Skip to main content

Advertisement

SpringerLink
Log in

Chronic oxidative stress as a mechanism for glucose toxicity of the beta cell in Type 2 diabetes

  • Original Paper
  • Published:
Cell Biochemistry and Biophysics Aims and scope Submit manuscript

Abstract

Type 2 diabetes is characterized by a relentless decline in pancreatic islet beta cell function and worsening hyperglycemia despite optimal medical treatment. Our central hypothesis is that residual hyperglycemia, especially after meals, generates reactive oxygen species (ROS), which in turn causes chronic oxidative stress on the beta cell. This hypothesis is supported by several observations. Exposure of isolated islets to high glucose concentrations induces increases in intracellular peroxide levels. The beta cell has very low intrinsic levels of antioxidant proteins and activities and thus is very vulnerable to ROS. Treatment with antioxidants protects animal models of type 2 diabetes against complete development of phenotypic hyperglycemia. The molecular mechanisms responsible for the glucose toxic effect on beta cell function involves disappearance of two important regulators of insulin promoter activity, PDX-1 and MafA. Antioxidant treatment in vitro prevents disappearance of these two transcription factors and normalizes insulin gene expression. These observations suggest that the ancillary treatment with antioxidants may improve outcomes of standard therapy of type 2 diabetes in humans.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Robertson, R. P. (2004). Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. The Journal of Biological Chemistry, 279, 42351–42354.

    Article  PubMed  CAS  Google Scholar 

  2. Grankvist, K., Marklund, S. L., & Taljedal, I. B. (1981). CuZn-superoxide dismutase, Mn-superoxide dismutase, catalase and glutathione peroxidase in pancreatic islets and other tissues in the mouse. The Biochemical Journal, 199, 393–398.

    PubMed  CAS  Google Scholar 

  3. Tiedge, M., Lortz, S., Drinkgern, J., & Lenzen, S. (1997). Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin-producing cells. Diabetesm, 46, 1733–1742.

    Article  CAS  Google Scholar 

  4. Robertson, R. P., Zhang, H. J., Pyzdrowski, K. L., & Walseth, T. F. (1992). Preservation of insulin mRNA levels and insulin secretion in HIT cells by avoidance of chronic exposure to high glucose concentrations. The Journal of Clinical Investigation, 90, 320–325.

    PubMed  CAS  Google Scholar 

  5. Olson, L. K., Redmon, J. B., Towle, H. C., & Robertson, R. P. (1993). Chronic exposure of HIT cells to high glucose concentrations paradoxically decreases insulin gene transcription and alters binding of insulin gene regulatory protein. The Journal of Clinical Investigation, 92, 514–519.

    PubMed  CAS  Google Scholar 

  6. Olson, L. K., Sharma, A., Peshavaria, M., Wright, C. V., Towle, H. C., Robertson, R. P., & Stein, R. (1995). Reduction of insulin gene transcription in HIT-T15 beta cells chronically exposed to a supraphysiologic glucose concentration is associated with loss of STF-1 transcription factor expression. Proceedings of the National Academy of Sciences of the United States of America, 92, 9127–9131.

    Article  PubMed  CAS  Google Scholar 

  7. Sharma, A., Olson, L. K., Robertson, R. P., & Stein, R. (1995). The reduction of insulin gene transcription in HIT-T15 beta cells chronically exposed to high glucose concentration is associated with the loss of RIPE3b1 and STF-1 transcription factor expression. Molecular Endocrinology, 9, 1127–1134.

    Article  PubMed  CAS  Google Scholar 

  8. Poitout, V., Olson, L. K., & Robertson, R. P. (1996). Chronic exposure of betaTC-6 cells to supraphysiologic concentrations of glucose decreases binding of the RIPE3b1 insulin gene transcription activator. The Journal of Clinical Investigation, 97, 1041–1046.

    Article  PubMed  CAS  Google Scholar 

  9. Moran, A., Zhang, H. J., Olson, L. K., Harmon, J. S., Poitout, V., & Robertson, R. P. (1997). Differentiation of glucose toxicity from beta cell exhaustion during the evolution of defective insulin gene expression in the pancreatic islet cell line, HIT-T15. The Journal of Clinical Investigation, 99, 534–539.

    PubMed  CAS  Google Scholar 

  10. Gleason, C. E., Gonzalez, M., Harmon, J. S., & Robertson, R. P. (2000). Determinants of glucose toxicity and its reversibility in the pancreatic islet beta-cell line, HIT-T15. American Journal of Physiology. Endocrinology and Metabolism, 279, E997–E1002.

    PubMed  CAS  Google Scholar 

  11. Harmon, J. S., Tanaka, Y., Olson, L. K., & Robertson, R. P. (1998). Reconstitution of glucotoxic HIT-T15 cells with somatostatin transcription factor-1 partially restores insulin promoter activity. Diabetes, 47, 900–904.

    Article  PubMed  CAS  Google Scholar 

  12. Harmon, J. S., Stein, R., & Robertson, R. P. (2005). Oxidative stress-mediated, post-translational loss of MafA protein as a contributing mechanism to loss of insulin gene expression in glucotoxic beta cells. The Journal of Biological Chemistry, 280, 11107–11113.

    Article  PubMed  CAS  Google Scholar 

  13. Tanaka, Y., Gleason, C. E., Tran, P. O., Harmon, J. S., & Robertson, R. P. (1999). Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants. Proceedings of the National Academy of Sciences of the United States of America, 96, 10857–10862.

    Article  PubMed  CAS  Google Scholar 

  14. Kaneto, H., Kajimoto, Y., Miyagawa, J., Matsuoka, T., Fujitani, Y., Umayahara, Y., Hanafusa, T., Matsuzawa, Y., Yamasaki, Y., & Hori, M. (1999). Beneficial effects of antioxidants in diabetes: Possible protection of pancreatic beta-cells against glucose toxicity. Diabetes, 48, 2398–2406.

    Article  PubMed  CAS  Google Scholar 

  15. Lu, M., Seufert, J., & Habener, J. F. (1997). Pancreatic beta-cell-specific repression of insulin gene transcription by CCAAT/enhancer-binding protein beta. Inhibitory interactions with basic helix-loop-helix transcription factor E47. The Journal of Biological Chemistry, 272, 28349–28359.

    Article  PubMed  CAS  Google Scholar 

  16. Kaneto, H., Xu, G., Fujii, N., Kim, S., Bonner-Weir, S., & Weir, G. C. (2002). Involvement of c-Jun N-terminal kinase in oxidative stress-mediated suppression of insulin gene expression. The Journal of Biological Chemistry, 277, 30010–30018.

    Article  PubMed  CAS  Google Scholar 

  17. Takahashi, H., Tran, P. O., LeRoy, E., Harmon, J. S., Tanaka, Y., & Robertson, R. P. (2004). d-Glyceraldehyde causes production of intracellular peroxide in pancreatic islets, oxidative stress, and defective beta cell function via non-mitochondrial pathways. The Journal of Biological Chemistry, 279, 37316–37323.

    Article  PubMed  CAS  Google Scholar 

  18. Taniguchi, S., Okinaka, M., Tanigawa, K., & Miwa, I. (2000). Difference in mechanism between glyceraldehyde- and glucose-induced insulin secretion from isolated rat pancreatic islets. The Journal of. Biochemistry (Tokyo), 127, 289–295.

    CAS  Google Scholar 

  19. Harmon, J. S., Gleason, C. E., Tanaka, Y., Poitout, V., & Robertson, R. P. (2001). Antecedent hyperglycemia, not hyperlipidemia, is associated with increased islet triacylglycerol content and decreased insulin gene mRNA level in Zucker diabetic fatty rats. Diabetes, 50, 2481–2486.

    Article  PubMed  CAS  Google Scholar 

  20. Maedler, K., Sergeev, P., Ris, F., Oberholzer, J., Joller-Jemelka, H. I., Spinas, G. A., Kaiser, N., Halban, P. A., & Donath, M. Y. (2002). Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. The Journal of Clinical Investigation, 110, 851–860.

    Article  PubMed  CAS  Google Scholar 

  21. Tran, P. O., Gleason, C. E., Poitout, V., & Robertson, R. P. (1999). Prostaglandin E(2) mediates inhibition of insulin secretion by interleukin-1beta. The Journal of Biological Chemistry, 274, 31245–31248.

    Article  PubMed  CAS  Google Scholar 

  22. Tran, P. O., Gleason, C. E., & Robertson, R. P. (2002). Inhibition of interleukin-1beta-induced COX-2 and EP3 gene expression by sodium salicylate enhances pancreatic islet beta-cell function. Diabetes, 51, 1772–1778.

    Article  PubMed  CAS  Google Scholar 

  23. Nourooz-Zadeh, J., Tajaddini-Sarmadi, J., McCarthy, S., Betteridge, D. J., & Wolff, S. P. (1995). Elevated levels of authentic plasma hydroperoxides in NIDDM. Diabetes, 44, 1054–1058.

    Article  PubMed  CAS  Google Scholar 

  24. Yoshida, K., Hirokawa, J., Tagami, S., Kawakami, Y., Urata, Y., & Kondo, T. (1995). Weakened cellular scavenging activity against oxidative stress in diabetes mellitus: Regulation of glutathione synthesis and efflux. Diabetologia, 38, 201–210.

    PubMed  CAS  Google Scholar 

  25. Dandona, P., Thusu, K., Cook, S., Snyder, B., Makowski, J., Armstrong, D., & Nicotera, T. (1996). Oxidative damage to DNA in diabetes mellitus. Lancet, 347, 444–445.

    Article  PubMed  CAS  Google Scholar 

  26. Ceriello, A., Falleti, E., Bortolotti, N., Motz, E., Cavarape, A., Russo, A., Gonano, F., & Bartoli, E. (1996). Increased circulating intercellular adhesion molecule-1 levels in type II diabetic patients: The possible role of metabolic control and oxidative stress. Metabolism, 45, 498–501.

    Article  PubMed  CAS  Google Scholar 

  27. Santini, S.A., Marra, G., Giardina, B., Cotroneo, P., Mordente, A., Martorana, G. E., Manto, A., & Ghirlanda, G. (1997). Defective plasma antioxidant defenses and enhanced susceptibility to lipid peroxidation in uncomplicated IDDM. Diabetes, 46, 1853–1858.

    Article  PubMed  CAS  Google Scholar 

  28. Leinonen, J., Lehtimaki, T., Toyokuni, S., Okada, K., Tanaka, T., Hiai, H., Ochi, H., Laippala, P., Rantalaiho, V., Wirta, O., Pasternack, A., & Alho, H. (1997). New biomarker evidence of oxidative DNA damage in patients with non-insulin-dependent diabetes mellitus. FEBS Letters, 417, 150–152.

    Article  PubMed  CAS  Google Scholar 

  29. Tran, P. O., Parker, S. M., LeRoy, E., Franklin, C. C., Kavanagh, T. J., Zhang, T., Zhou, H., Vliet, P., Oseid, E., Harmon, J. S., & Robertson, R. P. (2004). Adenoviral overexpression of the glutamylcysteine ligase catalytic subunit protects pancreatic islets against oxidative stress. The Journal of Biological Chemistry, 279, 53988–53993.

    Article  PubMed  CAS  Google Scholar 

  30. Catherwood, M. A., Powell, L.A., Anderson, P., McMaster, D., Sharpe, P. C., & Trimble, E. R. (2002). Glucose-induced oxidative stress in mesangial cells. Kidney International, 61, 599–608.

    Article  PubMed  CAS  Google Scholar 

  31. Lu, S. C., Bao, Y., Huang, Z. Z., Sarthy, V. P., & Kannan, R. (1999). Regulation of gamma-glutamylcysteine synthetase subunit gene expression in retinal Muller cells by oxidative stress. Investigative Ophthalmology & Visual Science, 40, 1776–1782.

    CAS  Google Scholar 

  32. Grankvist, K., Marklund, S., & Taljedal, I. B. (1981). Superoxide dismutase is a prophylactic against alloxan diabetes. Nature, 294, 158–160.

    Article  PubMed  CAS  Google Scholar 

  33. Kubisch, H. M., Wang, J., Luche, R., Carlson, E., Bray, T. M., Epstein, C. J., & Phillips, J. P. (1994). Transgenic copper/zinc superoxide dismutase modulates susceptibility to type I diabetes. Proceedings of the National Academy of Sciences of the United States of America, 91, 9956–9959.

    Article  PubMed  CAS  Google Scholar 

  34. Chen, H., Li, X., & Epstein, P. N. (2005). MnSOD and catalase transgenes demonstrate that protection of islets from oxidative stress does not alter cytokine toxicity. Diabetes, 54, 1437–1446.

    Article  PubMed  CAS  Google Scholar 

  35. Tiedge, M., Lortz, S., Munday, R., & Lenzen, S. (1998). Complementary action of antioxidant enzymes in the protection of bioengineered insulin-producing RINm5F cells against the toxicity of reactive oxygen species. Diabetes, 47, 1578–1585.

    Article  PubMed  CAS  Google Scholar 

  36. Xu, B., Moritz, J. T., & Epstein, P. N. (1999). Overexpression of catalase provides partial protection to transgenic mouse beta cells. Free Radical Biology & Medicine, 27, 830–837.

    Article  CAS  Google Scholar 

  37. Benhamou, P. Y., Moriscot, C., Richard, M. J., Beatrix, O., Badet, L., Pattou, F., Kerr-Conte, J., Chroboczek, J., Lemarchand, P., & Halimi S. (1998). Adenovirus-mediated catalase gene transfer reduces oxidant stress in human, porcine and rat pancreatic islets. Diabetologia, 41, 1093–1100.

    Article  PubMed  CAS  Google Scholar 

  38. Moriscot, C., Pattou, F., Kerr-Conte, J., Richard, M. J., Lemarchand, P., & Benhamou, P. Y. (2000). Contribution of adenoviral-mediated superoxide dismutase gene transfer to the reduction in nitric oxide-induced cytotoxicity on human islets and INS-1 insulin-secreting cells. Diabetologia, 43, 625–631.

    Article  PubMed  CAS  Google Scholar 

  39. Hohmeier, H. E., Thigpen, A., Tran, V. V., Davis, R., & Newgard, C. B. (1998). Stable expression of manganese superoxide dismutase (MnSOD) in insulinoma cells prevents IL-1beta-induced cytotoxicity and reduces nitric oxide production. The Journal of Clinical Investigation, 101, 1811–1820.

    PubMed  CAS  Google Scholar 

  40. Tanaka, Y., Tran, P. O., Harmon, J., & Robertson, R. P. (2002). A role for glutathione peroxidase in protecting pancreatic beta cells against oxidative stress in a model of glucose toxicity. Proceedings of the National Academy of Sciences of the United States of America, 99, 12363–12368.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This work is supported by NIH NIDDK RO1-38325.

Author information

Authors and Affiliations

  1. Pacific Northwest Research Institute, Seattle, WA, USA

    R. Paul Robertson, Huarong Zhou, Tao Zhang & Jamie S. Harmon

Authors
  1. R. Paul Robertson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Huarong Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jamie S. Harmon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. Paul Robertson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Robertson, R.P., Zhou, H., Zhang, T. et al. Chronic oxidative stress as a mechanism for glucose toxicity of the beta cell in Type 2 diabetes. Cell Biochem Biophys 48, 139–146 (2007). https://doi.org/10.1007/s12013-007-0026-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12013-007-0026-5

Keywords

Search

Navigation