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. 1994 Dec;94(6):2349–2356. doi: 10.1172/JCI117600

Impaired free fatty acid utilization by skeletal muscle in non-insulin-dependent diabetes mellitus.

D E Kelley 1, J A Simoneau 1
PMCID: PMC330064  PMID: 7989591

Abstract

This study was undertaken to assess utilization of FFA by skeletal muscle in patients with non-insulin-dependent diabetes mellitus (NIDDM). 11 NIDDM and 9 nondiabetic subjects were studied using leg balance methods to measure the fractional extraction of [3H]oleate. Limb indirect calorimetry was used to estimate RQ. Percutaneous muscle biopsy samples of vastus lateralis were analyzed for muscle fiber type distribution, capillary density, and metabolic potential as reflected by measurements of the activity of seven muscle enzyme markers of glycolytic and aerobic-oxidative pathways. During postabsorptive conditions, fractional extraction of oleate across the leg was lower in NIDDM subjects (0.31 +/- 0.08 vs. 0.43 +/- 0.10, P < 0.01), and there was reduced oleate uptake across the leg (66 +/- 8 vs. 82 +/- 13 nmol/min, P < 0.01). Postabsorptive leg RQ was increased in NIDDM (0.85 +/- 0.03 vs. 0.77 +/- 0.02, P < 0.01), and rates of lipid oxidation by skeletal muscle were lower while glucose oxidation was increased (P < 0.05). In subjects with NIDDM, proportions of type I, IIa, and IIb fibers were 37 +/- 2, 37 +/- 6, and 26 +/- 5%, respectively, which did not differ from nondiabetics; and capillary density, glycolytic, and aerobic-oxidative potentials were similar. During 6 h after ingestion of a mixed meal, arterial FFA remained greater in NIDDM subjects. Therefore, despite persistent reduced fractional extraction of oleate across the leg in NIDDM (0.34 +/- 0.04 vs. 0.38 +/- 0.03, P < 0.05), rates of oleate uptake across the leg were greater in NIDDM (54 +/- 7 vs. 45 +/- 8 nmol/min, P < 0.01). In summary, during postabsorptive conditions there is reduced utilization of FFA by muscle, while during postprandial conditions there is impaired suppression of FFA uptake across the leg in NIDDM. During both fasting and postprandial conditions, NIDDM subjects have reduced rates of lipid oxidation by muscle.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andersen P. Capillary density in skeletal muscle of man. Acta Physiol Scand. 1975 Oct;95(2):203–205. doi: 10.1111/j.1748-1716.1975.tb10043.x. [DOI] [PubMed] [Google Scholar]
  2. BALTZAN M. A., ANDRES R., CADER G., ZIERLER K. L. Heterogeneity of forearm metabolism with special reference to free fatty acids. J Clin Invest. 1962 Jan;41:116–125. doi: 10.1172/JCI104453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Boden G., Chen X., Ruiz J., White J. V., Rossetti L. Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest. 1994 Jun;93(6):2438–2446. doi: 10.1172/JCI117252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bonadonna R. C., Groop L. C., Zych K., Shank M., DeFronzo R. A. Dose-dependent effect of insulin on plasma free fatty acid turnover and oxidation in humans. Am J Physiol. 1990 Nov;259(5 Pt 1):E736–E750. doi: 10.1152/ajpendo.1990.259.5.E736. [DOI] [PubMed] [Google Scholar]
  5. Bouchard C. La génétique des obésités humaines. Ann Med Interne (Paris) 1992;143(7):463–471. [PubMed] [Google Scholar]
  6. Capaldo B., Napoli R., Di Marino L., Picardi A., Riccardi G., Sacca L. Quantitation of forearm glucose and free fatty acid (FFA) disposal in normal subjects and type II diabetic patients: evidence against an essential role for FFA in the pathogenesis of insulin resistance. J Clin Endocrinol Metab. 1988 Nov;67(5):893–898. doi: 10.1210/jcem-67-5-893. [DOI] [PubMed] [Google Scholar]
  7. Consoli A. Role of liver in pathophysiology of NIDDM. Diabetes Care. 1992 Mar;15(3):430–441. doi: 10.2337/diacare.15.3.430. [DOI] [PubMed] [Google Scholar]
  8. Dagenais G. R., Tancredi R. G., Zierler K. L. Free fatty acid oxidation by forearm muscle at rest, and evidence for an intramuscular lipid pool in the human forearm. J Clin Invest. 1976 Aug;58(2):421–431. doi: 10.1172/JCI108486. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Douglas A. R., Jones N. L., Reed J. W. Calculation of whole blood CO2 content. J Appl Physiol (1985) 1988 Jul;65(1):473–477. doi: 10.1152/jappl.1988.65.1.473. [DOI] [PubMed] [Google Scholar]
  10. Evans W. J., Phinney S. D., Young V. R. Suction applied to a muscle biopsy maximizes sample size. Med Sci Sports Exerc. 1982;14(1):101–102. [PubMed] [Google Scholar]
  11. Frayn K. N. Calculation of substrate oxidation rates in vivo from gaseous exchange. J Appl Physiol Respir Environ Exerc Physiol. 1983 Aug;55(2):628–634. doi: 10.1152/jappl.1983.55.2.628. [DOI] [PubMed] [Google Scholar]
  12. Frayn K. N., Lund P., Walker M. Interpretation of oxygen and carbon dioxide exchange across tissue beds in vivo. Clin Sci (Lond) 1993 Oct;85(4):373–384. doi: 10.1042/cs0850373. [DOI] [PubMed] [Google Scholar]
  13. Fraze E., Donner C. C., Swislocki A. L., Chiou Y. A., Chen Y. D., Reaven G. M. Ambient plasma free fatty acid concentrations in noninsulin-dependent diabetes mellitus: evidence for insulin resistance. J Clin Endocrinol Metab. 1985 Nov;61(5):807–811. doi: 10.1210/jcem-61-5-807. [DOI] [PubMed] [Google Scholar]
  14. Gauthier J. M., Thériault R., Thériault G., Gélinas Y., Simoneau J. A. Electrical stimulation-induced changes in skeletal muscle enzymes of men and women. Med Sci Sports Exerc. 1992 Nov;24(11):1252–1256. [PubMed] [Google Scholar]
  15. Ginsberg H. N. Very low density lipoprotein metabolism in diabetes mellitus. Diabetes Metab Rev. 1987 Apr;3(2):571–589. doi: 10.1002/dmr.5610030209. [DOI] [PubMed] [Google Scholar]
  16. Groop L. C., Bonadonna R. C., DelPrato S., Ratheiser K., Zyck K., Ferrannini E., DeFronzo R. A. Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest. 1989 Jul;84(1):205–213. doi: 10.1172/JCI114142. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Howard B. V. Lipoprotein metabolism in diabetes mellitus. J Lipid Res. 1987 Jun;28(6):613–628. [PubMed] [Google Scholar]
  18. Kelley D. E., Mandarino L. J. Hyperglycemia normalizes insulin-stimulated skeletal muscle glucose oxidation and storage in noninsulin-dependent diabetes mellitus. J Clin Invest. 1990 Dec;86(6):1999–2007. doi: 10.1172/JCI114935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kelley D. E., Mokan M., Mandarino L. J. Intracellular defects in glucose metabolism in obese patients with NIDDM. Diabetes. 1992 Jun;41(6):698–706. doi: 10.2337/diab.41.6.698. [DOI] [PubMed] [Google Scholar]
  20. Kelley D. E., Mokan M., Simoneau J. A., Mandarino L. J. Interaction between glucose and free fatty acid metabolism in human skeletal muscle. J Clin Invest. 1993 Jul;92(1):91–98. doi: 10.1172/JCI116603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kelley D. E., Reilly J. P., Veneman T., Mandarino L. J. Effects of insulin on skeletal muscle glucose storage, oxidation, and glycolysis in humans. Am J Physiol. 1990 Jun;258(6 Pt 1):E923–E929. doi: 10.1152/ajpendo.1990.258.6.E923. [DOI] [PubMed] [Google Scholar]
  22. Kelley D. E., Slasky B. S., Janosky J. Skeletal muscle density: effects of obesity and non-insulin-dependent diabetes mellitus. Am J Clin Nutr. 1991 Sep;54(3):509–515. doi: 10.1093/ajcn/54.3.509. [DOI] [PubMed] [Google Scholar]
  23. Lillioja S., Young A. A., Culter C. L., Ivy J. L., Abbott W. G., Zawadzki J. K., Yki-Järvinen H., Christin L., Secomb T. W., Bogardus C. Skeletal muscle capillary density and fiber type are possible determinants of in vivo insulin resistance in man. J Clin Invest. 1987 Aug;80(2):415–424. doi: 10.1172/JCI113088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lindgärde F., Eriksson K. F., Lithell H., Saltin B. Coupling between dietary changes, reduced body weight, muscle fibre size and improved glucose tolerance in middle-aged men with impaired glucose tolerance. Acta Med Scand. 1982;212(3):99–106. doi: 10.1111/j.0954-6820.1982.tb03179.x. [DOI] [PubMed] [Google Scholar]
  25. Mandarino L. J., Consoli A., Jain A., Kelley D. E. Differential regulation of intracellular glucose metabolism by glucose and insulin in human muscle. Am J Physiol. 1993 Dec;265(6 Pt 1):E898–E905. doi: 10.1152/ajpendo.1993.265.6.E898. [DOI] [PubMed] [Google Scholar]
  26. McGarry J. D. What if Minkowski had been ageusic? An alternative angle on diabetes. Science. 1992 Oct 30;258(5083):766–770. doi: 10.1126/science.1439783. [DOI] [PubMed] [Google Scholar]
  27. Miles J. M., Ellman M. G., McClean K. L., Jensen M. D. Validation of a new method for determination of free fatty acid turnover. Am J Physiol. 1987 Mar;252(3 Pt 1):E431–E438. doi: 10.1152/ajpendo.1987.252.3.E431. [DOI] [PubMed] [Google Scholar]
  28. Mårin P., Andersson B., Krotkiewski M., Björntorp P. Muscle fiber composition and capillary density in women and men with NIDDM. Diabetes Care. 1994 May;17(5):382–386. doi: 10.2337/diacare.17.5.382. [DOI] [PubMed] [Google Scholar]
  29. Nurjhan N., Consoli A., Gerich J. Increased lipolysis and its consequences on gluconeogenesis in non-insulin-dependent diabetes mellitus. J Clin Invest. 1992 Jan;89(1):169–175. doi: 10.1172/JCI115558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Nuutila P., Koivisto V. A., Knuuti J., Ruotsalainen U., Teräs M., Haaparanta M., Bergman J., Solin O., Voipio-Pulkki L. M., Wegelius U. Glucose-free fatty acid cycle operates in human heart and skeletal muscle in vivo. J Clin Invest. 1992 Jun;89(6):1767–1774. doi: 10.1172/JCI115780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Peeters R. A., in't Groen M. A., Veerkamp J. H. The fatty acid-binding protein from human skeletal muscle. Arch Biochem Biophys. 1989 Nov 1;274(2):556–563. doi: 10.1016/0003-9861(89)90470-0. [DOI] [PubMed] [Google Scholar]
  32. Randle P. J., Kerbey A. L., 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. doi: 10.1002/dmr.5610040702. [DOI] [PubMed] [Google Scholar]
  33. Simoneau J. A., Bouchard C. Human variation in skeletal muscle fiber-type proportion and enzyme activities. Am J Physiol. 1989 Oct;257(4 Pt 1):E567–E572. doi: 10.1152/ajpendo.1989.257.4.E567. [DOI] [PubMed] [Google Scholar]
  34. Simoneau J. A., Lortie G., Boulay M. R., Thibault M. C., Bouchard C. Repeatability of fibre type and enzyme activity measurements in human skeletal muscle. Clin Physiol. 1986 Aug;6(4):347–356. doi: 10.1111/j.1475-097x.1986.tb00240.x. [DOI] [PubMed] [Google Scholar]
  35. Simoneau J. A., Lortie G., Boulay M. R., Thibault M. C., Thériault G., Bouchard C. Skeletal muscle histochemical and biochemical characteristics in sedentary male and female subjects. Can J Physiol Pharmacol. 1985 Jan;63(1):30–35. doi: 10.1139/y85-005. [DOI] [PubMed] [Google Scholar]
  36. Sugden M. C., Holness M. J. Interactive regulation of the pyruvate dehydrogenase complex and the carnitine palmitoyltransferase system. FASEB J. 1994 Jan;8(1):54–61. doi: 10.1096/fasebj.8.1.8299890. [DOI] [PubMed] [Google Scholar]
  37. Tancredi R. G., Dagenais G. R., Zierler K. L. Free fatty acid metabolism in the forearm at rest: muscle uptake and adipose tissue release of free fatty acids. Johns Hopkins Med J. 1976 May;138(5):167–179. [PubMed] [Google Scholar]
  38. Taskinen M. R., Bogardus C., Kennedy A., Howard B. V. Multiple disturbances of free fatty acid metabolism in noninsulin-dependent diabetes. Effect of oral hypoglycemic therapy. J Clin Invest. 1985 Aug;76(2):637–644. doi: 10.1172/JCI112016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Wang N., Hikida R. S., Staron R. S., Simoneau J. A. Muscle fiber types of women after resistance training--quantitative ultrastructure and enzyme activity. Pflugers Arch. 1993 Sep;424(5-6):494–502. doi: 10.1007/BF00374913. [DOI] [PubMed] [Google Scholar]
  40. Yki-Järvinen H., Bogardus C., Howard B. V. Hyperglycemia stimulates carbohydrate oxidation in humans. Am J Physiol. 1987 Oct;253(4 Pt 1):E376–E382. doi: 10.1152/ajpendo.1987.253.4.E376. [DOI] [PubMed] [Google Scholar]

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