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Serum advanced glycation end products are associated with insulin resistance in male nondiabetic patients with obstructive sleep apnea

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Abstract

Purpose

Advanced glycation end products (AGEs) play an important role in the pathogenesis of diabetic vascular complications. Recently, growing evidence has shown that AGEs could be involved in the pathogenesis of insulin resistance. It has also been suggested that circulating AGE are associated with insulin resistance in nondiabetic patients. This study investigated whether serum AGEs levels are associated with insulin resistance in nondiabetic patients with obstructive sleep apnea (OSA).

Methods

A total of 139 male nondiabetic patients with OSA were recruited for participation in the study. Serum AGE levels were examined using an enzyme-linked immunosorbent assay. Insulin resistance was determined using the homeostasis model assessment index (HOMA-IR).

Results

There was a significant correlation between serum AGEs and the apnea-hypopnea index (AHI) (r = 0.281, p = 0.014), duration of SaO2 < 90 % (r = 0.267, p = 0.018), minimum SaO2 (r = −0.188, p = 0.046), high-sensitivity C-reactive protein (hsCRP) (r = 0.274, p = 0.012), and HOMA-IR (r = 0.303, p < 0.001). Multiple regression analysis showed that serum AGEs (p = 0.011), AHI (p = 0.024), waist circumference (p = 0.040), and hsCRP (p = 0.046) were independently associated with HOMA-IR (R 2 = 0.392). In addition, the strength of the correlation between serum AGEs and HOMA-IR was related to the severity of OSA.

Conclusions

The present study indicated that serum AGE levels were associated with insulin resistance in male nondiabetic patients with OSA. These findings suggest that AGEs may play a role in insulin resistance in OSA and may also be a biomarker for patients with OSA with high risk of developing type 2 diabetes.

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References

  1. Tasali E, Mokhlesi B, Van Cauter E (2008) Obstructive sleep apnea and type 2 diabetes: interacting epidemics. Chest 133:496–506. doi:10.1378/chest. 07-0828

    Article  PubMed  Google Scholar 

  2. Aurora RN, Punjabi NM (2013) Obstructive sleep apnoea and type 2 diabetes mellitus: a bidirectional association. Lancet Respir Med 1:329–338. doi:10.1016/S2213-2600(13)70039-0

    Article  PubMed  Google Scholar 

  3. Pamidi S, Wroblewski K, Broussard J, Day A, Hanlon E, Abraham V, Tasali E (2012) Obstructive sleep apnea in young lean men: impact on insulin sensitivity and secretion. Diabetes Care 35:2384–2389. doi:10.2337/dc12-0841

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Dyer DG, Blackledge JA, Thorpe SR, Baynes JW (1991) Formation of pentosidine during nonenzymatic browning of proteins by glucose. identification of glucose and other carbohydrates as possible precursors of pentosidine in vivo. J Biol Chem 266:11654–11660

    CAS  PubMed  Google Scholar 

  5. Ramasamy R, Yan SF, Schmidt AM (2012) Advanced glycation endproducts: from precursors to RAGE: round and round we go. Amino Acids 42:1151–1161. doi:10.1007/s00726-010-0773-2

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Xu Y, Toure F, Qu W, Lin L, Song F, Shen X, Rosario R, Garcia J, Schmidt AM, Yan SF (2010) Advanced glycation end product (AGE)-receptor for AGE (RAGE) signaling and up-regulation of Egr-1 in hypoxic macrophages. J Biol Chem 285:23233–23240. doi:10.1074/jbc.M110.117457

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Kimoff RJ, Hamid Q, Divangahi M, Hussain S, Bao W, Naor N, Payne RJ, Ariyarajah A, MulrainK PBJ (2011) Increased upper airway cytokines and oxidative stress in severe obstructive sleep apnoea. Eur Respir J 38:89–97. doi:10.1183/09031936.00048610

    Article  CAS  PubMed  Google Scholar 

  8. Tan KC, Chow WS, Lam JC, Lam B, Bucala R, Betteridge J, Ip MS (2006) Advanced glycation endproducts in nondiabetic patients with obstructive sleep apnea. Sleep 29(3):329–333

    PubMed  Google Scholar 

  9. Lam JC, Tan KC, Lai AY, Lam DC, Ip MS (2012) Increased serum levels of advanced glycation end-products is associated with severity of sleep disordered breathing but not insulin sensitivity in non-diabetic men with obstructive sleep apnoea. Sleep Med 13:15–20. doi:10.1016/j.sleep.2011.07.015

    Article  PubMed  Google Scholar 

  10. Celec P, Hodosy J, Behuliak M, Pálffy R, Gardlík R, Halčák L, Mucska I (2012) Oxidative and carbonyl stress in patients with obstructive sleep apnea treated with continuous positive airway pressure. Sleep Breath 16:393–398. doi:10.1007/s11325-011-0510-4

    Article  PubMed  Google Scholar 

  11. Yan SF, Ramasamy R, Schmidt AM (2010) The RAGE axis: a fundamental mechanism signaling danger to the vulnerable vasculature. Circ Res 106:842–853. doi:10.1161/CIRCRESAHA.109.212217

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Riboulet-Chavey A, Pierron A, Durand I, Murdaca J, Giudicelli J, Van Obberghen E (2006) Methylglyoxal impairs the insulin signaling pathways independently of the formation of intracellular reactive oxygen species. Diabetes 55:1289–1299

    Article  CAS  PubMed  Google Scholar 

  13. Unoki H, Bujo H, Yamagishi S, Takeuchi M, Imaizumi T, Saito Y (2007) Advanced glycation end products attenuate cellular insulin sensitivity by increasing the generation of intracellular reactive oxygen s pecies in adipocytes. Diabetes Res Clin Pract 76:236–244

    Article  CAS  PubMed  Google Scholar 

  14. Cai W, Ramdas M, Zhu L, Chen X, Striker GE, Vlassara H (2012) Oral advanced glycation endproducts (AGEs) promote insulin resistance and diabetes by depleting the antioxidant defenses AGE receptor-1 and sirtuin 1. Proc Natl Acad Sci U S A 109:15888–15893

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Mark AB, Poulsen MW, Andersen S, Andersen JM, Bak MJ, Ritz C, Holst JJ, Nielsen J, de Courten B, Dragsted LO, Bügel SG (2014) Consumption of a diet low in advanced glycation end products for 4 weeks improves insulin sensitivity in overweight women. Diabetes Care 37:88–95. doi:10.2337/dc13-0842

    Article  CAS  PubMed  Google Scholar 

  16. Uribarri J1, Cai W, Ramdas M, Goodman S, Pyzik R, Chen X, Zhu L, Striker GE, Vlassara H (2011) Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of AGER1 and SIRT1. Diabetes Care 34:1610–1616. doi:10.2337/dc11-0091

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Tan KC, Shiu SW, Wong Y, Tam X (2011) Serum advanced glycation end products (AGEs) are associated with insulin resistance. Diabetes Metab Res Rev 27:488–492. doi:10.1002/dmrr.1188

    Article  CAS  PubMed  Google Scholar 

  18. Tahara N, Yamagishi S, Matsui T, Takeuchi M, Nitta Y, Kodama N, Mizoguchi M, Imaizumi T (2012) Serum levels of advanced glycation end products (AGEs) are independent correlates of insulin resistance in nondiabetic subjects. Cardiovasc Ther 30:42–48. doi:10.1111/j.1755-5922.2010.00177.x

    Article  CAS  PubMed  Google Scholar 

  19. Hamilton MT, Hamilton DG, Zderic TW (2007) Role of low energy expenditure and sitting in obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease. Diabetes 56:2655–2667

    Article  CAS  PubMed  Google Scholar 

  20. Stöhr R, Federici M (2013) Insulin resistance and atherosclerosis: convergence between metabolic pathways and inflammatory nodes. Biochem J 454:1–11. doi:10.1042/BJ20130121

    Article  PubMed  Google Scholar 

  21. Bohlender JM, Franke S, Stein G, Wolf G (2005) Advanced glycation end products and the kidney. Am J Renal Physiol 289:F645–F659

    Article  CAS  Google Scholar 

  22. Tasali E, Leproult R, Ehrmann DA, Cauter EV (2008) Slow-wave sleep and the risk of type 2 diabetes in humans. PNAS 105:1044–1049

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Shi YK, Chen JX, Huang Y, Li AY (2014) Serum S100A12 levels are associated with the presence and severity of obstructive sleep apnea syndrome in male patients. Sleep Breath 18:269–274. doi:10.1007/s11325-013-0876-6

    Article  PubMed  Google Scholar 

  24. Miele C, Riboulet A, Maitan MA, Oriente F, Romano C, Formisano P, Giudicelli J, Beguinot F, Van Obberghen E (2003) Human glycated albumin affects glucose metabolism in L6 skeletal muscle cells by impairing insulin-induced insulin receptor substrate (IRS) signaling through a protein kinase C alpha-mediated mechanism. J Biol Chem 278:47376–47387

    Article  CAS  PubMed  Google Scholar 

  25. Basta G, Lazzerini G, Massaro M, Simoncini T, Tanganelli P, Fu C, Kislinger T, Stern DM, Schmidt AM, De Caterina R (2002) Advanced glycation end products activate endothelium through signal-transduction receptor rage: a mechanism for amplification of inflammatory responses. Circulation 105:816–822

    Article  CAS  PubMed  Google Scholar 

  26. Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS (2002) A central role for JNK in obesity and insulin resistance. Nature 420:333–336

    Article  CAS  PubMed  Google Scholar 

  27. Sandu O, Song K, Cai W, Zheng F, Uribarri J, Vlassara H (2005) Insulin resistance and type 2 diabetes in high-fat-fed mice are linked to high glycotoxin intake. Diabetes 54:2314–2319

    Article  CAS  PubMed  Google Scholar 

  28. Hofmann SM, Dong HJ, Li Z, Cai W, Altomonte J, Thung SN, Zeng F, Fisher EA, Vlassara H (2002) Improved insulin sensitivity is associated with restricted intake of dietary glycoxidation products in the db/db mouse. Diabetes 51:2082–2089

    Article  CAS  PubMed  Google Scholar 

  29. Vlassara H1, Cai W, Goodman S, Pyzik R, Yong A, Chen X, Zhu L, Neade T, Beeri M, Silverman JM, Ferrucci L, Tansman L, Striker GE, Uribarri J (2009) Protection against loss of innate defenses in adulthood by low advanced glycation end products (AGE) intake: role of the antiinflammatory AGE receptor-1. J Clin Endocrinol Metab 94:4483–4491. doi:10.1210/jc.2009-0089

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Takeuchi M, Yamagishi S (2008) Possible involvement of advanced glycation end-products (AGEs) in the pathogenesis of Alzheimer’s disease. Curr Pharm Des 14:973–978

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank all patients who participated in this study. The study was supported by grants from the National Natural Science Funds of China (no. 81160105, 81360017) and the Jiangxi Provincial Natural Science Funds of China (no. 2010GZY0325, 20114BAB205006).

Conflict of interest

The authors declare that they have no conflict of interest.

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Correspondence to Wei Zhang.

Additional information

Ji-xiong Xu and Wei Cai contributed equally to this work.

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Xu, Jx., Cai, W., Sun, Jf. et al. Serum advanced glycation end products are associated with insulin resistance in male nondiabetic patients with obstructive sleep apnea. Sleep Breath 19, 827–833 (2015). https://doi.org/10.1007/s11325-014-1100-z

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  • DOI: https://doi.org/10.1007/s11325-014-1100-z

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