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Obesity Surgery

, Volume 25, Issue 4, pp 656–665 | Cite as

Duodenal-Jejunal Bypass Restores Insulin Action and Βeta-Cell Function in Hypothalamic-Obese Rats

  • Maria Lúcia Bonfleur
  • Rosane Aparecida Ribeiro
  • Audrei Pavanello
  • Raul Soster
  • Camila Lubaczeuski
  • Allan Cezar Faria Araujo
  • Antonio Carlos Boschero
  • Sandra Lucinei Balbo
Original Contributions

Abstract

Background

Bariatric operations are frequently used to improve metabolic profile and comorbidities in obese subjects, but the effects of this procedure in hypothalamic-obese (HyO) patients are controversial. Here, using HyO rats, we investigate the effects of duodenal-jejunal bypass (DJB) upon obesity, serum lipid levels, glucose tolerance, and insulin action and secretion.

Methods

Hypothalamic obesity was induced in male rats by the administration of monosodium glutamate [4 g/kg body weight (BW), HyO group] during the first 5 days of life. Control (CTL) group received saline (1.25 g/kg BW). At 90 days of age, HyO rats were submitted to DJB (HyO DJB group) or sham surgery. After 2 months, lipid levels, glucose tolerance, obesity parameters, and insulin sensitivity and secretion were verified.

Results

HyO rats displayed obesity, hypertriglyceridemia, hypercholesterolemia, glucose intolerance, and hyperinsulinemia. A higher HOMA-IR and no alteration in the ratio of phospho (p)-Akt related to Akt protein content in the liver, after insulin stimulus, demonstrated that HyO rats were insulin resistant. Islets isolated from HyO rats hypersecreted insulin in response to glucose and carbachol (Cch). At 2 months after DJB, HyO rats still displayed higher fat stores, but showed normal serum lipids and insulin levels. The HyO DJB group displayed better glucose tolerance, associated with a normal hepatic insulin activation of Akt. Normal glucose and Cch-induced insulin secretion was observed in HyO DJB islets.

Conclusions

DJB ameliorated glucose homeostasis, restored hepatic insulin action, and normalized islet function in HyO rats, indicating that this surgery may be useful for the treatment of hypothalamic obesity.

Keywords

Duodenal-jejunal bypass Hypothalamic obesity Insulin resistance Insulin secretion MSG rats 

Notes

Acknowledgments

We are grateful to Assis Roberto Escher for animal care and Nicola Conran for editing English.

Funding

This study was supported by grants from Fundação Araucária, Conselho Nacional para o Desenvolvimento Científico e Tecnológico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

Conflicts of Interest

All contributing authors declare that they have no conflicts of interest.

Statement of Informed Consent

This article does not contain any studies with human participants.

Statement of Human and Animal Rights

All experiments were approved by the University’s Committee on Ethics in Animal Experimentation (CEEAAP/UNIOESTE, protocol no. 62/10), and all applicable institutional and/or national guidelines for the care and use of animals were followed.

References

  1. 1.
    Serra-Majem L, Bautista-Castano I. Etiology of obesity: two “key issues” and other emerging factors. Nutr Hosp. 2013;28 Suppl 5:32–43.PubMedGoogle Scholar
  2. 2.
    Hochberg I, Hochberg Z. Expanding the definition of hypothalamic obesity. Obesity ereviews. Off J Int Assoc Study Obes. 2010;11:709–21.CrossRefGoogle Scholar
  3. 3.
    Lee M, Korner J. Review of physiology, clinical manifestations, and management of hypothalamic obesity in humans. Pituitary. 2009;12:87–95.CrossRefPubMedGoogle Scholar
  4. 4.
    Bingham NC, Rose SR, Inge TH. Bariatric surgery in hypothalamic obesity. Front Endocrinol. 2012;3:23.CrossRefGoogle Scholar
  5. 5.
    Muller HL, Gebhardt U, Wessel V, Schroder S, Kolb R, Sorensen N, et al. First experiences with laparoscopic adjustable gastric banding (LAGB) in the treatment of patients with childhood craniopharyngioma and morbid obesity. Klin Padiatr. 2007;219:323–5.CrossRefPubMedGoogle Scholar
  6. 6.
    Inge TH, Pfluger P, Zeller M, Rose SR, Burget L, Sundararajan S, et al. Gastric bypass surgery for treatment of hypothalamic obesity after craniopharyngioma therapy. Nature clinical practice. Endocrinol Metab. 2007;3:606–9.Google Scholar
  7. 7.
    Schultes B, Ernst B, Schmid F, Thurnheer M. Distal gastric bypass surgery for the treatment of hypothalamic obesity after childhood craniopharyngioma. Eur J EndocrinolEur Fed Endocr Soc. 2009;161:201–6.CrossRefGoogle Scholar
  8. 8.
    Bretault M, Boillot A, Muzard L, Poitou C, Oppert JM, Barsamian C, et al. Bariatric surgery following treatment for craniopharyngioma: a systematic review and individual-level data meta-analysis. J Clin Endocrinol Metab. 2013;98:2239–46.CrossRefPubMedGoogle Scholar
  9. 9.
    Weismann D, Pelka T, Bender G, Jurowich C, Fassnacht M, Thalheimer A, et al. Bariatric surgery for morbid obesity in craniopharyngioma. Clin Endocrinol (Oxf). 2013;78:385–90.CrossRefGoogle Scholar
  10. 10.
    Panchal SK, Brown L. Rodent models for metabolic syndrome research. J Biomed Biotechnol. 2011;2011:351982.CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Olney JW. Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science. 1969;164:719–21.CrossRefPubMedGoogle Scholar
  12. 12.
    Arees EA, Mayer J. Monosodium glutamate-induced brain lesions: electron microscopic examination. Science. 1970;170:549–50.CrossRefPubMedGoogle Scholar
  13. 13.
    Balbo SL, Mathias PC, Bonfleur ML, Alves HF, Siroti FJ, Monteiro OG, et al. Vagotomy reduces obesity in MSG-treated rats. Res Commun Mol Pathol Pharmacol. 2000;108:291–6.PubMedGoogle Scholar
  14. 14.
    Maiter D, Underwood LE, Martin JB, Koenig JI. Neonatal treatment with monosodium glutamate: effects of prolonged growth hormone (GH)-releasing hormone deficiency on pulsatile GH secretion and growth in female rats. Endocrinology. 1991;128:1100–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Nagata M, Suzuki W, Iizuka S, Tabuchi M, Maruyama H, Takeda S, et al. Type 2 diabetes mellitus in obese mouse model induced by monosodium glutamate. Exp Anim Japan Assoc Lab Anim Sci. 2006;55:109–15.Google Scholar
  16. 16.
    Balbo SL, Grassiolli S, Ribeiro RA, Bonfleur ML, Gravena C, Brito MON, et al. Fat storage is partially dependent on vagal activity and insulin secretion of hypothalamic obese rat. Endocrine. 2007;31:142–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Nardelli TR, Ribeiro RA, Balbo SL, Vanzela EC, Carneiro EM, Boschero AC, et al. Taurine prevents fat deposition and ameliorates plasma lipid profile in monosodium glutamate-obese rats. Amino Acids. 2011;41:901–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Ribeiro RA, Balbo SL, Roma LP, Camargo RL, Barella LF, Vanzela EC, et al. Impaired muscarinic type 3 (M3) receptor/PKC and PKA pathways in islets from MSG-obese rats. Mol Biol Rep. 2013;40:4521–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Ribeiro, R. A., Bonfleur, M. L., Vanzela, E. C., Zotti, A. I., Scomparin, D. X., Boschero, A. C., and Balbo, S. L. Physical exercise introduced after weaning enhances pancreatic islet responsiveness to glucose and potentiating agents in adult msg-obese rats. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2014.Google Scholar
  20. 20.
    Hirata AE, Andrade IS, Vaskevicius P, Dolnikoff MS. Monosodium glutamate (MSG)-obese rats develop glucose intolerance and insulin resistance to peripheral glucose uptake. Brazilian journal of medical and biological research. Revista Bras Pesquisas Med Biologicas Soc Bras Biofisica. 1997;30:671–4.Google Scholar
  21. 21.
    Hirata AE, Alvarez-Rojas F, Carvalheira JB, Carvalho CR, Dolnikoff MS, Abdalla Saad MJ. Modulation of IR/PTP1B interaction and downstream signaling in insulin sensitive tissues of MSG-rats. Life Sci. 2003;73:1369–81.CrossRefPubMedGoogle Scholar
  22. 22.
    Dawson R, Pelleymounter MA, Millard WJ, Liu S, Eppler B. Attenuation of leptin-mediated effects by monosodium glutamate-induced arcuate nucleus damage. Am J Physiol. 1997;273:E202–206.PubMedGoogle Scholar
  23. 23.
    Oida K, Nakai T, Hayashi T, Miyabo S, Takeda R. Plasma lipoproteins of monosodium glutamate-induced obese rats. Int J Obes (Lond). 1984;8:385–91.Google Scholar
  24. 24.
    Meguid MM, Ramos EJ, Suzuki S, Xu Y, George ZM, Das UN, et al. A surgical rat model of human Roux-en-Y gastric bypass. J Gastrointest Surg Off J Soc Surg Aliment Tract. 2004;8:621–30.CrossRefGoogle Scholar
  25. 25.
    Jurowich CF, Rikkala PR, Thalheimer A, Wichelmann C, Seyfried F, Sander V, et al. Duodenal-jejunal bypass improves glycemia and decreases SGLT1-mediated glucose absorption in rats with streptozotocin-induced type 2 diabetes. Ann Surg. 2013;258:89–97.CrossRefPubMedGoogle Scholar
  26. 26.
    Batista TM, da Silva PM, Amaral AG, Ribeiro RA, Boschero AC, Carneiro EM. Taurine supplementation restores insulin secretion and reduces ER stress markers in protein-malnourished mice. Adv Exp Med Biol. 2013;776:129–39.CrossRefPubMedGoogle Scholar
  27. 27.
    Bernardis LL, Patterson BD. Correlation between ‘Lee index’ and carcass fat content in weanling and adult female rats with hypothalamic lesions. J Endocrinol. 1968;40:527–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Ribeiro RA, Vanzela EC, Oliveira CA, Bonfleur ML, Boschero AC, Carneiro EM. Taurine supplementation: involvement of cholinergic/phospholipase C and protein kinase A pathways in potentiation of insulin secretion and Ca2+ handling in mouse pancreatic islets. Br J Nutr. 2010;104:1148–55.CrossRefPubMedGoogle Scholar
  29. 29.
    Bonora E, Targher G, Alberiche M, Bonadonna RC, Saggiani F, Zenere MB, 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;23:57–63.CrossRefPubMedGoogle Scholar
  30. 30.
    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Folch J, Lees M, Sloane Stanley GH. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957;226:497–509.PubMedGoogle Scholar
  32. 32.
    Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248–54.CrossRefPubMedGoogle Scholar
  33. 33.
    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;239:1–11.CrossRefPubMedCentralPubMedGoogle Scholar
  34. 34.
    Rubino F. Bariatric surgery: effects on glucose homeostasis. Curr Opin Clin Nutr Metab Care. 2006;9:497–507.CrossRefPubMedGoogle Scholar
  35. 35.
    Araujo AC, Bonfleur ML, Balbo SL, Ribeiro RA, de Freitas AC. Duodenal-jejunal bypass surgery enhances glucose tolerance and beta-cell function in Western diet obese rats. Obes Surg. 2012;22:819–26.CrossRefPubMedGoogle Scholar
  36. 36.
    Zechner JF, Mirshahi UL, Satapati S, Berglund ED, Rossi J, Scott MM, et al. Weight-independent effects of roux-en-Y gastric bypass on glucose homeostasis via melanocortin-4 receptors in mice and humans. Gastroenterology. 2013;144:580–590 e587.CrossRefPubMedGoogle Scholar
  37. 37.
    Strader AD, Vahl TP, Jandacek RJ, Woods SC, D’Alessio DA, Seeley RJ. Weight loss through ileal transposition is accompanied by increased ileal hormone secretion and synthesis in rats. Am J Physiol Endocrinol Metab. 2005;288:E447–453.CrossRefPubMedGoogle Scholar
  38. 38.
    Speck M, Cho YM, Asadi A, Rubino F, Kieffer TJ. 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:E923–932.CrossRefPubMedGoogle Scholar
  39. 39.
    Salinari S, le Roux CW, Bertuzzi A, Rubino F, Mingrone G. Duodenal-jejunal bypass and jejunectomy improve insulin sensitivity in Goto-Kakizaki diabetic rats without changes in incretins or insulin secretion. Diabetes. 2014;63:1069–78.CrossRefPubMedGoogle Scholar
  40. 40.
    Gatta B, Nunes ML, Bailacq-Auder C, Etchechoury L, Collet D, Tabarin A. Is bariatric surgery really inefficient in hypothalamic obesity? Clin Endocrinol (Oxf). 2013;78:636–8.CrossRefGoogle Scholar
  41. 41.
    Rottembourg D, O’Gorman CS, Urbach S, Garneau PY, Langer JC, Van Vliet G, et al. Outcome after bariatric surgery in two adolescents with hypothalamic obesity following treatment of craniopharyngioma. J Pediatr Endocrinol Metab. 2009;22:867–72.CrossRefPubMedGoogle Scholar
  42. 42.
    Zhang SY, Sun XJ, Zheng JB, Wang W, Liu D, Chen NZ, et al. Preserve common limb in duodenal-jejunal bypass surgery benefits rats with type 2-like diabetes. Obes Surg. 2014;24:405–11.CrossRefPubMedGoogle Scholar
  43. 43.
    Geloneze B, Geloneze SR, Fiori C, Stabe C, Tambascia MA, Chaim EA, et al. Surgery for nonobese type 2 diabetic patients: an interventional study with duodenal-jejunal exclusion. Obes Surg. 2009;19:1077–83.CrossRefPubMedGoogle Scholar
  44. 44.
    Rubino F, Gagner M, Gentileschi P, Kini S, Fukuyama S, Feng J, et al. The early effect of the Roux-en-Y gastric bypass on hormones involved in body weight regulation and glucose metabolism. Ann Surg. 2004;240:236–42.CrossRefPubMedCentralPubMedGoogle Scholar
  45. 45.
    Sun D, Wang K, Yan Z, Zhang G, Liu S, Liu F, 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.CrossRefPubMedGoogle Scholar
  46. 46.
    Strader AD, Clausen TR, Goodin SZ, Wendt D. Ileal interposition improves glucose tolerance in low dose streptozotocin-treated diabetic and euglycemic rats. Obes Surg. 2009;19:96–104.CrossRefPubMedGoogle Scholar
  47. 47.
    Pacheco D, de Luis DA, Romero A, Gonzalez Sagrado M, Conde R, Izaola O, et al. The effects of duodenal-jejunal exclusion on hormonal regulation of glucose metabolism in Goto-Kakizaki rats. Am J Surg. 2007;194:221–4.CrossRefPubMedGoogle Scholar
  48. 48.
    Mackenzie RW, Elliott BT. Akt/PKB activation and insulin signaling: a novel insulin signaling pathway in the treatment of type 2 diabetes. Diabetes Metab Syndrome Obes Targets Ther. 2014;7:55–64.CrossRefGoogle Scholar
  49. 49.
    Boucher, J., Kleinridders, A., and Kahn, C. R. Insulin receptor signaling in normal and insulin-resistant states. Cold spring harbor perspectives in biology. 2014;6:Google Scholar
  50. 50.
    Seely BL, Staubs PA, Reichart DR, Berhanu P, Milarski KL, Saltiel AR, et al. Protein tyrosine phosphatase 1B interacts with the activated insulin receptor. Diabetes. 1996;45:1379–85.CrossRefPubMedGoogle Scholar
  51. 51.
    Bell GI, Kayano T, Buse JB, Burant CF, Takeda J, Lin D, et al. Molecular biology of mammalian glucose transporters. Diabetes Care. 1990;13:198–208.CrossRefPubMedGoogle Scholar
  52. 52.
    Manna P, Jain SK. Decreased hepatic phosphatidylinositol-3,4,5-triphosphate (PIP3) levels and impaired glucose homeostasis in type 1 and type 2 diabetic rats. Cellular physiology and biochemistry. Int J Exp Cell Physiol Biochem Pharmacol. 2012;30:1363–70.CrossRefGoogle Scholar
  53. 53.
    David-Silva A, Freitas HS, Okamoto MM, Sabino-Silva R, Schaan BD, Machado UF. Hepatocyte nuclear factors 1α/4α and forkhead box A2 regulate the solute carrier 2A2 (Slc2a2) gene expression in the liver and kidney of diabetic rats. Life Sci. 2013;93:805–13.CrossRefPubMedGoogle Scholar
  54. 54.
    Yamamoto T, Fukumoto H, Koh G, Yano H, Yasuda K, Masuda K, et al. Liver and muscle-fat type glucose transporter gene expression in obese and diabetic rats. Biochem Biophys Res Commun. 1991;175:995–1002.CrossRefPubMedGoogle Scholar
  55. 55.
    Donglei Z, Liesheng L, Xun J, Chenzhu Z, Weixing D. Effects and mechanism of duodenal-jejunal bypass and sleeve gastrectomy on GLUT2 and glucokinase in diabetic Goto-Kakizaki rats. Eur J Med Res. 2012;17:15.CrossRefPubMedCentralPubMedGoogle Scholar
  56. 56.
    Rubino F, Forgione A, Cummings DE, Vix M, Gnuli D, Mingrone G, 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;244:741–9.CrossRefPubMedCentralPubMedGoogle Scholar
  57. 57.
    Woods M, Lan Z, Li J, Wheeler MB, Wang H, Wang R. Antidiabetic effects of duodenojejunal bypass in an experimental model of diabetes induced by a high-fat diet. Br J Surg. 2011;98:686–96.CrossRefPubMedGoogle Scholar
  58. 58.
    Salinari S, Bertuzzi A, Asnaghi S, Guidone C, Manco M, Mingrone G. First-phase insulin secretion restoration and differential response to glucose load depending on the route of administration in type 2 diabetic subjects after bariatric surgery. Diabetes Care. 2009;32:375–80.CrossRefPubMedCentralPubMedGoogle Scholar
  59. 59.
    Villanueva-Penacarrillo ML, Marquez L, Gonzalez N, Diaz-Miguel M, Valverde I. Effect of GLP-1 on lipid metabolism in human adipocytes. Horm Metab Res. 2001;33:73–7.CrossRefPubMedGoogle Scholar
  60. 60.
    MacAulay K, Doble BW, Patel S, Hansotia T, Sinclair EM, Drucker DJ, et al. Glycogen synthase kinase 3alpha-specific regulation of murine hepatic glycogen metabolism. Cell Metab. 2007;6:329–37.CrossRefPubMedGoogle Scholar
  61. 61.
    Kaidanovich-Beilin O, Eldar-Finkelman H. Long-term treatment with novel glycogen synthase kinase-3 inhibitor improves glucose homeostasis in ob/ob mice: molecular characterization in liver and muscle. J Pharmacol Exp Ther. 2006;316:17–24.CrossRefPubMedGoogle Scholar
  62. 62.
    Rao R, Hao CM, Redha R, Wasserman DH, McGuinness OP, Breyer MD. Glycogen synthase kinase 3 inhibition improves insulin-stimulated glucose metabolism but not hypertension in high-fat-fed C57BL/6J mice. Diabetologia. 2007;50:452–60.CrossRefPubMedGoogle Scholar
  63. 63.
    Lochhead PA, Coghlan M, Rice SQ, Sutherland C. Inhibition of GSK-3 selectively reduces glucose-6-phosphatase and phosphatase and phosphoenolypyruvate carboxykinase gene expression. Diabetes. 2001;50:937–46.CrossRefPubMedGoogle Scholar
  64. 64.
    Scomparin DX, Gomes RM, Grassiolli S, Rinaldi W, Martins AG, de Oliveira JC, et al. Autonomic activity and glycemic homeostasis are maintained by precocious and low intensity training exercises in MSG-programmed obese mice. Endocrine. 2009;36:510–7.CrossRefPubMedGoogle Scholar
  65. 65.
    Balbo SL, Bonfleur ML, Carneiro EM, Amaral ME, Filiputti E, Mathias PC. Parasympathetic activity changes insulin response to glucose and neurotransmitters. Diabetes Metab. 2002;28:3S13–17. discussion 13S108-112.PubMedGoogle Scholar
  66. 66.
    Mari A, Manco M, Guidone C, Nanni G, Castagneto M, Mingrone G, et al. Restoration of normal glucose tolerance in severely obese patients after bilio-pancreatic diversion: role of insulin sensitivity and beta cell function. Diabetologia. 2006;49:2136–43.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Maria Lúcia Bonfleur
    • 1
  • Rosane Aparecida Ribeiro
    • 2
  • Audrei Pavanello
    • 1
  • Raul Soster
    • 1
  • Camila Lubaczeuski
    • 1
  • Allan Cezar Faria Araujo
    • 3
  • Antonio Carlos Boschero
    • 4
  • Sandra Lucinei Balbo
    • 1
  1. 1.Laboratório de Fisiologia Endócrina e Metabolismo, Centro de Ciências Biológicas e da SaúdeUniversidade Estadual do Oeste do Paraná (UNIOESTE)CascavelBrazil
  2. 2.Universidade Federal do Rio de Janeiro, Campus UFRJ-MacaéMacaéBrazil
  3. 3.Centro de Ciências Médicas e FarmacêuticasUNIOESTECascavelBrazil
  4. 4.Laboratório de Pâncreas Endócrino e Metabolismo, Departamento de Biologia Estrutural e Funcional, Instituto de BiologiaUniversidade Estadual de Campinas (UNICAMP)CampinasBrazil

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