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. 1995 Dec;96(6):2802–2808. doi: 10.1172/JCI118350

Skeletal muscle membrane lipid composition is related to adiposity and insulin action.

D A Pan 1, S Lillioja 1, M R Milner 1, A D Kriketos 1, L A Baur 1, C Bogardus 1, L H Storlien 1
PMCID: PMC185990  PMID: 8675650

Abstract

The cellular basis of insulin resistance is still unknown; however, relationships have been demonstrated between insulin action in muscle and the fatty acid profile of the major membrane structural lipid (phospholipid). The present study aimed to further investigate the hypothesis that insulin action and adiposity are associated with changes in the structural lipid composition of the cell. In 52 adult male Pima Indians, insulin action (euglycemic clamp), percentage body fat (pFAT; underwater weighing), and muscle phospholipid fatty acid composition (percutaneous biopsy of vastus lateralis) were determined. Insulin action (high-dose clamp; MZ) correlated with composite measures of membrane unsaturation (% C20-22 polyunsaturated fatty acids [r= 0.463, P < 0.001], unsaturation index [r= -0.369, P < 0.01]), a number of individual fatty acids and with delta5 desaturase activity (r= 0.451, P < 0.001). pFAT (range 14-53%) correlated with a number of individual fatty acids and delta5 desaturase activity (r= -0.610, P < 0.0001). Indices of elongase activity (r= -0.467, P < 0.001), and delta9 desaturase activity (r= 0.332, P < 0.05) were also related to pFAT but not insulin action. The results demonstrate that delta5 desaturase activity is independently related to both insulin resistance and obesity. While determining the mechanisms underlying this relationship is important for future investigations, strategies aimed at restoring "normal" enzyme activities, and membrane unsaturation, may have therapeutic importance in the "syndromes of insulin resistance."

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Selected References

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  1. Barnett A. H., Eff C., Leslie R. D., Pyke D. A. Diabetes in identical twins. A study of 200 pairs. Diabetologia. 1981 Feb;20(2):87–93. doi: 10.1007/BF00262007. [DOI] [PubMed] [Google Scholar]
  2. Beynen A. C., Hermus R. J., Hautvast J. G. A mathematical relationship between the fatty acid composition of the diet and that of the adipose tissue in man. Am J Clin Nutr. 1980 Jan;33(1):81–85. doi: 10.1093/ajcn/33.1.81. [DOI] [PubMed] [Google Scholar]
  3. Borkman M., Storlien L. H., Pan D. A., Jenkins A. B., Chisholm D. J., Campbell L. V. The relation between insulin sensitivity and the fatty-acid composition of skeletal-muscle phospholipids. N Engl J Med. 1993 Jan 28;328(4):238–244. doi: 10.1056/NEJM199301283280404. [DOI] [PubMed] [Google Scholar]
  4. Brand M. D., Couture P., Else P. L., Withers K. W., Hulbert A. J. Evolution of energy metabolism. Proton permeability of the inner membrane of liver mitochondria is greater in a mammal than in a reptile. Biochem J. 1991 Apr 1;275(Pt 1):81–86. doi: 10.1042/bj2750081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Clarke S. D., Jump D. B. Regulation of gene transcription by polyunsaturated fatty acids. Prog Lipid Res. 1993;32(2):139–149. doi: 10.1016/0163-7827(93)90013-m. [DOI] [PubMed] [Google Scholar]
  6. Cunnane S. C., McAdoo K. R., Horrobin D. F. n-3 Essential fatty acids decrease weight gain in genetically obese mice. Br J Nutr. 1986 Jul;56(1):87–95. doi: 10.1079/bjn19860088. [DOI] [PubMed] [Google Scholar]
  7. Dayton S., Hashimoto S., Dixon W., Pearce M. L. Composition of lipids in human serum and adipose tissue during prolonged feeding of a diet high in unsaturated fat. J Lipid Res. 1966 Jan;7(1):103–111. [PubMed] [Google Scholar]
  8. 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]
  9. DeFronzo R. A., Tobin J. D., Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979 Sep;237(3):E214–E223. doi: 10.1152/ajpendo.1979.237.3.E214. [DOI] [PubMed] [Google Scholar]
  10. FOLCH J., LEES M., SLOANE STANLEY G. H. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957 May;226(1):497–509. [PubMed] [Google Scholar]
  11. Gottlieb M. S., Root H. F. Diabetes mellitus in twins. Diabetes. 1968 Nov;17(11):693–704. doi: 10.2337/diab.17.11.693. [DOI] [PubMed] [Google Scholar]
  12. Jeffcoat R. The biosynthesis of unsaturated fatty acids and its control in mammalian liver. Essays Biochem. 1979;15:1–36. [PubMed] [Google Scholar]
  13. Jones P. J., Schoeller D. A. Polyunsaturated:saturated ratio of diet fat influences energy substrate utilization in the human. Metabolism. 1988 Feb;37(2):145–151. doi: 10.1016/s0026-0495(98)90009-9. [DOI] [PubMed] [Google Scholar]
  14. KEYS A., BROZEK J. Body fat in adult man. Physiol Rev. 1953 Jul;33(3):245–325. doi: 10.1152/physrev.1953.33.3.245. [DOI] [PubMed] [Google Scholar]
  15. Knowler W. C., Bennett P. H., Hamman R. F., Miller M. Diabetes incidence and prevalence in Pima Indians: a 19-fold greater incidence than in Rochester, Minnesota. Am J Epidemiol. 1978 Dec;108(6):497–505. doi: 10.1093/oxfordjournals.aje.a112648. [DOI] [PubMed] [Google Scholar]
  16. Knowler W. C., Pettitt D. J., Savage P. J., Bennett P. H. Diabetes incidence in Pima indians: contributions of obesity and parental diabetes. Am J Epidemiol. 1981 Feb;113(2):144–156. doi: 10.1093/oxfordjournals.aje.a113079. [DOI] [PubMed] [Google Scholar]
  17. Knowler W. C., Williams R. C., Pettitt D. J., Steinberg A. G. Gm3;5,13,14 and type 2 diabetes mellitus: an association in American Indians with genetic admixture. Am J Hum Genet. 1988 Oct;43(4):520–526. [PMC free article] [PubMed] [Google Scholar]
  18. Leyton J., Drury P. J., Crawford M. A. Differential oxidation of saturated and unsaturated fatty acids in vivo in the rat. Br J Nutr. 1987 May;57(3):383–393. doi: 10.1079/bjn19870046. [DOI] [PubMed] [Google Scholar]
  19. Lillioja S., Bogardus C. Insulin resistance in Pima Indians. A combined effect of genetic predisposition and obesity-related skeletal muscle cell hypertrophy. Acta Med Scand Suppl. 1988;723:103–119. [PubMed] [Google Scholar]
  20. 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]
  21. Lillioja S., Bogardus C. Obesity and insulin resistance: lessons learned from the Pima Indians. Diabetes Metab Rev. 1988 Aug;4(5):517–540. doi: 10.1002/dmr.5610040508. [DOI] [PubMed] [Google Scholar]
  22. Lillioja S., Foley J., Bogardus C., Mott D., Howard B. V. Free fatty acid metabolism and obesity in man: in vivo in vitro comparisons. Metabolism. 1986 Jun;35(6):505–514. doi: 10.1016/0026-0495(86)90006-5. [DOI] [PubMed] [Google Scholar]
  23. Lillioja S., Mott D. M., Howard B. V., Bennett P. H., Yki-Järvinen H., Freymond D., Nyomba B. L., Zurlo F., Swinburn B., Bogardus C. Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians. N Engl J Med. 1988 May 12;318(19):1217–1225. doi: 10.1056/NEJM198805123181901. [DOI] [PubMed] [Google Scholar]
  24. Lillioja S., Mott D. M., Spraul M., Ferraro R., Foley J. E., Ravussin E., Knowler W. C., Bennett P. H., Bogardus C. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. N Engl J Med. 1993 Dec 30;329(27):1988–1992. doi: 10.1056/NEJM199312303292703. [DOI] [PubMed] [Google Scholar]
  25. Lillioja S., Mott D. M., Zawadzki J. K., Young A. A., Abbott W. G., Knowler W. C., Bennett P. H., Moll P., Bogardus C. In vivo insulin action is familial characteristic in nondiabetic Pima Indians. Diabetes. 1987 Nov;36(11):1329–1335. doi: 10.2337/diab.36.11.1329. [DOI] [PubMed] [Google Scholar]
  26. MOHRHAUER H., HOLMAN R. T. THE EFFECT OF DOSE LEVEL OF ESSENTIAL FATTY ACIDS UPON FATTY ACID COMPOSITION OF THE RAT LIVER. J Lipid Res. 1963 Apr;4:151–159. [PubMed] [Google Scholar]
  27. Mather H. M., Keen H. The Southall Diabetes Survey: prevalence of known diabetes in Asians and Europeans. Br Med J (Clin Res Ed) 1985 Oct 19;291(6502):1081–1084. doi: 10.1136/bmj.291.6502.1081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. McMurchie E. J., Margetts B. M., Beilin L. J., Croft K. D., Vandongen R., Armstrong B. K. Dietary-induced changes in the fatty acid composition of human cheek cell phospholipids: correlation with changes in the dietary polyunsaturated/saturated fat ratio. Am J Clin Nutr. 1984 Jun;39(6):975–980. doi: 10.1093/ajcn/39.6.975. [DOI] [PubMed] [Google Scholar]
  29. NEEL J. V. Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"? Am J Hum Genet. 1962 Dec;14:353–362. [PMC free article] [PubMed] [Google Scholar]
  30. Nakamura M. T., Tang A. B., Villanueva J., Halsted C. H., Phinney S. D. Selective reduction of delta 6 and delta 5 desaturase activities but not delta 9 desaturase in micropigs chronically fed ethanol. J Clin Invest. 1994 Jan;93(1):450–454. doi: 10.1172/JCI116981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Ntambi J. M. Dietary regulation of stearoyl-CoA desaturase 1 gene expression in mouse liver. J Biol Chem. 1992 May 25;267(15):10925–10930. [PubMed] [Google Scholar]
  32. Pan D. A., Hulbert A. J., Storlien L. H. Dietary fats, membrane phospholipids and obesity. J Nutr. 1994 Sep;124(9):1555–1565. doi: 10.1093/jn/124.9.1555. [DOI] [PubMed] [Google Scholar]
  33. Pan D. A., Storlien L. H. Dietary lipid profile is a determinant of tissue phospholipid fatty acid composition and rate of weight gain in rats. J Nutr. 1993 Mar;123(3):512–519. doi: 10.1093/jn/123.3.512. [DOI] [PubMed] [Google Scholar]
  34. Paulsrud J. R., Pensler L., Whitten C. F., Stewart S., Holman R. T. Essential fatty acid deficiency in infants induced by fat-free intravenous feeding. Am J Clin Nutr. 1972 Sep;25(9):897–904. doi: 10.1093/ajcn/25.9.897. [DOI] [PubMed] [Google Scholar]
  35. Prochazka M., Lillioja S., Tait J. F., Knowler W. C., Mott D. M., Spraul M., Bennett P. H., Bogardus C. Linkage of chromosomal markers on 4q with a putative gene determining maximal insulin action in Pima Indians. Diabetes. 1993 Apr;42(4):514–519. doi: 10.2337/diab.42.4.514. [DOI] [PubMed] [Google Scholar]
  36. Ravussin E., Bogardus C. Energy expenditure in the obese: is there a thrifty gene? Infusionstherapie. 1990 Apr;17(2):108–112. doi: 10.1159/000222456. [DOI] [PubMed] [Google Scholar]
  37. Reaven G. M. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988 Dec;37(12):1595–1607. doi: 10.2337/diab.37.12.1595. [DOI] [PubMed] [Google Scholar]
  38. Reaven G. M. Role of insulin resistance in human disease (syndrome X): an expanded definition. Annu Rev Med. 1993;44:121–131. doi: 10.1146/annurev.me.44.020193.001005. [DOI] [PubMed] [Google Scholar]
  39. 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]
  40. Storlien L. H., Jenkins A. B., Chisholm D. J., Pascoe W. S., Khouri S., Kraegen E. W. Influence of dietary fat composition on development of insulin resistance in rats. Relationship to muscle triglyceride and omega-3 fatty acids in muscle phospholipid. Diabetes. 1991 Feb;40(2):280–289. doi: 10.2337/diab.40.2.280. [DOI] [PubMed] [Google Scholar]
  41. Stubbs C. D., Smith A. D. The modification of mammalian membrane polyunsaturated fatty acid composition in relation to membrane fluidity and function. Biochim Biophys Acta. 1984 Jan 27;779(1):89–137. doi: 10.1016/0304-4157(84)90005-4. [DOI] [PubMed] [Google Scholar]
  42. Swinburn B. A., Nyomba B. L., Saad M. F., Zurlo F., Raz I., Knowler W. C., Lillioja S., Bogardus C., Ravussin E. Insulin resistance associated with lower rates of weight gain in Pima Indians. J Clin Invest. 1991 Jul;88(1):168–173. doi: 10.1172/JCI115274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Vessby B., Tengblad S., Lithell H. Insulin sensitivity is related to the fatty acid composition of serum lipids and skeletal muscle phospholipids in 70-year-old men. Diabetologia. 1994 Oct;37(10):1044–1050. doi: 10.1007/BF00400468. [DOI] [PubMed] [Google Scholar]

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