Horm Metab Res 2011; 43(11): 748-753
DOI: 10.1055/s-0031-1286305
Original Basic
© Georg Thieme Verlag KG Stuttgart · New York

Oxidative Stress Present in the Blood from Obese Patients Modifies the Structure and Function of Insulin

I. M. Olivares-Corichi
1   Postgraduate Studies and Research Section, School of Medicine National Polytechnique Institute, Mexico Distrito Federal, Mexico
,
M. J. Rincon Viquez
1   Postgraduate Studies and Research Section, School of Medicine National Polytechnique Institute, Mexico Distrito Federal, Mexico
,
L. Gutierrez-Lopez
1   Postgraduate Studies and Research Section, School of Medicine National Polytechnique Institute, Mexico Distrito Federal, Mexico
,
G. M. Ceballos-Reyes
1   Postgraduate Studies and Research Section, School of Medicine National Polytechnique Institute, Mexico Distrito Federal, Mexico
,
J. R. Garcia-Sanchez
1   Postgraduate Studies and Research Section, School of Medicine National Polytechnique Institute, Mexico Distrito Federal, Mexico
› Author Affiliations
Further Information

Publication History

received 05 April 2011

accepted 12 July 2011

Publication Date:
18 October 2011 (online)

Abstract

Obesity and its associated disorders constitute a growing epidemic across the world. Numerous studies have demonstrated the presence of systemic oxidative stress in patients with obesity. In this study, we show the effects of oxidative stress present in the blood from obese patients on recombinant human insulin. Insulin was incubated with whole blood (WB) from overweight subjects (OW), obese 1 patients (O1), or normal weight volunteers (NW) (n=16 for each group). Whole blood from OW and O1, unlike WB from NW, increased the carbonyl content of insulin; however, only whole blood from O1 patients increased the amount of formazan present in the hormone. Interestingly, the incubation of insulin with WB from O1 provoked a decrease in the hypoglycemic activity of the hormone (18%), an effect due to insulin polymerization. In addition, we showed that the formation of the insulin polymer generated the formation of new epitopes and the development of a new immunogenicity. These observations show that oxidative stress present in the WB of O1 patients can result in abolition of the biological activity of insulin and contribute to the development of an immune response to the hormone.

 
  • References

  • 1 Vincent HK, Taylor AG. Biomarkers and potential mechanisms of obesity-induced oxidant stress in humans. Int J Obes 2006; 30: 400-418
  • 2 Tilg H, Moschen AR. Adipocytokines: Mediator linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006; 6: 772-783
  • 3 Trayhurn P, Wood IS. Adipokines: Inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 2004; 92: 347-355
  • 4 Konukoglu D, Serin O, Turhan MS. Plasma leptin and its relationship with lipid peroxidation and nitric oxide in obese female patients with or without hypertension. Arch Med Res 2006; 37: 602-606
  • 5 Olusi SO. Obesity is an independent risk factor for plasma lipid peroxidation and depletion of erythrocyte cytoprotectic enzymes in humans. Int J Obes 2002; 26: 1159-1164
  • 6 Duncan E, Ezzat V, Kearney M. Insulin and endothelial function: physiological environment defines effect on atherosclerotic risk. Curr Diabetes Rev 2006; 2: 51-61
  • 7 Halliwell B. Lipid peroxidation, antioxidants and cardiovascular disease: how should we move forward?. Cardiovasc Res 2000; 47: 410-418
  • 8 Wilborn C, Beckham J, Campbell B, Harvey T, Galbreath M, La Bounty P, Nassar E, Wismann J, Kreider R. Obesity: prevalence, theories, medical consequences, management, and research directions. J Int Soc Sports Nutr 2005; 2: 4-31
  • 9 Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2004; 114: 1752-1761
  • 10 McGill Jr HC, CMcMahan A, Herderick EE, Zieske AW, Malcom GT, Tracy RE, Strong JP. Obesity Accelerates the Progression of Coronary Atherosclerosis in Young Men. Circulation 2002; 105: 2712-2718
  • 11 Reaven GM. All obese individuals are not created equal: insulin resistance is the major determinant of cardiovascular disease in overweight/obese individuals. Diab Vasc Dis Res 2005; 2: 105-112
  • 12 Choi K, Kim YB. Molecular mechanism of insulin resistance in obesity and type 2 diabetes. Korean J Intern Med 2010; 25: 119-129
  • 13 Montes-Cortes DH, Hicks JJ, Ceballos-Reyes GM, Garcia-Sanchez JR, Medina-Navarro R, Olivares-Corichi IM. Chemical and functional changes of human insulin by in vitro incubation with blood from diabetic patients in oxidative stress. Metabolism 2010; 59: 935-942
  • 14 Uzun H, Konukoglu D, Gelisgen R, Zengin K, Taskin M. Plasma protein carbonyl and thiol stress before and after laparoscopic gastric banding in morbidly obese patients. Obes Surg 2007; 17: 1367-1373
  • 15 Yagi K. Sample procedure for specific assay of lipid hydroperoxides in serum or plasma. Methods Mol Biol 1998; 108: 107-110
  • 16 Gieseg SP, Simpson JA, Charlton TS, Duncan MW, Dean RT. Protein-bound 3,4 dihydroxyphenylalanine is a major reductant formed during hydroxyl radical damage to proteins. Biochemistry 1993; 32: 4780-4786
  • 17 Reznick AZ, Packer L. Oxidative damage to proteins: spectrophotometric method for carbonyl assay. Methods Enzymol 1994; 233: 357-363
  • 18 Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193: 265-275
  • 19 Ellman GL. Tissue sulffhydryl groups. Arch Biochem Biophys 1959; 82: 70-77
  • 20 Smith AJ. Electrophoretic separation of proteins. In: Ausubel FM. ed Short Protocols in Molecular Biology. New York: Wiley; 1992: 1023-1026
  • 21 Sasse J, Gallagher SR.. Detection of proteins. In: Ausubel FM. ed. Short Protocols in Molecular Biology. New YorK: Wiley; 1992: 1029-1030
  • 22 Lane D. Monoclonal antibodies. In: Harlow E. ed Antibodies, A Laboratory Manual. New York: Cold Spring Harbor Laboratory Press; 1990: 139-244
  • 23 Lane D. Immunoblotting. In: Harlow E. ed. Antibodies, A Laboratory Manual. New York: Cold Spring Harbor Laboratory Press; 1990: 471-510
  • 24 Ozaydin A, Onaran I, Yeşim TE, Sargin H, Avşar K, Sultuybek G. Increased glutathione conjugate transport: a possible compensatory protection mechanism against oxidative stress in obesity?. Int J Obes 2006; 30: 134-140
  • 25 João Cabrera E, Valezi AC, Delfino VD, Lavado EL, Barbosa DS. Reduction in plasma levels of inflammatory and oxidative stress indicators after Roux-en-Y gastric bypass. Obes Surg 2009; 20: 42-49
  • 26 Dalle-Donne I, Rossi R, Giustarini D, Milzani A, Colombo R. Protein carbonyl groups as biomarkers of oxidative stress. Clin Chim Acta 2003; 329: 23-38
  • 27 Halliwell B, Whiteman M. Measuring reactive species and oxidative damage in vivo and in cell culture: how should you do it and what do the results mean?. Br J Pharmacol 2004; 142: 231-255
  • 28 Olivares-Corichi IM, Ceballos G, Medina-Santillan R, Medina-Navarro R, Guzman-Grenfell AM, Hicks JJ. Oxidation by reactive oxygen species (ROS) alters the structure of human insulin and decreases the insulin-dependent D-glucose-C14 utilization by human adipose tissue. Front Biosci 2005; 10: 3127-3131
  • 29 Shoelson S, Haneda M, Blix P, Nanjo A, Sanke T, Inouye K, Steiner D, Rubenstein A, Tager H. Three mutant insulins in man. Nature 1983; 302: 540-543
  • 30 Steiner DF, Tager HS, Chan SJ, Nanjo K, Sanke T, Rubenstein AH. Lesson learned from molecular biology of insulin-gene mutation. Diabetes Care 1990; 13: 600-609
  • 31 Imlay JA. Pathways of oxidative damage. Annu Rev Microbiol 2003; 57: 395-418
  • 32 Nystrom T. Role of oxidative carbonylation in protein quality control and senescence. EMBO J 2005; 24: 1311-1317
  • 33 Gomez-Mejiba SE, Zhai Z, Akram H, Pye QN, Hensley K, Kurien BT, Scofield RH, Ramirez DC. Inhalation of environmental stressors & chronic inflammation: autoimmunity and neurodegeneration. Mutat Res 2009; 674: 62-72
  • 34 Dandona P, Mohanty P, Ghanim H, Aljada A, Browne R, Hamouda W, Prabhala A, Afzal A, Garg R. The suppressive effect of dietary restriction and weight loss in the obese on the generation of reactive oxygen species by leukocytes, lipid peroxidation, and protein carbonylation. J Clin Endocrinol Metab 2001; 86: 355-362