Skip to main content

The role of the immune system in the insulin resistance syndrome

Abstract

The complex relationship between immunity and the insulin resistance syndrome is likely mediated to a significant degree by cytokines and the inflammatory proteins they induce. Epidemiologic work has revealed associations between cytokines and clinically evident insulin resistance, and mechanistic studies have yielded insight into the induction of insulin resistance at the cellular level by cytokines such as tumor necrosis factor-α. Genetic polymorphisms significantly influence this relationship, and variations in cellular immunity as manifested by T-helper cell phenotype are likely to be important as well. Further elucidation of the link between immunity and insulin resistance may lead to more effective treatment, and potentially prevention, of the insulin resistance syndrome.

This is a preview of subscription content, access via your institution.

References and Recommended Reading

  1. Ross R: Atherosclerosis—an inflammatory disease. N Engl J Med 1999, 340:115–126.

    PubMed  Article  CAS  Google Scholar 

  2. Pickup JC, Crook MA: Is type 2 diabetes mellitus a disease of the innate immune system? Diabetologia 1998, 41: 1241–1248. Effectively summarizes much of the data relating immunity to insulin resistance and presents a model linking long-term activation of the acute phase response and type 2 diabetes.

    PubMed  Article  CAS  Google Scholar 

  3. Zimmet P, Turner R, McCarty D, et al.: Crucial points at diagnosis. Type 2 diabetes or slow type 1 diabetes. Diabetes Care 1999, 22(suppl 2):B59-B64.

    PubMed  Google Scholar 

  4. Pietropaolo M, Barinas-Mitchell E, Pietropaolo SL, et al.: Evidence of islet cell autoimmunity in elderly patients with type 2 diabetes. Diabetes 2000, 49:32–38.

    PubMed  Article  CAS  Google Scholar 

  5. Schmidt MI, Duncan BB, Sharrett AR, et al.: Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study. Lancet 1999, 353:1649–1652. This landmark analysis of epidemiologic data from the Atherosclerosis Risk in Communities study demonstrated associations between baseline levels of acute phase proteins and subsequent development of type 2 diabetes in middle-aged adults.

    PubMed  Article  CAS  Google Scholar 

  6. Festa A, D’Agostino R Jr, Howard G, et al.: Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 2000, 102: 42–47.

    PubMed  CAS  Google Scholar 

  7. Yudkin JS, Stehouwer CD, Emeis JJ, et al.: C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vas c Bi ol 1999, 19:972–978.

    CAS  Google Scholar 

  8. Bastard JP, Jardel C, Bruckert E, et al.: Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J Clin Endocrinol Metab 2000, 85:3338–3342.

    PubMed  Article  CAS  Google Scholar 

  9. Cheung AT, Ree D, Kolls JK, et al.: An in vivo model for elucidation of the mechanism of tumor necrosis factor-alpha (TNF-alpha)-induced insulin resistance: evidence for differential regulation of insulin signaling by TNF-alpha. Endocrinology 1998, 139:4928–4935.

    PubMed  Article  CAS  Google Scholar 

  10. Aggarwal BB: Tumour necrosis factors receptor associated signalling molecules and their role in activation of apoptosis, JNK and NF-kappaB. Ann Rheum Dis 2000, 59(suppl 1):i6–16.

    PubMed  Article  CAS  Google Scholar 

  11. Sewter CP, Digby JE, Blows F, et al.: Regulation of tumour necrosis factor-alpha release from human adipose tissue in vitro. J Endocrinol 1999, 163:33–38.

    PubMed  Article  CAS  Google Scholar 

  12. Morohoshi M, Fujisawa K, Uchimura I, et al.: Glucose-dependent interleukin 6 and tumor necrosis factor production by human peripheral blood monocytes in vitro. Diabetes 1996, 45:954–959.

    PubMed  Article  Google Scholar 

  13. Hotamisligil GS, Arner P, Caro JF, et al.: Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 1995, 95:2409–2415.

    PubMed  CAS  Google Scholar 

  14. Winkler G, Salamon F, Harmos G, et al.: Elevated serum tumor necrosis factor-alpha concentrations and bioactivity in type diabetics and patients with android type obesity. Diabetes Res Clin Pract 1998, 42:169–174.

    PubMed  Article  CAS  Google Scholar 

  15. del AguilaLF, Claffey KP, Kirwan JP: TNF-alpha impairs insulin signaling and insulin stimulation of glucose uptake in C2C12 muscle cells. Am J Physiol 1999, 276:E849-E855.

    PubMed  Google Scholar 

  16. Qi C, Pekala PH: Tumor necrosis factor-alpha-induced insulin resistance in adipocytes. Proc Soc Exp Biol Med 2000, 223:128–135.

    PubMed  Article  CAS  Google Scholar 

  17. Hotamisligil GS: Molecular mechanisms of insulin resistance and the role of the adipocyte. Int J Obes Relat Metab Disord 2000, 24(suppl 4):S23-S27. Provides an excellent overview of the current understanding of the role of TNF-á in insulin resistance.

    PubMed  CAS  Google Scholar 

  18. Huber SA, Sakkinen P, David C, et al.: T helper-cell phenotype regulates atherosclerosis in mice under conditions of mild hypercholesterolemia. Circulation 2001, 103: 2610–2616.

    PubMed  CAS  Google Scholar 

  19. Waite KJ, Floyd ZE, Arbour-Reily P, et al.: Interferon-gamma-induced regulation of peroxisome proliferator-activated receptor gamma and STATs in adipocytes. J Biol Chem 2001, 276:7062–7068.

    PubMed  Article  CAS  Google Scholar 

  20. Winkler G, Dworak O, Salamon F, et al.: Increased interleukin-12 plasma concentrations in both, insulin-dependent and non-insulin-dependent diabetes mellitus. Diabetologia 1998, 41: 488.

    PubMed  Article  CAS  Google Scholar 

  21. Mooney RA, Senn J, Cameron S, et al.: Suppressors of cytokine signaling-1 and -6 associate with and inhibit the insulin receptor. a potential mechanism for cytokine-mediated insulin resistance. J Biol Chem 2001, 276:25889–25893.

    PubMed  Article  CAS  Google Scholar 

  22. Diehl S, Anguita J, Hoffmeyer A, et al.: Inhibition of Th1 differentiation by IL-6 is mediated by SOCS1. Immunity 2000, 13:805–815.

    PubMed  Article  CAS  Google Scholar 

  23. Barroso I, Gurnell M, Crowley VE, et al.: Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 1999, 402:880–883.

    PubMed  CAS  Google Scholar 

  24. Tanaka T, Itoh H, Doi K, et al.: Down regulation of peroxisome proliferator-activated receptor gamma expression by inflammatory cytokines and its reversal by thiazolidine-diones. Diabetologia 1999, 42:702–710.

    PubMed  Article  CAS  Google Scholar 

  25. Hsueh WA, Jackson S, Law RE: Control of vascular cell proliferation and migration by PPAR-gamma: a new approach to the macrovascular complications of diabetes. Diabetes Care 2001, 24:392–397.

    PubMed  Article  CAS  Google Scholar 

  26. Tontonoz P, Nagy L, Alvarez JG, et al.: PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 1998, 93:241–252.

    PubMed  Article  CAS  Google Scholar 

  27. Wilson AG, Symons JA, McDowell TL, et al.: Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci U S A 1997, 94:3195–3199.

    PubMed  Article  CAS  Google Scholar 

  28. Lee SC, Pu YB, Thomas GN, et al.: Tumor necrosis factor alpha gene G-308A polymorphism in the metabolic syndrome. Metabolism 2000, 49:1021–1024.

    PubMed  Article  CAS  Google Scholar 

  29. Walston J, Seibert M, Yen CJ, et al.: Tumor necrosis factor-alpha-238 and -308 polymorphisms do not associate with traits related to obesity and insulin resistance. Diabetes 1999, 48:2096–2098.

    PubMed  Article  CAS  Google Scholar 

  30. Day CP, Grove J, Daly AK, et al.: Tumour necrosis factor-alpha gene promoter polymorphism and decreased insulin resistance. Diabetologia 1998, 41: 430–434.

    PubMed  Article  CAS  Google Scholar 

  31. Matsushita M, Tsuchiya N, Nakayama T, et al.: Allele typing of human TNFA 5’-flanking region using polymerase chain reaction-preferential homoduplex formation assay (PCR-PHFA): linkage disequilibrium with HLA class I and class II genes in Japanese. Tissue Antigens 1999, 54:478–484. Data presented here suggest a possible relationship between TNF-á expression and Th cell differentiation mediated by links between polymorphisms in the TNFA promoter region and DRB1 alleles.

    PubMed  Article  CAS  Google Scholar 

  32. Fishman D, Faulds G, Jeffery R, et al.: The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis.J Clin Invest 1998, 102: 1369–1376.

    PubMed  CAS  Article  Google Scholar 

  33. Fernandez-Real JM, Broch M, Vendrell J, et al.: Interleukin-6 gene polymorphism and insulin sensitivity. Diabetes 2000, 49:517–520.

    PubMed  Article  CAS  Google Scholar 

  34. Sakkinen PA, Wahl P, Cushman M, et al.: Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome. Am J Epidemiol 2000, 152:897–907. This application of factor analysis to epidemiologic data suggests that although there are links between markers of inflammation and the established metabolic components of the IRS, inflammation may contribute independently to the syndrome.

    PubMed  Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lewis, M.R., Tracy, R.P. The role of the immune system in the insulin resistance syndrome. Curr Diab Rep 2, 96–99 (2002). https://doi.org/10.1007/s11892-002-0064-8

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11892-002-0064-8

Keywords

  • Insulin Resistance
  • Insulin Resistance Syndrome
  • DRB1 Allele
  • Decrease Insulin Resistance
  • Tumor Necrosis Factor Alpha Gene