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Duodenal-Jejunal Bypass Surgery Ameliorates Glucose Homeostasis and Reduces Endoplasmic Reticulum Stress in the Liver Tissue in a Diabetic Rat Model

Obesity Surgery volume 26, pages 1002–1009 (2016)Cite this article

Abstract

Background

Duodenal-jejunal bypass (DJB) has been shown to be an effective surgical treatment for type 2 diabetes mellitus (T2DM). However, the underlying mechanisms are poorly understood. Recently, accumulating evidences suggest that endoplasmic reticulum (ER) stress plays an important role in the development of insulin resistance in T2DM. The present study was designed to investigate the effect of DJB on glucose homeostasis, the ER stress state in the liver tissue, and the involving signaling independently of weight loss.

Methods

Thirty adult male T2DM Sprague-Dawley (SD) rats induced by high-fat diet and low dose of streptozotocin (STZ) were randomly divided into DJB and sham groups. Ten age-matched male SD rats were assigned as the control group. The parameters of body weight and calorie intake were measured at indicated time points. The glucose tolerance and insulin resistance were detected to evaluate the glucose homeostasis. Serum insulin was determined by enzyme-linked immunosorbent assay (ELISA). The markers of ER stress, the activity of c-Jun N-terminal kinase (JNK) and serine phosphorylation of insulin receptor substrate 1 (IRS-1) in the liver tissue, were determined by Western blotting.

Results

DJB induced significant improvements in glucose homeostasis and insulin sensitivity, but without weight loss. DJB improved the ER stress state indicated by decreased protein kinase RNA (PKR)-like ER protein kinase (PERK) and inositol-requiring enzyme 1 (IRE-1) phosphorylation in the liver tissue. The JNK activity and serine phosphorylation of IRS-1 in the liver tissue were significantly reduced after DJB.

Conclusions

DJB ameliorates glucose homeostasis. Meanwhile, our study helps to reveal that the reduced hepatic ER stress and the decreased JNK activity may contribute to the improved glucose homeostasis after DJB.

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References

  1. Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature. 2001;414(6865):782–7. PMID:11742409.

    CAS  Article  PubMed  Google Scholar 

  2. Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010;87(1):4–14. PMID: 19896746.

    CAS  Article  PubMed  Google Scholar 

  3. Guariguata L, Whiting DR, Hambleton I, et al. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract. 2014;103(2):137–49. PMID: 24630390.

    CAS  Article  PubMed  Google Scholar 

  4. International Diabetes Federation. IDF Diabetes Atlas. 6th ed. Brussels: International Diabetes Federation; 2013.

    Google Scholar 

  5. Beagley J, Guariguata L, Weil C, et al. Global estimates of undiagnosed diabetes in adults. Diabetes Res Clin Pract. 2014;103(2):150–60. PMID: 24300018.

    Article  PubMed  Google Scholar 

  6. Peng L, Li T, Liu X, et al. An artificial immune network based algorithm for diabetes diagnosis. Protein Pept Lett. 2008;15(5):484–7. PMID: 18537738.

    CAS  Article  PubMed  Google Scholar 

  7. Rubino F, Marescaux J. Effect of duodenal-jejunal exclusion in a non-obese animal model of type 2 diabetes: a new perspective for an old disease. Ann Surg. 2004;239(1):1–11. PMID: 14685093.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Rubino F, Forgione A, Cummings DE, et al. The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes. Ann Surg. 2006;244(5):741–9. PMID:17060767.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Speck M, Cho YM, Asadi A, et al. Duodenal-jejunal bypass protects GK rats from {beta}-cell loss and aggravation of hyperglycemia and increases enteroendocrine cells coexpressing GIP and GLP-1. Am J Physiol Endocrinol Metab. 2011;300(5):E923–32. PMID: 21304061.

    CAS  Article  PubMed  Google Scholar 

  10. Liu SZ, Sun D, Zhang GY, et al. A high-fat diet reverses improvement in glucose tolerance induced by duodenal-jejunal bypass in type 2 diabetic rats. Chin Med J. 2012;125(5):912–9. PMID: 22490596.

    CAS  PubMed  Google Scholar 

  11. Sun D, Wang K, Yan Z, et al. Duodenal-jejunal bypass surgery up-regulates the expression of the hepatic insulin signaling proteins and the key regulatory enzymes of intestinal gluconeogenesis in diabetic Goto-Kakizaki rats. Obes Surg. 2013;23:1734–42. PMID: 23700236.

    Article  PubMed  Google Scholar 

  12. Han H, Hu C, Wang L, et al. Duodenal-jejunal bypass surgery suppresses hepatic de novo lipogenesis and alleviates liver fat accumulation in a diabetic rat model. Obes Surg. 2014;24(12):2152–60. PMID:24898720.

    Article  PubMed  Google Scholar 

  13. Cohen RV, Schiavon CA, Pinheiro JS, et al. Duodenal-jejunal bypass for the treatment of type 2 diabetes in patients with body mass index of 22–34 kg/m2: a report of 2 cases. Surg Obes Relat Dis. 2007;3(2):195–7. PMID: 17386401.

    Article  PubMed  Google Scholar 

  14. Cohen R, Caravatto PP, Correa JL, et al. Glycemic control after stomach-sparing duodenal-jejunal bypass surgery in diabetic patients with low body mass index. Surg Obes Relat Dis. 2012;8(4):375–80. PMID: 22410638.

    Article  PubMed  Google Scholar 

  15. Geloneze B, Geloneze SR, Fiori C, et al. Surgery for non-obese type 2 diabetic patients: an interventional study with duodenal-jejunal exclusion. Obes Surg. 2009;19(8):1077–83. PMID: 19475464.

    Article  PubMed  Google Scholar 

  16. Ramos AC, Galvao NM, de Souza YM, et al. Laparoscopic duodenal-jejunal exclusion in the treatment of type 2 diabetes mellitus in patients with BMI < 30 kg/m2 (LBMI). Obes Surg. 2009;19(3):307–12. PMID: 18987919.

    Article  PubMed  Google Scholar 

  17. Lee HC, Kim MK, Kwon HS, et al. Early changes in incretin secretion after laparoscopic duodenal-jejunal bypass surgery in type 2 diabetic patients. Obes Surg. 2010;20(11):1530–5. PMID: 20803098.

    Article  PubMed  Google Scholar 

  18. DeFronzo RA, Simonson D, Ferrannini E. Hepatic and peripheral insulin resistance: a common feature of type 2 (non-insulin-dependent) and type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1982;23(4):313–9. PMID: 6754515.

    CAS  Article  PubMed  Google Scholar 

  19. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37(12):1595–607. PMID: 3056758.

    CAS  Article  PubMed  Google Scholar 

  20. Ozcan U, Cao Q, Yilmaz E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004;306(5695):457–61. PMID:15486293.

    Article  PubMed  Google Scholar 

  21. Nakatani Y, Kaneto H, Kawamori D, et al. Involvement of endoplasmic reticulum stress in insulin resistance and diabetes. J Biol Chem. 2005;280(1):847–51. PMID: 15509553.

    CAS  Article  PubMed  Google Scholar 

  22. Ozawa K, Miyazaki M, Matsuhisa M, et al. The endoplasmic reticulum chaperone improves insulin resistance in type 2 diabetes. Diabetes. 2005;54(3):657–63. PMID: 15734840.

    CAS  Article  PubMed  Google Scholar 

  23. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005;115(5):1111–9. PMID: 15864338.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Eizirik DL, Cardozo AK, Cnop M. The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev. 2008;29(1):42–61. PMID: 18048764.

    CAS  Article  PubMed  Google Scholar 

  25. Flamment M, Hajduch E, Ferre P, et al. New insights into ER stress-induced insulin resistance. Trends Endocrinol Metab. 2012;23(8):381–90. PMID: 22770719.

    CAS  Article  PubMed  Google Scholar 

  26. Srinivasan K, Viswanad B, Asrat L, et al. Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacol Res. 2005;52(4):313–20. PMID: 15979893.

    CAS  Article  PubMed  Google Scholar 

  27. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412–9. PMID: 3899825.

    CAS  Article  PubMed  Google Scholar 

  28. Bonora E, Targher G, Alberiche M, et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care. 2000;23(1):57–63. PMID: 10857969.

    CAS  Article  PubMed  Google Scholar 

  29. Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999;22(9):1462–70. PMID: 10480510.

    CAS  Article  PubMed  Google Scholar 

  30. Ozcan U, Yilmaz E, Ozcan L, et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 2006;313(5790):1137–40. PMID:16931765.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Jiao J, Bae EJ, Bandyopadhyay G, et al. Restoration of euglycemia after duodenal bypass surgery is reliant on central and peripheral inputs in Zucker fa/fa rats. Diabetes. 2013;62(4):1074–83. PMID:23248171.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Muniyappa R, Lee S, Chen H, et al. Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab. 2008;294(1):E15–26. PMID:17957034.

    CAS  Article  PubMed  Google Scholar 

  33. Lai E, Teodoro T, Volchuk A. Endoplasmic reticulum stress: signaling the unfolded protein response. Physiology (Bethesda). 2007;22:193–201. PMID: 17557940.

    CAS  Article  Google Scholar 

  34. Gregor MF, Yang L, Fabbrini E, et al. Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss. Diabetes. 2009;58(3):693–700. PMID: 19066313.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Boden G, Duan X, Homko C, et al. Increase in endoplasmic reticulum stress-related proteins and genes in adipose tissue of obese, insulin-resistant individuals. Diabetes. 2008;57(9):2438–44. PMID: 18567819.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Aguirre V, Uchida T, Yenush L, et al. The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). J Biol Chem. 2000;275(12):9047–54. PMID: 10722755.

    CAS  Article  PubMed  Google Scholar 

  37. Hotamisligil GS, Peraldi P, Budavari A, et al. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science. 1996;271(5249):665–8. 5249 PMID: 8571133.

    CAS  Article  PubMed  Google Scholar 

  38. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414(6865):799–806. PMID: 11742412.

    CAS  Article  PubMed  Google Scholar 

  39. Hu C, Su Q, Li F, et al. Duodenal-jejunal bypass improves glucose homeostasis in association with decreased proinflammatory response and activation of JNK in the liver and adipose tissue in a T2DM rat model. Obes Surg. 2014;24(9):1453–62. PMID:24728905.

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant No. 81270888/H0713, No. 81300286/H0308, No. 81300286/H0308) and the Natural Science Foundation of Shandong Province (Grant No. ZR2012HQ030).

Conflict of Interest

All authors declare that we have no conflict of interest.

Statement of Informed Consent

Informed consent does not apply in this study.

Statement of Human and Animal Rights

All applicable institutional and national guidelines for the care and use of animals were followed.

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Affiliations

  1. Department of General Surgery, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, 250012, Shandong, People’s Republic of China

    Maogang Li, Yanmin Wang, Xiang Zhang, Teng Liu, Mingwei Zhong, Haifeng Han, Shaozhuang Liu & Sanyuan Hu

  2. Department of General Surgery, Laigang Hospital Affiliated to Taishan Medical University, No. 68, Xinxing Road, Laiwu, 271126, Shandong, People’s Republic of China

    Maogang Li, Hengping Li & Zhigang Zhou

  3. Department of Internal Medicine, Laigang Hospital Affiliated to Taishan Medical University, No. 68, Xinxing Road, Laiwu, 271126, Shandong, People’s Republic of China

    Yanggui Zhou

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  1. Maogang Li
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Correspondence to Sanyuan Hu.

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Li, M., Li, H., Zhou, Z. et al. Duodenal-Jejunal Bypass Surgery Ameliorates Glucose Homeostasis and Reduces Endoplasmic Reticulum Stress in the Liver Tissue in a Diabetic Rat Model. OBES SURG 26, 1002–1009 (2016). https://doi.org/10.1007/s11695-015-1816-2

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  • DOI: https://doi.org/10.1007/s11695-015-1816-2

Keywords

  • Duodenal-jejunal bypass
  • Type 2 diabetes mellitus
  • Glucose homeostasis
  • Endoplasmic reticulum stress
  • Hepatic insulin resistance
  • c-Jun N-terminal kinase
  • Liver tissue