Langenbeck's Archives of Surgery

, Volume 402, Issue 6, pp 901–910 | Cite as

Gastric bypass simultaneously improves adipose tissue function and insulin-dependent type 2 diabetes mellitus

  • Adrian T. Billeter
  • Spiros Vittas
  • Barbara Israel
  • Katharina M. Scheurlen
  • Asa Hidmark
  • Thomas H. Fleming
  • Stefan Kopf
  • Markus W. Büchler
  • Beat P. Müller-Stich



The underlying causes of type 2 diabetes (T2DM) remain poorly understood. Adipose tissue dysfunction with high leptin, inflammation, and increased oxidative stress may play a pivotal role in T2DM development in obese patients. Little is known about the changes in the adipose tissue after Roux-Y gastric bypass (RYGB) in non-severely obese patients (BMI < 35 kg/m2) and since these patients have more T2DM-associated complications than obese patients (“obesity paradox”), we investigated changes in adipose tissue function in a cohort of BMI <35 kg/m2 with insulin-dependent T2DM after RYGB surgery which resolves T2DM.


Twenty patients with insulin-dependent T2DM and BMI <35 kg/m2 underwent RYGB. Insulin-resistance, leptin, oxidative stress, and cytokines were determined over 24 months. Expression of cytokines and NF-kappaB pathway genes were measured in leukocytes (PBMC). Adipose tissue inflammation was examined histologically preoperatively and 24 months after RGYB in subcutaneous adipose tissue.


Insulin-resistance, leptin, oxidative stress as well as adipose tissue inflammation decreased significantly after RYGB. Similarly, systemic inflammation was reduced and peripheral blood mononuclear cells (PBMCs) were reprogrammed towards an M2-type inflammation. Loss of BMI correlated with leptin levels (r = 0.891, p < 0.0001), insulin resistance (r = 0.527, p = 0.003), and oxidative stress (r = 0.592, p = 0.016). Leptin correlated with improved insulin resistance (r = 0.449, p = 0.032) while reduced leptin showed a strong association with improved oxidative stress (r = 0.809, p = 0.001). Lastly, reduced oxidative stress correlated strongly with improved insulin-resistance (r = 0.776, p = 0.001).


RYGB improves adipose tissue function and inflammation. Leptin as marker for adipose tissue dysfunction may be the mediating factor between insulin resistance and oxidative stress and thereby likely improving T2DM.


Diabetes T2DM Inflammation Adipose tissue Macrophages Gastric bypass RYGB 



This study was supported by the German Research Society (DFG) awarded to Prof. P. Nawroth (SFB 1118).

Compliance with ethical standards

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.

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

Statement of competing financial interests

None of the authors has any competing financial interests.

Conflict of interest

The authors declared that they have no conflict of interest.

Supplementary material

423_2017_1601_MOESM1_ESM.docx (12 kb)
Supplemental Table 1 (DOCX 12 kb)


  1. 1.
    Wild S, Roglic G, Green A, Sicree R, King H (2004) Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27:1047–1053CrossRefPubMedGoogle Scholar
  2. 2.
    Despres JP, Lemieux I (2006) Abdominal obesity and metabolic syndrome. Nature 444:881–887CrossRefPubMedGoogle Scholar
  3. 3.
    Picot J, Jones J, Colquitt JL et al (2009) The clinical effectiveness and cost-effectiveness of bariatric (weight loss) surgery for obesity: a systematic review and economic evaluation. Health Technol Assess 13(41):1–190, 215–357Google Scholar
  4. 4.
    Franz MJ, Boucher JL, Rutten-Ramos S, Van Wormer JJ (2015) Lifestyle weight-loss intervention outcomes in overweight and obese adults with type 2 diabetes: a systematic review and meta-analysis of randomized clinical trials. J Acad Nutr Diet 115:1447–1463CrossRefPubMedGoogle Scholar
  5. 5.
    Mingrone G, Panunzi S, De Gaetano A et al (2015) Bariatric-metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomised controlled trial. Lancet 386:964–973CrossRefPubMedGoogle Scholar
  6. 6.
    Muller-Stich BP, Senft JD, Warschkow R, et al. (2014) Surgical versus medical treatment of type 2 diabetes mellitus in nonseverely obese patients: a systematic review and meta-analysis. Ann SurgGoogle Scholar
  7. 7.
    Buchwald H, Estok R, Fahrbach K et al (2009) Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis. Am J Med 122:248–256 e245CrossRefPubMedGoogle Scholar
  8. 8.
    Schauer PR, Bhatt DL, Kirwan JP, et al. (2014) Bariatric surgery versus intensive medical therapy for diabetes −3-year outcomes. N Engl J MedGoogle Scholar
  9. 9.
    Kohli R, Stefater MA, Inge TH (2011) Molecular insights from bariatric surgery. Rev Endocr Metab Disord 12:211–217CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444:860–867CrossRefPubMedGoogle Scholar
  11. 11.
    Le KA, Mahurkar S, Alderete TL et al (2011) Subcutaneous adipose tissue macrophage infiltration is associated with hepatic and visceral fat deposition, hyperinsulinemia, and stimulation of NF-kappaB stress pathway. Diabetes 60:2802–2809CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Aroor AR, DeMarco VG (2014) Oxidative stress and obesity: the chicken or the egg? Diabetes 63:2216–2218CrossRefPubMedGoogle Scholar
  13. 13.
    Ouchi N, Parker JL, Lugus JJ, Walsh K (2011) Adipokines in inflammation and metabolic disease. Nat Rev Immunol 11:85–97CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Amato MC, Pizzolanti G, Torregrossa V, Misiano G, Milano S, Giordano C (2014) Visceral adiposity index (VAI) is predictive of an altered adipokine profile in patients with type 2 diabetes. PLoS One 9:e91969CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Gruen ML, Hao M, Piston DW, Hasty AH (2007) Leptin requires canonical migratory signaling pathways for induction of monocyte and macrophage chemotaxis. Am J Physiol Cell Physiol 293:C1481–C1488CrossRefPubMedGoogle Scholar
  16. 16.
    Surmi BK, Hasty AH (2008) Macrophage infiltration into adipose tissue: initiation, propagation and remodeling. Futur Lipidol 3:545–556CrossRefGoogle Scholar
  17. 17.
    Friedman JM, Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395:763–770CrossRefPubMedGoogle Scholar
  18. 18.
    Rizzo MR, Barbieri M, Marfella R, Paolisso G (2012) Reduction of oxidative stress and inflammation by blunting daily acute glucose fluctuations in patients with type 2 diabetes: role of dipeptidyl peptidase-IV inhibition. Diabetes Care 35:2076–2082CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Youn JY, Siu KL, Lob HE, Itani H, Harrison DG, Cai H (2014) Role of vascular oxidative stress in obesity and metabolic syndrome. Diabetes 63:2344–2355CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Xu XJ, Apovian C, Hess D, Carmine B, Saha A, Ruderman N (2015) Improved insulin sensitivity 3 months after RYGB surgery is associated with increased subcutaneous adipose tissue AMPK activity and decreased oxidative stress. Diabetes 64:3155–3159CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Chatterjee S, Ganini D, Tokar EJ et al (2013) Leptin is key to peroxynitrite-mediated oxidative stress and Kupffer cell activation in experimental non-alcoholic steatohepatitis. J Hepatol 58:778–784CrossRefPubMedGoogle Scholar
  22. 22.
    Shi X, Chen Y, Nadeem L, Xu G (2013) Beneficial effect of TNF-alpha inhibition on diabetic peripheral neuropathy. J Neuroinflammation 10:69PubMedPubMedCentralGoogle Scholar
  23. 23.
    Forbes JM, Cooper ME (2013) Mechanisms of diabetic complications. Physiol Rev 93:137–188CrossRefPubMedGoogle Scholar
  24. 24.
    Furukawa S, Fujita T, Shimabukuro M et al (2004) Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 114:1752–1761CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Woelnerhanssen B, Peterli R, Steinert RE, Peters T, Borbely Y, Beglinger C (2011) Effects of postbariatric surgery weight loss on adipokines and metabolic parameters: comparison of laparoscopic roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy—a prospective randomized trial. Surg Obes Relat Dis 7:561–568CrossRefPubMedGoogle Scholar
  26. 26.
    Murri M, Garcia-Fuentes E, Garcia-Almeida JM et al (2010) Changes in oxidative stress and insulin resistance in morbidly obese patients after bariatric surgery. Obes Surg 20:363–368CrossRefPubMedGoogle Scholar
  27. 27.
    Muller-Stich BP, Billeter AT, Fleming T, Fischer L, Buchler MW, Nawroth PP (2014) Nitrosative stress but not glycemic parameters correlate with improved neuropathy in nonseverely obese diabetic patients after roux-Y gastric bypass. Surg Obes Relat Dis Off J Am Soc Bariatric SurgGoogle Scholar
  28. 28.
    Sharma AM, Kushner RF (2009) A proposed clinical staging system for obesity. Int J Obes 33:289–295CrossRefGoogle Scholar
  29. 29.
    Padwal RS, Pajewski NM, Allison DB, Sharma AM (2011) Using the Edmonton obesity staging system to predict mortality in a population-representative cohort of people with overweight and obesity. CMAJ: Can Med Assoc J J l'Assoc Med Can 183:E1059–E1066CrossRefGoogle Scholar
  30. 30.
    Tobias DK, Pan A, Jackson CL et al (2014) Body-mass index and mortality among adults with incident type 2 diabetes. N Engl J Med 370:233–244CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Costanzo P, Cleland JG, Pellicori P et al (2015) The obesity paradox in type 2 diabetes mellitus: relationship of body mass index to prognosis: a cohort study. Ann Intern Med 162:610–618CrossRefPubMedGoogle Scholar
  32. 32.
    Muller-Stich BP, Fischer L, Kenngott HG et al (2013) Gastric bypass leads to improvement of diabetic neuropathy independent of glucose normalization—results of a prospective cohort study (DiaSurg 1 study). Ann Surg 258:760–765 discussion 765-766CrossRefPubMedGoogle Scholar
  33. 33.
    Billeter AT, Probst P, Fischer L, et al. (2015) Risk of malnutrition, trace metal, and vitamin deficiency post roux-en-Y gastric bypass-a prospective study of 20 patients with BMI <35 kg/m. Obes SurgGoogle Scholar
  34. 34.
    Billeter ATKS, Zeier M, Scheurlen K, Fischer L, Schulte TM, Kenngott HG, Israel B, Knefeli P, Büchler MW, Nawroth PP, Müller-Stich BP (2016) Renal function in type 2 diabetes following gastric bypass—a prospective cohort study in mildly obese insulin-dependent patients. Dtsch Arztebl Int 113:2016Google Scholar
  35. 35.
    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419CrossRefPubMedGoogle Scholar
  36. 36.
    Schneider CA, Rasband WS, Eliceiri KW (2012) NIH image to ImageJ: 25 years of image analysis. Nat Methods 9:671–675CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Nguyen D (2013) Quantifying chromogen intensity in immunohistochemistry via reciprocal intensity. Protocol ExchGoogle Scholar
  38. 38.
    Spandidos A, Wang X, Wang H, Seed B (2010) PrimerBank: a resource of human and mouse PCR primer pairs for gene expression detection and quantification. Nucleic Acids Res 38:D792–D799CrossRefPubMedGoogle Scholar
  39. 39.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25:402–408CrossRefPubMedGoogle Scholar
  40. 40.
    Weisberg SP, Hunter D, Huber R et al (2006) CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 116:115–124CrossRefPubMedGoogle Scholar
  41. 41.
    Strissel KJ, Stancheva Z, Miyoshi H et al (2007) Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes 56:2910–2918CrossRefPubMedGoogle Scholar
  42. 42.
    Folli F, Corradi D, Fanti P et al (2011) The role of oxidative stress in the pathogenesis of type 2 diabetes mellitus micro- and macrovascular complications: avenues for a mechanistic-based therapeutic approach. Curr Diabetes Rev 7:313–324CrossRefPubMedGoogle Scholar
  43. 43.
    Evans JL, Goldfine ID, Maddux BA, Grodsky GM (2002) Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr Rev 23:599–622CrossRefPubMedGoogle Scholar
  44. 44.
    Yanagawa T, Taniguchi A, Fukushima M et al (2007) Leptin, triglycerides, and interleukin 6 are independently associated with C-reactive protein in Japanese type 2 diabetic patients. Diabetes Res Clin Pract 75:2–6CrossRefPubMedGoogle Scholar
  45. 45.
    Stefanovic A, Kotur-Stevuljevic J, Spasic S, Bogavac-Stanojevic N, Bujisic N (2008) The influence of obesity on the oxidative stress status and the concentration of leptin in type 2 diabetes mellitus patients. Diabetes Res Clin Pract 79:156–163CrossRefPubMedGoogle Scholar
  46. 46.
    Pandey G, Shihabudeen MS, David HP, Thirumurugan E, Thirumurugan K (2015) Association between hyperleptinemia and oxidative stress in obese diabetic subjects. J Diabetes Metab Disord 14:24CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Fischer S, Hanefeld M, Haffner SM et al (2002) Insulin-resistant patients with type 2 diabetes mellitus have higher serum leptin levels independently of body fat mass. Acta Diabetol 39:105–110CrossRefPubMedGoogle Scholar
  48. 48.
    Malmstrom R, Taskinen MR, Karonen SL, Yki-Jarvinen H (1996) Insulin increases plasma leptin concentrations in normal subjects and patients with NIDDM. Diabetologia 39:993–996CrossRefPubMedGoogle Scholar
  49. 49.
    Kitade H, Sawamoto K, Nagashimada M et al (2012) CCR5 plays a critical role in obesity-induced adipose tissue inflammation and insulin resistance by regulating both macrophage recruitment and M1/M2 status. Diabetes 61:1680–1690CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Kanda H, Tateya S, Tamori Y et al (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 116:1494–1505CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117:175–184CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Martinez FO, Gordon S (2014) The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000prime Rep 6:13CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Kousathana F, Georgitsi M, Lambadiari V, Giamarellos-Bourboulis EJ, Dimitriadis G, Mouktaroudi M (2017) Defective production of interleukin-1 beta in patients with type 2 diabetes mellitus: restoration by proper glycemic control. Cytokine 90:177–184CrossRefPubMedGoogle Scholar
  54. 54.
    Marseglia L, Manti S, D'Angelo G et al (2014) Oxidative stress in obesity: a critical component in human diseases. Int J Mol Sci 16:378–400CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Henriksen EJ, Diamond-Stanic MK, Marchionne EM (2011) Oxidative stress and the etiology of insulin resistance and type 2 diabetes. Free Radic Biol Med 51:993–999CrossRefPubMedGoogle Scholar
  56. 56.
    Panunzi S, De Gaetano A, Carnicelli A, Mingrone G (2015) Predictors of remission of diabetes mellitus in severely obese individuals undergoing bariatric surgery: do BMI or procedure choice matter? A meta-analysis. Ann Surg 261:459–467CrossRefPubMedGoogle Scholar
  57. 57.
    Farb MG, Bigornia S, Mott M et al (2011) Reduced adipose tissue inflammation represents an intermediate cardiometabolic phenotype in obesity. J Am Coll Cardiol 58:232–237CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Tamboli RA, Breitman I, Marks-Shulman PA et al (2014) Early weight regain after gastric bypass does not affect insulin sensitivity but is associated with elevated ghrelin. Obesity 22:1617–1622CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Adrian T. Billeter
    • 1
  • Spiros Vittas
    • 2
  • Barbara Israel
    • 1
  • Katharina M. Scheurlen
    • 1
  • Asa Hidmark
    • 2
  • Thomas H. Fleming
    • 2
  • Stefan Kopf
    • 2
  • Markus W. Büchler
    • 1
  • Beat P. Müller-Stich
    • 1
  1. 1.From the Department of General, Visceral, and Transplantation SurgeryUniversity of HeidelbergHeidelbergGermany
  2. 2.From the Department of Internal Medicine I and Clinical ChemistryUniversity of HeidelbergHeidelbergGermany

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