Skip to main content
NCBI home page
Journal of the Royal Society of Medicine logoLink to Journal of the Royal Society of Medicine
. 2002;95(Suppl 42):39–45.

Ectopic fat accumulation: an important cause of insulin resistance in humans.

Hannele Yki-Järvinen 1
PMCID: PMC1308944  PMID: 12216326

Full Text

The Full Text of this article is available as a PDF (638.1 KB).

Selected References

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

  1. Arioglu E., Duncan-Morin J., Sebring N., Rother K. I., Gottlieb N., Lieberman J., Herion D., Kleiner D. E., Reynolds J., Premkumar A. Efficacy and safety of troglitazone in the treatment of lipodystrophy syndromes. Ann Intern Med. 2000 Aug 15;133(4):263–274. doi: 10.7326/0003-4819-133-4-200008150-00009. [DOI] [PubMed] [Google Scholar]
  2. Bisschop P. H., de Metz J., Ackermans M. T., Endert E., Pijl H., Kuipers F., Meijer A. J., Sauerwein H. P., Romijn J. A. Dietary fat content alters insulin-mediated glucose metabolism in healthy men. Am J Clin Nutr. 2001 Mar;73(3):554–559. doi: 10.1093/ajcn/73.3.554. [DOI] [PubMed] [Google Scholar]
  3. Boden G., Lebed B., Schatz M., Homko C., Lemieux S. Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Diabetes. 2001 Jul;50(7):1612–1617. doi: 10.2337/diabetes.50.7.1612. [DOI] [PubMed] [Google Scholar]
  4. Boesch C., Slotboom J., Hoppeler H., Kreis R. In vivo determination of intra-myocellular lipids in human muscle by means of localized 1H-MR-spectroscopy. Magn Reson Med. 1997 Apr;37(4):484–493. doi: 10.1002/mrm.1910370403. [DOI] [PubMed] [Google Scholar]
  5. Brechtel K., Dahl D. B., Machann J., Bachmann O. P., Wenzel I., Maier T., Claussen C. D., Häring H. U., Jacob S., Schick F. Fast elevation of the intramyocellular lipid content in the presence of circulating free fatty acids and hyperinsulinemia: a dynamic 1H-MRS study. Magn Reson Med. 2001 Feb;45(2):179–183. doi: 10.1002/1522-2594(200102)45:2<179::aid-mrm1023>3.0.co;2-d. [DOI] [PubMed] [Google Scholar]
  6. Brechtel K., Jacob S., Machann J., Hauer B., Nielsen M., Meissner H. P., Matthaei S., Haering H. U., Claussen C. D., Schick F. Acquired generalized lipoatrophy (AGL): highly selective MR lipid imaging and localized (1)H-MRS. J Magn Reson Imaging. 2000 Aug;12(2):306–310. doi: 10.1002/1522-2586(200008)12:2<306::aid-jmri13>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
  7. Chao L., Marcus-Samuels B., Mason M. M., Moitra J., Vinson C., Arioglu E., Gavrilova O., Reitman M. L. Adipose tissue is required for the antidiabetic, but not for the hypolipidemic, effect of thiazolidinediones. J Clin Invest. 2000 Nov;106(10):1221–1228. doi: 10.1172/JCI11245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cruickshank E. W. On the production and utilisation of glycogen in normal and diabetic animals. J Physiol. 1913 Oct 17;47(1-2):1–14. doi: 10.1113/jphysiol.1913.sp001608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Diehl A. M. Nonalcoholic steatohepatitis. Semin Liver Dis. 1999;19(2):221–229. doi: 10.1055/s-2007-1007111. [DOI] [PubMed] [Google Scholar]
  10. Ellis B. A., Poynten A., Lowy A. J., Furler S. M., Chisholm D. J., Kraegen E. W., Cooney G. J. Long-chain acyl-CoA esters as indicators of lipid metabolism and insulin sensitivity in rat and human muscle. Am J Physiol Endocrinol Metab. 2000 Sep;279(3):E554–E560. doi: 10.1152/ajpendo.2000.279.3.E554. [DOI] [PubMed] [Google Scholar]
  11. Essén-Gustavsson B., Tesch P. A. Glycogen and triglyceride utilization in relation to muscle metabolic characteristics in men performing heavy-resistance exercise. Eur J Appl Physiol Occup Physiol. 1990;61(1-2):5–10. doi: 10.1007/BF00236686. [DOI] [PubMed] [Google Scholar]
  12. Falck-Ytter Y., Younossi Z. M., Marchesini G., McCullough A. J. Clinical features and natural history of nonalcoholic steatosis syndromes. Semin Liver Dis. 2001;21(1):17–26. doi: 10.1055/s-2001-12926. [DOI] [PubMed] [Google Scholar]
  13. Fong D. G., Nehra V., Lindor K. D., Buchman A. L. Metabolic and nutritional considerations in nonalcoholic fatty liver. Hepatology. 2000 Jul;32(1):3–10. doi: 10.1053/jhep.2000.8978. [DOI] [PubMed] [Google Scholar]
  14. Garg A. Lipodystrophies. Am J Med. 2000 Feb;108(2):143–152. doi: 10.1016/s0002-9343(99)00414-3. [DOI] [PubMed] [Google Scholar]
  15. Gavrilova O., Marcus-Samuels B., Graham D., Kim J. K., Shulman G. I., Castle A. L., Vinson C., Eckhaus M., Reitman M. L. Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest. 2000 Feb;105(3):271–278. doi: 10.1172/JCI7901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Goodpaster B. H., Theriault R., Watkins S. C., Kelley D. E. Intramuscular lipid content is increased in obesity and decreased by weight loss. Metabolism. 2000 Apr;49(4):467–472. doi: 10.1016/s0026-0495(00)80010-4. [DOI] [PubMed] [Google Scholar]
  17. Griffin M. E., Marcucci M. J., Cline G. W., Bell K., Barucci N., Lee D., Goodyear L. J., Kraegen E. W., White M. F., Shulman G. I. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes. 1999 Jun;48(6):1270–1274. doi: 10.2337/diabetes.48.6.1270. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Hellerstein M. K. De novo lipogenesis in humans: metabolic and regulatory aspects. Eur J Clin Nutr. 1999 Apr;53 (Suppl 1):S53–S65. doi: 10.1038/sj.ejcn.1600744. [DOI] [PubMed] [Google Scholar]
  20. Hoppeler H., Howald H., Conley K., Lindstedt S. L., Claassen H., Vock P., Weibel E. R. Endurance training in humans: aerobic capacity and structure of skeletal muscle. J Appl Physiol (1985) 1985 Aug;59(2):320–327. doi: 10.1152/jappl.1985.59.2.320. [DOI] [PubMed] [Google Scholar]
  21. Hoppeler H., Lüthi P., Claassen H., Weibel E. R., Howald H. The ultrastructure of the normal human skeletal muscle. A morphometric analysis on untrained men, women and well-trained orienteers. Pflugers Arch. 1973 Nov 28;344(3):217–232. doi: 10.1007/BF00588462. [DOI] [PubMed] [Google Scholar]
  22. Howald H., Hoppeler H., Claassen H., Mathieu O., Straub R. Influences of endurance training on the ultrastructural composition of the different muscle fiber types in humans. Pflugers Arch. 1985 Apr;403(4):369–376. doi: 10.1007/BF00589248. [DOI] [PubMed] [Google Scholar]
  23. Hurley B. F., Nemeth P. M., Martin W. H., 3rd, Hagberg J. M., Dalsky G. P., Holloszy J. O. Muscle triglyceride utilization during exercise: effect of training. J Appl Physiol (1985) 1986 Feb;60(2):562–567. doi: 10.1152/jappl.1986.60.2.562. [DOI] [PubMed] [Google Scholar]
  24. Ikai E., Ishizaki M., Suzuki Y., Ishida M., Noborizaka Y., Yamada Y. Association between hepatic steatosis, insulin resistance and hyperinsulinaemia as related to hypertension in alcohol consumers and obese people. J Hum Hypertens. 1995 Feb;9(2):101–105. [PubMed] [Google Scholar]
  25. Jackson R. A., Hawa M. I., Jaspan J. B., Sim B. M., Disilvio L., Featherbe D., Kurtz A. B. Mechanism of metformin action in non-insulin-dependent diabetes. Diabetes. 1987 May;36(5):632–640. doi: 10.2337/diab.36.5.632. [DOI] [PubMed] [Google Scholar]
  26. Jacob S., Machann J., Rett K., Brechtel K., Volk A., Renn W., Maerker E., Matthaei S., Schick F., Claussen C. D. Association of increased intramyocellular lipid content with insulin resistance in lean nondiabetic offspring of type 2 diabetic subjects. Diabetes. 1999 May;48(5):1113–1119. doi: 10.2337/diabetes.48.5.1113. [DOI] [PubMed] [Google Scholar]
  27. James O. F., Day C. P. Non-alcoholic steatohepatitis (NASH): a disease of emerging identity and importance. J Hepatol. 1998 Sep;29(3):495–501. doi: 10.1016/s0168-8278(98)80073-1. [DOI] [PubMed] [Google Scholar]
  28. Katoh S., Hata S., Matsushima M., Ikemoto S., Inoue Y., Yokoyama J., Tajima N. Troglitazone prevents the rise in visceral adiposity and improves fatty liver associated with sulfonylurea therapy--a randomized controlled trial. Metabolism. 2001 Apr;50(4):414–417. doi: 10.1053/meta.2001.21691. [DOI] [PubMed] [Google Scholar]
  29. Kawasaki T., Hashimoto N., Kikuchi T., Takahashi H., Uchiyama M. The relationship between fatty liver and hyperinsulinemia in obese Japanese children. J Pediatr Gastroenterol Nutr. 1997 Mar;24(3):317–321. doi: 10.1097/00005176-199703000-00015. [DOI] [PubMed] [Google Scholar]
  30. Kiens B., Essen-Gustavsson B., Gad P., Lithell H. Lipoprotein lipase activity and intramuscular triglyceride stores after long-term high-fat and high-carbohydrate diets in physically trained men. Clin Physiol. 1987 Feb;7(1):1–9. doi: 10.1111/j.1475-097x.1987.tb00628.x. [DOI] [PubMed] [Google Scholar]
  31. Kim J. K., Gavrilova O., Chen Y., Reitman M. L., Shulman G. I. Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J Biol Chem. 2000 Mar 24;275(12):8456–8460. doi: 10.1074/jbc.275.12.8456. [DOI] [PubMed] [Google Scholar]
  32. Knobler H., Schattner A., Zhornicki T., Malnick S. D., Keter D., Sokolovskaya N., Lurie Y., Bass D. D. Fatty liver--an additional and treatable feature of the insulin resistance syndrome. QJM. 1999 Feb;92(2):73–79. doi: 10.1093/qjmed/92.2.73. [DOI] [PubMed] [Google Scholar]
  33. Krssak M., Falk Petersen K., Dresner A., DiPietro L., Vogel S. M., Rothman D. L., Roden M., Shulman G. I. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia. 1999 Jan;42(1):113–116. doi: 10.1007/s001250051123. [DOI] [PubMed] [Google Scholar]
  34. Levin K., Daa Schroeder H., Alford F. P., Beck-Nielsen H. Morphometric documentation of abnormal intramyocellular fat storage and reduced glycogen in obese patients with Type II diabetes. Diabetologia. 2001 Jul;44(7):824–833. doi: 10.1007/s001250100545. [DOI] [PubMed] [Google Scholar]
  35. 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]
  36. Marceau P., Biron S., Hould F. S., Marceau S., Simard S., Thung S. N., Kral J. G. Liver pathology and the metabolic syndrome X in severe obesity. J Clin Endocrinol Metab. 1999 May;84(5):1513–1517. doi: 10.1210/jcem.84.5.5661. [DOI] [PubMed] [Google Scholar]
  37. Marchesini G., Brizi M., Bianchi G., Tomassetti S., Bugianesi E., Lenzi M., McCullough A. J., Natale S., Forlani G., Melchionda N. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes. 2001 Aug;50(8):1844–1850. doi: 10.2337/diabetes.50.8.1844. [DOI] [PubMed] [Google Scholar]
  38. Marchesini G., Brizi M., Morselli-Labate A. M., Bianchi G., Bugianesi E., McCullough A. J., Forlani G., Melchionda N. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med. 1999 Nov;107(5):450–455. doi: 10.1016/s0002-9343(99)00271-5. [DOI] [PubMed] [Google Scholar]
  39. Meltzer A. A., Everhart J. E. Association between diabetes and elevated serum alanine aminotransferase activity among Mexican Americans. Am J Epidemiol. 1997 Oct 1;146(7):565–571. doi: 10.1093/oxfordjournals.aje.a009315. [DOI] [PubMed] [Google Scholar]
  40. Memon R. A., Tecott L. H., Nonogaki K., Beigneux A., Moser A. H., Grunfeld C., Feingold K. R. Up-regulation of peroxisome proliferator-activated receptors (PPAR-alpha) and PPAR-gamma messenger ribonucleic acid expression in the liver in murine obesity: troglitazone induces expression of PPAR-gamma-responsive adipose tissue-specific genes in the liver of obese diabetic mice. Endocrinology. 2000 Nov;141(11):4021–4031. doi: 10.1210/endo.141.11.7771. [DOI] [PubMed] [Google Scholar]
  41. Mitrakou A., Kelley D., Veneman T., Jenssen T., Pangburn T., Reilly J., Gerich J. Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM. Diabetes. 1990 Nov;39(11):1381–1390. doi: 10.2337/diab.39.11.1381. [DOI] [PubMed] [Google Scholar]
  42. Morgan T. E., Short F. A., Cobb L. A. Effect of long-term exercise on skeletal muscle lipid composition. Am J Physiol. 1969 Jan;216(1):82–86. doi: 10.1152/ajplegacy.1969.216.1.82. [DOI] [PubMed] [Google Scholar]
  43. Oberholzer F., Claassen H., Moesch H., Howald H. Ultrastrukturelle, biochemische und energetische Aanlyse einer extremen Dauerleistung (100 Km-Lauf) Schweiz Z Sportmed. 1976;24(2):71–98. [PubMed] [Google Scholar]
  44. Pan D. A., Lillioja S., Kriketos A. D., Milner M. R., Baur L. A., Bogardus C., Jenkins A. B., Storlien L. H. Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes. 1997 Jun;46(6):983–988. doi: 10.2337/diab.46.6.983. [DOI] [PubMed] [Google Scholar]
  45. Perseghin G., Scifo P., De Cobelli F., Pagliato E., Battezzati A., Arcelloni C., Vanzulli A., Testolin G., Pozza G., Del Maschio A. Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: a 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents. Diabetes. 1999 Aug;48(8):1600–1606. doi: 10.2337/diabetes.48.8.1600. [DOI] [PubMed] [Google Scholar]
  46. Reitman M. L., Arioglu E., Gavrilova O., Taylor S. I. Lipoatrophy revisited. Trends Endocrinol Metab. 2000 Dec;11(10):410–416. doi: 10.1016/s1043-2760(00)00309-x. [DOI] [PubMed] [Google Scholar]
  47. Ryysy L., Häkkinen A. M., Goto T., Vehkavaara S., Westerbacka J., Halavaara J., Yki-Järvinen H. Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes. 2000 May;49(5):749–758. doi: 10.2337/diabetes.49.5.749. [DOI] [PubMed] [Google Scholar]
  48. Schmitz-Peiffer C. Signalling aspects of insulin resistance in skeletal muscle: mechanisms induced by lipid oversupply. Cell Signal. 2000 Oct;12(9-10):583–594. doi: 10.1016/s0898-6568(00)00110-8. [DOI] [PubMed] [Google Scholar]
  49. Szczepaniak L. S., Babcock E. E., Schick F., Dobbins R. L., Garg A., Burns D. K., McGarry J. D., Stein D. T. Measurement of intracellular triglyceride stores by H spectroscopy: validation in vivo. Am J Physiol. 1999 May;276(5 Pt 1):E977–E989. doi: 10.1152/ajpendo.1999.276.5.E977. [DOI] [PubMed] [Google Scholar]
  50. Thompson A. L., Cooney G. J. Acyl-CoA inhibition of hexokinase in rat and human skeletal muscle is a potential mechanism of lipid-induced insulin resistance. Diabetes. 2000 Nov;49(11):1761–1765. doi: 10.2337/diabetes.49.11.1761. [DOI] [PubMed] [Google Scholar]
  51. Virkamäki A., Korsheninnikova E., Seppälä-Lindroos A., Vehkavaara S., Goto T., Halavaara J., Häkkinen A. M., Yki-Järvinen H. Intramyocellular lipid is associated with resistance to in vivo insulin actions on glucose uptake, antilipolysis, and early insulin signaling pathways in human skeletal muscle. Diabetes. 2001 Oct;50(10):2337–2343. doi: 10.2337/diabetes.50.10.2337. [DOI] [PubMed] [Google Scholar]
  52. Wanless I. R., Lentz J. S. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology. 1990 Nov;12(5):1106–1110. doi: 10.1002/hep.1840120505. [DOI] [PubMed] [Google Scholar]
  53. Yamauchi T., Waki H., Kamon J., Murakami K., Motojima K., Komeda K., Miki H., Kubota N., Terauchi Y., Tsuchida A. Inhibition of RXR and PPARgamma ameliorates diet-induced obesity and type 2 diabetes. J Clin Invest. 2001 Oct;108(7):1001–1013. doi: 10.1172/JCI12864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Ye J. M., Doyle P. J., Iglesias M. A., Watson D. G., Cooney G. J., Kraegen E. W. Peroxisome proliferator-activated receptor (PPAR)-alpha activation lowers muscle lipids and improves insulin sensitivity in high fat-fed rats: comparison with PPAR-gamma activation. Diabetes. 2001 Feb;50(2):411–417. doi: 10.2337/diabetes.50.2.411. [DOI] [PubMed] [Google Scholar]
  55. Yki-Järvinen H., Helve E., Sane T., Nurjhan N., Taskinen M. R. Insulin inhibition of overnight glucose production and gluconeogenesis from lactate in NIDDM. Am J Physiol. 1989 Jun;256(6 Pt 1):E732–E739. doi: 10.1152/ajpendo.1989.256.6.E732. [DOI] [PubMed] [Google Scholar]

Articles from Journal of the Royal Society of Medicine are provided here courtesy of Royal Society of Medicine Press

RESOURCES