Skip to main content
SpringerLink
Log in

Elevated circulating free fatty acids levels causing pancreatic islet cell dysfunction through oxidative stress

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Background: Elevated plasma free fatty acids (FFA) concentration is predictive of the conversion from normal glucose tolerance and impaired glucose tolerance to diabetes. Aims: To evaluate the effects of prolonged exposure to FFA on basal and glucose-stimulated insulin secretion (GSIS) of pancreatic β-cell, and to investigate the role of oxidative stress in FFA-induced decrease in β-cell function. Methods: Rats were assigned to 3 groups and underwent 96-h infusions of normal saline (NS), intralipid plus heparin (IH), or intralipid plus heparin and N-acetylcysteine (IH+NAC). The plasma insulin, malonyldialdehyde (MDA), reduced glutathione (GSH), and oxidized glutathione (GSSG) were measured. In vivo intravenous glucose tolerance test (IVGTT) and ex vivo isolated pancreatic tissues perfusion were performed. Results: In IH group GSIS both in IVGTT and perifused pancreatic tissues were impaired (p<0.05), the GSH/GSSG ratio was declined and MDA levels increased (p<0.05), the volume density score of nuclear factor κB and inducible nitric oxide synthase in pancreatic islets were increased compared to the NS group (p<0.01). In IH + NAC group, NAC intervention partly restored the GSH/GSSG ratio and MDA level, and improved FFA induced GSIS impairment.Conclusion: Elevated circulating FFA levels may contribute to causing the abnormalities of pancreatic islet cell function through active oxidative stress and oxidative stress-sensitive signaling pathway, which may play a key role in the development of impaired insulin secretion seen in obese Type 2 diabetes.

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

Similar content being viewed by others

References

  1. Charles MA, Eschwège E, Thibult N, et al. The role of non-esterified fatty acids in the deterioration of glucose tolerance in Caucasian subject: results of the Paris Prospective Study. Diabetologia 1997, 40: 1101–6.

    Article  PubMed  CAS  Google Scholar 

  2. Chen S, Ogawa A, Ohneda M, Unger RH, Foster DW, McGarry JD. More direct evidence for a malonyl-CoA-carnitine palmitoyltransferase I interaction as a key event in pancreatic beta-cell signaling. Diabetes 1994, 43: 878–83.

    Article  PubMed  CAS  Google Scholar 

  3. Prentki M, Joly E, El Assaad W, Roduit R. Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in β-cell adaptation and failure in the etiology of diabetes. Diabetes 2002, 51 (Suppl 3): S405–13.

    Article  PubMed  CAS  Google Scholar 

  4. Dobbins RL, Chester MW, Daniels MB, McGarry JD, Stein DT. Circulating fatty acids are essential for efficient glucose-stimulated insulin secretion after prolonged fasting in humans. Diabetes 1998, 47: 1613–8.

    Article  PubMed  CAS  Google Scholar 

  5. Paolisso G. Opposite effects of short- and long-term fatty acid infusion on insulin secretion in healthy subjects. Diabetologia 1995, 38: 1295–9.

    Article  PubMed  CAS  Google Scholar 

  6. Boden G, Chen X, Rosner J, Barton M. Effects of a 48-h fat infusion on insulin secretion and glucose utilization. Diabetes 1995, 44: 1239–42.

    Article  PubMed  CAS  Google Scholar 

  7. Carlsson C, Borg LA, Welsh N. Sodium palmitate induces partial mitochondrial uncoupling and reactive oxygen species in rat pancreatic islets in vitro. Endocrinology 1999, 140: 3422–8.

    PubMed  CAS  Google Scholar 

  8. Maestre I, Jordán J, Calvo S, et al. Mitochondrial dysfunction is involved in apoptosis induced by serum withdrawal and fatty acids in the beta-cell line INS-1. Endocrinology 2003, 144: 335–45.

    Article  PubMed  CAS  Google Scholar 

  9. Wang X, Li H, De Leo D,et al. Gene and protein kinase expression profiling of reactive oxygen species-associated lipotoxicity in the pancreatic β-cell line MIN6. Diabetes 2004, 53: 129–40.

    Article  PubMed  CAS  Google Scholar 

  10. Oprescu AI, Bikopoulos G, Naassan A, et al. Free fatty acid-induced reduction in glucose-stimulated insulin secretion. Evidence for a role of oxidative stress in vitro and in vivo. Diabetes 2007, 56: 2927–37.

    Article  PubMed  CAS  Google Scholar 

  11. Xiao C, Giacca A, Lewis GF. Oral taurine but not N-acetylcysteine ameliorates NEFA-induced impairment in insulin sensitivity and beta cell function in obese and overweight, non-diabetic men. Diabetologia 2008, 51: 139–46.

    Article  PubMed  CAS  Google Scholar 

  12. Moore PC, Ugas MA, Hagman DK, Parazzoli SD, Poitout V. Evidence against the involvement of oxidative stress in fatty acid inhibition of insulin secretion. Diabetes 2004, 53: 2610–6.

    Article  PubMed  CAS  Google Scholar 

  13. Giustarini D, Dalle-Donne I, Colombo R, Milzani A, Rossi R. An improved HPLC measurement for GSH and GSSG in human blood. Free Radic Biol Med 2003, 35: 1365–72.

    Article  PubMed  CAS  Google Scholar 

  14. Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 1997, 46: 3–10.

    Article  PubMed  CAS  Google Scholar 

  15. Magnan C, Collins S, Berthault MF, et al. Lipid infusion lowers sympathetic nervous activity and leads to increased beta-cell responsiveness to glucose. J Clin Invest 1999, 103: 413–9.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  16. Magnan C, Cruciani C, Clement L, et al. Glucose-induced insulin hypersecretion in lipid-infused healthy subjects is associated with a decrease in plasma norepinephrine concentration and urinary excretion. J Clin Endocrinol Metab 2001, 86: 4901–7.

    Article  PubMed  CAS  Google Scholar 

  17. Carpentier A, Mittelman SD, Lamarche B, Bergman RN, Giacca A, Lewis GF. Acute enhancement of insulin secretion by FFA in humans is lost with prolonged FFA elevation. Am J Physiol 1999, 276: E1055–66.

    PubMed  CAS  Google Scholar 

  18. Stefan N, Wahl HG, Fritsche A, Häring H, Stumvoll M. Effect of the pattern of elevated free fatty acids on insulin sensitivity and insulin secretion in healthy humans. Horm Metab Res 2001, 33: 432–8.

    Article  PubMed  CAS  Google Scholar 

  19. Leung N, Sakaue T, Carpentier A, Uffelman K, Giacca A, Lewis GF. Prolonged increase of plasma non-esterified fatty acids fully abolishes the stimulatory effect of 24 hours of moderate hyperglycaemia on insulin sensitivity and pancreatic beta-cell function in obese men. Diabetologia 2004, 47: 204–13.

    Article  PubMed  CAS  Google Scholar 

  20. Mason TM, Goh T, Tchipashvili V, et al. Prolonged elevation of plasma free fatty acids desensitizes the insulin secretory response to glucose in vivo in rats. Diabetes 1999, 48: 524–30.

    Article  PubMed  CAS  Google Scholar 

  21. Kashyap S, Belfort R, Gastaldelli A, et al. A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes 2003, 52: 2461–74.

    Article  PubMed  CAS  Google Scholar 

  22. Paolisso G, Tagliamonte MR, Rizzo MR, et al. Lowering fatty acids potentiates acute insulin response in first degree relatives of people with type II diabetes. Diabetologia 1998, 41: 1127–32.

    Article  PubMed  CAS  Google Scholar 

  23. Goh TT, Mason TM, Gupta N, et al. Lipid-induced β-cell dysfunction in vivo in models of progressive β-cell failure. Am J Physiol Endocrinol Metab 2007, 292: E549–60.

    Article  PubMed  CAS  Google Scholar 

  24. Shimabukuro M, Zhou YT, Levi M, Unger RH. Fatty acid-induced beta cell apoptosis: a link between obesity and diabetes. Proc Natl Acad Sci U S A 1998, 95: 2498–502.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  25. Lupi R, Dotta F, Marselli L, et al. Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: Evidence that cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Diabetes 2002, 51: 1437–42.

    Article  PubMed  CAS  Google Scholar 

  26. Grankvist K, Marklund SL, Taljedal IB. CuZn-superoxide dismutase, Mnsuperoxide dismutase, catalase and glutathione peroxidase in pancreatic islets and other tissues in the mouse. Biochem J 1981, 199: 393–8.

    PubMed Central  PubMed  CAS  Google Scholar 

  27. Tiedge M, Lortz S, Munday R, Lenzen S. Complementary action of antioxidant enzymes in the protection of bioengineered insulinproducing RINm5F cells against the toxicity of reactive oxygen species. Diabetes 1998, 47: 1578–85.

    Article  PubMed  CAS  Google Scholar 

  28. Karin M, Ben Neriah Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu Rev Immunol 2000, 18: 621–63.

    Article  PubMed  CAS  Google Scholar 

  29. Karin M. How NF-κB is activated: the role of the IκB kinase (IKK) complex. Oncogene 1991, 18: 6867–74.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Endocrinology and Metabolism, Sichuan University, West China Hospital, #37 Guoxue Road, Cheng Du, China

    X. Zhang, L. Ke & Y. Yu MD

  2. West China Medical School, Sichuan University, West China Hospital, Chengdu, China

    Y. Bao

Authors
  1. X. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y. Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. Ke
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y. Yu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y. Yu MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, X., Bao, Y., Ke, L. et al. Elevated circulating free fatty acids levels causing pancreatic islet cell dysfunction through oxidative stress. J Endocrinol Invest 33, 388–394 (2010). https://doi.org/10.1007/BF03346609

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03346609

Keywords

Search

Navigation