Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Feb 15;97(4):1111–1116. doi: 10.1172/JCI118504

The expression of TNF alpha by human muscle. Relationship to insulin resistance.

M Saghizadeh 1, J M Ong 1, W T Garvey 1, R R Henry 1, P A Kern 1
PMCID: PMC507159  PMID: 8613535

Abstract

TNFalpha is orverexpressed in the adipose tissue of obese rodents and humans, and is associated with insulin resistance. To more closely link TNF expression with whole body insulin action, we examined the expression of TNF by muscle, which is responsible for the majority of glucose uptake in vivo. Using RT-PCR, TNF was detected in human heart, in skeletal muscle from humans and rats, and in cultured human myocytes. Using competitive RT-PCR, TNF was quantitated in the muscle biopsy specimens from 15 subjects whose insulin sensitivity had been characterized using the glucose clamp. technique. TNF expression in the insulin resistant subjects and the diabetic patients was fourfold higher than in the insulin sensitive subjects, and there was a significant inverse linear relationship between maximal glucose disposal rate and muscle TNF (r = -0.60, P < 0.02). In nine subjects, muscle cells from vastus lateralis muscle biopsies were placed into tissue culture for 4 wk, and induced to differentiate into myotubes. TNF was secreted into the medium from these cells, and cells from diabetic patients expressed threefold more TNF than cells from nondiabetic subjects. Thus, TNF is expressed in human muscle, and is expressed at a higher level in the muscle tissue and in the cultured muscle cells from insulin resistant and diabetic subjects. These data suggest another mechanism by which TNF may play an important role in human insulin resistance.

Full Text

The Full Text of this article is available as a PDF (249.4 KB).

Selected References

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

  1. Andus T., Targan S. R., Deem R., Toyoda H. Measurement of tumor necrosis factor alpha mRNA in small numbers of cells by quantitative polymerase chain reaction. Reg Immunol. 1993 Jan-Feb;5(1):11–17. [PubMed] [Google Scholar]
  2. Bouchard C., Tremblay A., Després J. P., Nadeau A., Lupien P. J., Thériault G., Dussault J., Moorjani S., Pinault S., Fournier G. The response to long-term overfeeding in identical twins. N Engl J Med. 1990 May 24;322(21):1477–1482. doi: 10.1056/NEJM199005243222101. [DOI] [PubMed] [Google Scholar]
  3. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. 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]
  6. Fried S. K., Zechner R. Cachectin/tumor necrosis factor decreases human adipose tissue lipoprotein lipase mRNA levels, synthesis, and activity. J Lipid Res. 1989 Dec;30(12):1917–1923. [PubMed] [Google Scholar]
  7. Garvey W. T., Olefsky J. M., Griffin J., Hamman R. F., Kolterman O. G. The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes. 1985 Mar;34(3):222–234. doi: 10.2337/diab.34.3.222. [DOI] [PubMed] [Google Scholar]
  8. Grunfeld C., Feingold K. R. Metabolic disturbances and wasting in the acquired immunodeficiency syndrome. N Engl J Med. 1992 Jul 30;327(5):329–337. doi: 10.1056/NEJM199207303270506. [DOI] [PubMed] [Google Scholar]
  9. Grunfeld C., Gulli R., Moser A. H., Gavin L. A., Feingold K. R. Effect of tumor necrosis factor administration in vivo on lipoprotein lipase activity in various tissues of the rat. J Lipid Res. 1989 Apr;30(4):579–585. [PubMed] [Google Scholar]
  10. Henry R. R., Abrams L., Nikoulina S., Ciaraldi T. P. Insulin action and glucose metabolism in nondiabetic control and NIDDM subjects. Comparison using human skeletal muscle cell cultures. Diabetes. 1995 Aug;44(8):936–946. doi: 10.2337/diab.44.8.936. [DOI] [PubMed] [Google Scholar]
  11. Hotamisligil G. S., Arner P., Caro J. F., Atkinson R. L., Spiegelman B. M. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995 May;95(5):2409–2415. doi: 10.1172/JCI117936. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hotamisligil G. S., Budavari A., Murray D., Spiegelman B. M. Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha. J Clin Invest. 1994 Oct;94(4):1543–1549. doi: 10.1172/JCI117495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hotamisligil G. S., Budavari A., Murray D., Spiegelman B. M. Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha. J Clin Invest. 1994 Oct;94(4):1543–1549. doi: 10.1172/JCI117495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hotamisligil G. S., Murray D. L., Choy L. N., Spiegelman B. M. Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4854–4858. doi: 10.1073/pnas.91.11.4854. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hotamisligil G. S., Shargill N. S., Spiegelman B. M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993 Jan 1;259(5091):87–91. doi: 10.1126/science.7678183. [DOI] [PubMed] [Google Scholar]
  16. Hotamisligil G. S., Spiegelman B. M. Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Diabetes. 1994 Nov;43(11):1271–1278. doi: 10.2337/diab.43.11.1271. [DOI] [PubMed] [Google Scholar]
  17. Kern P. A., Saghizadeh M., Ong J. M., Bosch R. J., Deem R., Simsolo R. B. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest. 1995 May;95(5):2111–2119. doi: 10.1172/JCI117899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Patton J. S., Shepard H. M., Wilking H., Lewis G., Aggarwal B. B., Eessalu T. E., Gavin L. A., Grunfeld C. Interferons and tumor necrosis factors have similar catabolic effects on 3T3 L1 cells. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8313–8317. doi: 10.1073/pnas.83.21.8313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Sims E. A. Experimental obesity, dietary-induced thermogenesis, and their clinical implications. Clin Endocrinol Metab. 1976 Jul;5(2):377–395. doi: 10.1016/s0300-595x(76)80027-8. [DOI] [PubMed] [Google Scholar]
  20. Socher S. H., Martinez D., Craig J. B., Kuhn J. G., Oliff A. Tumor necrosis factor not detectable in patients with clinical cancer cachexia. J Natl Cancer Inst. 1988 Jun 15;80(8):595–598. doi: 10.1093/jnci/80.8.595. [DOI] [PubMed] [Google Scholar]
  21. Stephens J. M., Pekala P. H. Transcriptional repression of the GLUT4 and C/EBP genes in 3T3-L1 adipocytes by tumor necrosis factor-alpha. J Biol Chem. 1991 Nov 15;266(32):21839–21845. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES