Skip to main content
SpringerLink
Log in

Sera of Obese Type 2 Diabetic Patients Undergoing Metabolic Surgery Instead of Conventional Treatment Exert Beneficial Effects on Beta Cell Survival and Function: Results of a Randomized Clinical Study

  • Original Contributions
  • Published:
Obesity Surgery Aims and scope Submit manuscript

Abstract

Background

Pancreatic beta cells are highly sensitive to oxidative and endoplasmic reticulum (ER) stress, commonly occurring in type 2 diabetes (T2D) and obesity.

Objective

We aimed at investigating cellular responses of human beta cells exposed to sera from obese T2D patients treated differently, namely by conventional therapy or laparoscopic sleeve gastrectomy (LSG).

Methods

Serum samples from obese T2D men randomized to conventional treatment or LSG were taken at baseline and 6 months later. After exposing 1.1B4 cells to study patients’ sera, the following were assessed: cellular viability and proliferation (by MTT and xCELLigence assays), reactive oxygen species (ROS) production (with DCFH-DA), and expression of ER stress markers, oxidative- or autophagy-related proteins and insulin (by real-time PCR and Western blot).

Results

At 6-month follow-up, patients undergoing LSG achieved an adequate glycemic control, whereas conventionally treated patients did not. As compared to 1.1B4 cells incubated with baseline sera (control), cells exposed to sera from LSG-treated participants exhibited (i) increased viability and proliferation (p < 0.05); (ii) diminished levels of ROS and p53 (p < 0.05); (iii) enhanced protein expression of autophagy-related SIRT1 and p62/SQSTM1 (p < 0.05); (iv) significantly decreased transcript levels of ER stress markers (p < 0.05); and (v) augmented insulin expression (p < 0.05). Conversely, the 6-month conventional therapy appeared not to impact on circulating redox status. Moreover, 1.1B4 cells exposed to sera from conventionally treated patients experienced mild ER stress.

Conclusion

Circulating factors in patients with improved diabetes after metabolic surgery exerted favorable effects on beta cell function and survival.

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

Similar content being viewed by others

References

  1. UK Prospective Diabetes Study Group. UK Prospective Diabetes Study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes. 1995;44(11):1249–58.

    Article  Google Scholar 

  2. Fonseca V, McDuffie R, Calles J, et al. Determinants of weight gain in the action to control cardiovascular risk in diabetes trial. Diabetes Care. 2013;36:2162–8.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Cummings DE, Rubino F. Metabolic surgery for the treatment of type 2 diabetes in obese individuals. Diabetologia. 2018;61(2):257–64.

    Article  PubMed  Google Scholar 

  4. Schauer PR, Bhatt DL, Kirwan JP, et al. Bariatric surgery versus intensive medical therapy for diabetes - 5-year outcomes. N Engl J Med. 2017;376:641–51.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ferrannini E, Mingrone G. Impact of different bariatric surgical procedures on insulin action and beta-cell function in type 2 diabetes. Diabetes Care. 2009;32(3):514–20.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Dutia R, Brakoniecki K, Bunker P, et al. Limited recovery of β-cell function after gastric bypass despite clinical diabetes remission. Diabetes. 2014;63:1214–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Fonseca SG, Gromada J, Urano F. Endoplasmic reticulum stress and pancreatic β-cell death. Trends Endocrinol Metab. 2011;22(7):266–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011;334(6059):1081–6.

    Article  CAS  PubMed  Google Scholar 

  9. Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 2004;11(4):381–9.

    Article  CAS  PubMed  Google Scholar 

  10. White MG, Shaw JA, Taylor R. Type 2 diabetes: the pathologic basis of reversible β-cell dysfunction. Diabetes Care. 2016;39(11):2080–8.

    Article  CAS  PubMed  Google Scholar 

  11. Leonetti F, Capoccia D, Coccia F, et al. Obesity, type 2 diabetes mellitus, and other comorbidities: a prospective cohort study of laparoscopic sleeve gastrectomy vs medical treatment. Arch Surg. 2012;147(8):694–700.

    Article  CAS  PubMed  Google Scholar 

  12. Stefan DS, Mihai A, Bajko D, et al. Comparison of sleeve gastrectomy and conservatory treatment effect on biochemical and hormonal profile of obese type 2 diabetes subjects: CREDOR randomized controlled study results. Rev.Chim. 2017;68(7):1622–7.

    CAS  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. Hayes HL, Peterson BS, Haldeman JM, et al. Delayed apoptosis allows islet β-cells to implement an autophagic mechanism to promote cell survival. PLoS One. 2017;12(2):e0172567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ryan KK, Tremaroli V, Clemmensen C, et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature. 2014;509:183–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Motta MC, Divecha N, Lemieux M, et al. Mammalian SIRT1 represses forkhead transcription factors. Cell. 2004;116:551–63.

    Article  CAS  PubMed  Google Scholar 

  17. Luu L, Dai FF, Prentice KJ, et al. The loss of Sirt1 in mouse pancreatic beta cells impairs insulin secretion by disrupting glucose sensing. Diabetologia. 2013;56(9):2010–20.

    Article  CAS  PubMed  Google Scholar 

  18. Li Y, Xu S, Giles A, et al. Hepatic overexpression of SIRT1 in mice attenuates endoplasmic reticulum stress and insulin resistance in the liver. FASEB J. 2011;25:1664–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Guo H, Chen Y, Liao L, et al. Resveratrol protects HUVECs from oxidized-LDL induced oxidative damage by autophagy upregulation via the AMPK/SIRT1 pathway. Cardiovasc Drugs Ther. 2013;27:189–98.

    Article  CAS  PubMed  Google Scholar 

  20. Geetha T, Zheng C, Vishwaprakash N, et al. Sequestosome 1/p62, a scaffolding protein, is a newly identified partner of IRS-1 protein. J Biol Chem. 2012;287(35):29672–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Park JS, Oh SY, Lee DH, et al. p62/SQSTM1 is required for the protection against endoplasmic reticulum stress-induced apoptotic cell death. Free Radic Res. 2016;50(12):1408–21.

    Article  CAS  PubMed  Google Scholar 

  22. Kennedy J, Katsuta H, Jung MH, et al. Protective unfolded protein response in human pancreatic beta cells transplanted into mice. PLoS One. 2010;5:e11211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yang H, Liu R, Cui Z, et al. Functional characterization of 58-kilodalton inhibitor of protein kinase in protecting against diabetic retinopathy via the endoplasmic reticulum stress pathway. Mol Vis. 2011;17:78–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Synofzik M, Haack TB, Kopajtich R, et al. Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration. Am J Hum Genet. 2014;95(6):689–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wilhelm M, Schlegl J, Hahne H, et al. Mass-spectrometry-based draft of the human proteome. Nature. 2014;509:582–7.

    Article  CAS  PubMed  Google Scholar 

  26. Vogel C, Marcotte EM. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet. 2012;13(4):227–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Schwanhäusser B, Busse D, Li N, et al. Global quantification of mammalian gene expression control. Nature. 2011;473(7347):337–42.

    Article  CAS  PubMed  Google Scholar 

  28. Liew H-K, Chen P-K, Peng H-F, et al. Downregulation of GRP78 chaperone protein triggers pro-apoptotic CHOP signaling cascade in acute intracerebral hemorrhage rats. FASEB J. 2017;31(1 Suppl):815.5.

    Google Scholar 

  29. Wang J, Lee J, Liem D, et al. HSPA5 gene encoding Hsp70 chaperone BiP in the endoplasmic reticulum. Gene. 2017;618:14–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Han J, Back SH, Hur J, et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat Cell Biol. 2013;15:481–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Huang CJ, Lin CY, Haataja L, et al. High expression rates of human islet amyloid polypeptide induce endoplasmic reticulum stress mediated beta-cell apoptosis, a characteristic of humans with type 2 but not type 1 diabetes. Diabetes. 2007;56(8):2016–27.

    Article  CAS  PubMed  Google Scholar 

  32. Teodoro T, Odisho T, Sidorova E, et al. Pancreatic β-cells depend on basal expression of active ATF6α-p50 for cell survival even under non-stress conditions. Am J Physiol Cell Physiol. 2012;302:C992–1003.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We are grateful to all the patients who participated in this study. We would like to thank Dr. Daniela Lixandru (Carol Davila University of Medicine and Pharmacy, Bucharest) for providing the 1.1B4 pancreatic beta cells. We also acknowledge the valuable technical assistance of Ms. Marilena Isachi and Ms. Marcela Toader.

Funding

This study was supported by the Romanian National Authority for Scientific Research and Innovation, CNCS-UEFISCDI, through the projects PN-II-PT-PCCA-2013-4-2154, PN-III-P1-1.2-PCCDI-2017-0797, and PN-III-P1-1.2-PCCDI-2017-0527 and by the Romanian Academy.

Author information

Authors and Affiliations

  1. Pathophysiology and Pharmacology Department, Institute of Cellular Biology and Pathology ‘Nicolae Simionescu’ of the Romanian Academy, 8, BP Hasdeu Street, PO Box 35-14, 050568, Bucharest, Romania

    Alina Constantin, Mădălina Dumitrescu, Miruna Nemecz, Nicoleta Alexandru, Adriana Georgescu & Gabriela Tanko

  2. Institute of Diabetes, Nutrition and Metabolic Diseases “Prof. Dr N. Paulescu”, Bucharest, Romania

    Ariana Picu & Cristian Guja

  3. Regina Maria Hospital, Bucharest, Romania

    Bogdan Smeu

Authors
  1. Alina Constantin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mădălina Dumitrescu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Miruna Nemecz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ariana Picu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bogdan Smeu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cristian Guja
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nicoleta Alexandru
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Adriana Georgescu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gabriela Tanko
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gabriela Tanko.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Statement of Human and Animal Rights

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and /or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Constantin, A., Dumitrescu, M., Nemecz, M. et al. Sera of Obese Type 2 Diabetic Patients Undergoing Metabolic Surgery Instead of Conventional Treatment Exert Beneficial Effects on Beta Cell Survival and Function: Results of a Randomized Clinical Study. OBES SURG 29, 1485–1497 (2019). https://doi.org/10.1007/s11695-019-03710-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11695-019-03710-0

Keywords

Search

Navigation