi: 10.2337/diab.14.12.771. [DOI] [PubMed] [Google Scholar]
  39. Tappy L., Owen O. E., Boden G. Effect of hyperinsulinemia on urea pool size and substrate oxidation rates. Diabetes. 1988 Sep;37(9):1212–1216. doi: 10.2337/diab.37.9.1212. [DOI] [PubMed] [Google Scholar]
  40. Thiébaud D., DeFronzo R. A., Jacot E., Golay A., Acheson K., Maeder E., Jéquier E., Felber J. P. Effect of long chain triglyceride infusion on glucose metabolism in man. Metabolism. 1982 Nov;31(11):1128–1136. doi: 10.1016/0026-0495(82)90163-9. [DOI] [PubMed] [Google Scholar]
  41. Thomas J. A., Schlender K. K., Larner J. A rapid filter paper assay for UDPglucose-glycogen glucosyltransferase, including an improved biosynthesis of UDP-14C-glucose. Anal Biochem. 1968 Oct 24;25(1):486–499. doi: 10.1016/0003-2697(68)90127-9. [DOI] [PubMed] [Google Scholar]
  42. Wititsuwannakul D., Kim K. H. Mechanism of palmityl coenzyme A inhibition of liver glycogen synthase. J Biol Chem. 1977 Nov 10;252(21):7812–7817. [PubMed] [Google Scholar]
  43. Wolfe B. M., Klein S., Peters E. J., Schmidt B. F., Wolfe R. R. Effect of elevated free fatty acids on glucose oxidation in normal humans. Metabolism. 1988 Apr;37(4):323–329. doi: 10.1016/0026-0495(88)90131-x. [DOI] [PubMed] [Google Scholar]
  44. Yki-Järvinen H., Young A. A., Lamkin C., Foley J. E. Kinetics of glucose disposal in whole body and across the forearm in man. J Clin Invest. 1987 Jun;79(6):1713–1719. doi: 10.1172/JCI113011. [DOI] [PMC free article] [PubMed] [Google Scholar]

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