Effect of metformin and pioglitazone on β-catenin and biochemical markers in sitagliptin-induced pancreatitis in diabetic rats

Abstract

This study was designed to investigate effect of metformin or pioglitazone on β-catenin and biochemical indicators in sitagliptin-induced pancreatitis. Type 2 diabetes mellitus was induced by high-fat diet/low-dose streptozotocin. Six groups (n = 8) were used: diabetic control group and five treated groups given, for 6 weeks by oral gavage, metformin (100 mg/kg/day), pioglitazone (20 mg/kg/day), sitagliptin (30 mg/kg/day), metformin + sitagliptin (MS), and pioglitazone + sitagliptin (PS). Body weight (BW) and biochemical parameters (fasting blood sugar (FBS), glycated hemoglobin (HbA1c), insulin, total cholesterol (TC), triglycerides (TG), malondialdehyde (MDA), and amylase) were measured. Pancreatic sections were examined using hematoxylin and eosin staining and immunohistochemical staining for β-catenin protein. Only pioglitazone significantly increased BW. All treatments significantly decreased FBS, HbA1c, TC, TG, MDA, and amylase minimally with sitagliptin and maximally with combination therapies. Moreover, all treatments significantly increased insulin except pioglitazone which showed a nonsignificant decrease. Both metformin and pioglitazone ameliorated the diabetic-induced changes while sitagliptin-treated rats showed signs suggestive of pancreatitis. Sitagliptin failed to inhibit the inappropriately increased β-catenin expression predisposing for pancreatitis but helping regenerate streptozotocin-damaged islets. Metformin and pioglitazone alone or combined with sitagliptin decreased the inappropriate β-catenin expression. In conclusion, the decrease in β-catenin seems to be involved in reversal of sitagliptin-associated pancreatitis by metformin or pioglitazone. The better regeneration of islets with metformin and pioglitazone, than sitagliptin, may be due to better effectiveness in controlling diabetes. Sitagliptin should be used in combination with metformin or pioglitazone. Further studies are needed to determine mechanisms underlying role of Wnt/β-catenin in regeneration of islets and exocrine pancreas.

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References

  1. 1.

    Abe M, Okada K, Soma M. Antidiabetic agents in patients with chronic kidney disease and end-stage renal disease on dialysis: metabolism and clinical practice. Curr Drug Metab. 2011;12:57–69.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Pala L, Pezzatini A, Dicembrini I, Ciani S, Gelmini S, Vannelli BG, et al. Different modulation of dipeptidyl peptidase-4 activity between microvascular and macrovascular human endothelial cells. Acta Diabetol. 2010;49 Suppl 1:59–63.

    Google Scholar 

  3. 3.

    Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci. 2012;122:253–70.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  4. 4.

    Larsen PJ, Wulff EM, Gotfredsen CF, Brand CL, Sturis J, Vrang N, et al. Combination of the insulin sensitizer, pioglitazone, and the long-acting GLP-1 human analog, liraglutide, exerts potent synergistic glucose-lowering efficacy in severely diabetic ZDF rats. Diabetes Obes Metab. 2008;10:301–11.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Olansky L. Q: Do incretin drugs for type 2 diabetes increase the risk of acute pancreatitis? Cleve Clin J Med. 2010;77:503–5.

    Article  PubMed  Google Scholar 

  6. 6.

    Matveyenko AV, Dry S, Cox HI, Moshtaghian A, Gurlo T, Galasso R, et al. Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: interactions with metformin. Diabetes. 2009;58:1604–15.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  7. 7.

    Reddy RC, Hao Y, Lee SH, Gangireddy SR, Owyang C, DiMagno MJ. Pioglitazone reverses insulin resistance and impaired CCK-stimulated pancreatic secretion in eNOS(-/-) mice: therapy for exocrine pancreatic disorders? Am J Physiol Gastrointest Liver Physiol. 2007;293:G112–20.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Elghazi L, Gould AP, Weiss AJ, Barker DJ, Callaghan J, Opland D, et al. Importance of β-catenin in glucose and energy homeostasis. Sci Rep. 2012;2:693.

    PubMed Central  Article  PubMed  Google Scholar 

  9. 9.

    Welters HJ, Kulkarni RN. Wnt signaling: relevance to beta-cell biology and diabetes. Trends Endocrinol Metab. 2008;19:349–55.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Keefe MD, Wang H, De La OJP, Khan A, Firpo MA. Murtaugh LC β-catenin is selectively required for the expansion and regeneration of mature pancreatic acinar cells in mice. Dis Model Mech. 2012;5:503–14.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  11. 11.

    Srinivasan K, Viswanad B, Asrat L, Kaul CL, Ramarao P. Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacol Res. 2005;52:313–20.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Tatarkiewicz K, Smith PA, Sablan EJ, Polizzi CJ, Aumann DE, Villescaz C, et al. Exenatide does not evoke pancreatitis and attenuates chemically induced pancreatitis in normal and diabetic rodents. Am J Physiol Endocrinol Metab. 2010;299:E1076–86.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  13. 13.

    Sun X, Han F, Yi J, Han L, Wang B. Effect of aspirin on the expression of hepatocyte NF-κB and serum TNF-α in streptozotocin-induced type 2 diabetic rats. J Korean Med Sci. 2011;26:765–70.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  14. 14.

    Ding SY, Shen ZF, Chen YT, Sun SJ, Liu Q, Xie MZ. Pioglitazone can ameliorate insulin resistance in low-dose streptozotocin and high sucrose-fat diet induced obese rats. Acta Pharmacol Sin. 2005;26:575–80.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Chen B, Moore A, Escobedo LV, Koletsky MS, Hou D, Koletsky RJ, et al. Sitagliptin lowers glucagon and improves glucose tolerance in prediabetic obese SHROB rats. Exp Biol Med. 2011;236:309–14.

    CAS  Article  Google Scholar 

  16. 16.

    Ferreira L, Teixeira-de-Lemos E, Pinto F, Parada B, Mega C, Vala H, et al. Effects of sitagliptin treatment on dysmetabolism, inflammation, and oxidative stress in an animal model of type 2 diabetes (ZDF Rat). Med Inflam. 2010; Article ID 592760, 11 pages

  17. 17.

    Wang Q-M, Zhang Y, Yang K-M, Zhou H-Y, Yang H-J. Wnt/β-catenin signaling pathway is active in pancreatic development of rat embryo. World J Gastroenterol. 2006;12:2615–19.

    PubMed Central  CAS  PubMed  Google Scholar 

  18. 18.

    Mu J, Petrov A, Eiermann GJ, Woods J, Zhou YP, Li Z, et al. Inhibition of DPP-4 with sitagliptin improves glycemic control and restores islet cell mass and function in a rodent model of type 2 diabetes. Eur J Pharmacol. 2009;623:148–54.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Mega C, de Lemos ET, Vala H, Fernandes R, Oliveira J, Mascarenhas-Melo F, et al. Diabetic nephropathy amelioration by a low-dose sitagliptin in an animal model of type 2 diabetes (Zucker diabetic fatty rat). Exp Diab Res. 2011; Article ID 162092, 12 pages

  20. 20.

    Reimer RA, Grover GJ, Koetzner L, Gahler RJ, Juneja P, Lyon MR, et al. Sitagliptin reduces hyperglycemia and increases satiety hormone secretion more effectively when used with a novel polysaccharide in obese Zucker rats. J Nutr. 2012;142:1812–20.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  21. 21.

    Yeom JA, Kim ES, Park HS, Ham DS, Sun C, Kim JW, et al. Both sitagliptin analogue & pioglitazone preserve the beta-cell proportion in the islets with different mechanism in non-obese and obese diabetic mice. BMB Rep. 2011;44:713–8.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Sartori DRS, Kawakami CL, Orsatti CL, Sforcin JM. Propolis effect on streptozotocin-induced diabetic rats. J Venom Anim Toxins incl Trop Dis. 2009;15:93–102.

    CAS  Article  Google Scholar 

  23. 23.

    Mayer J, Rau B, Gansauge F, Beger HG. Inflammatory mediators in human acute pancreatitis: clinical and pathophysiological implications. Gut. 2000;47:546–52.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  24. 24.

    Di Sebastiano P, di Mola FF, Di Febbo C, Baccante G, Porreca E, Innocenti P, et al. Expression of interleukin 8 (IL-8) and substance P in human chronic pancreatitis. Gut. 2000;47:423–8.

    Article  PubMed  Google Scholar 

  25. 25.

    Butler PC, Matveyenko AV, Dry S, Bhushan A, Elashoff R. Glucagon-like peptide-1 therapy and the exocrine pancreas: innocent bystander or friendly fire? Diabetologia. 2010;53:1–6.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  26. 26.

    Reichert M. Rustgi AK pancreatic ductal cells in development, regeneration, and neoplasia. J Clin Invest. 2011;121:4572–8.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  27. 27.

    Scotti ML, Smith KE, Butler AM, Calcagno SR, Crawford HC, Leitges M, et al. Protein kinase C iota regulates pancreatic acinar-to-ductal metaplasia. PLoS ONE. 2012;7:e30509.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  28. 28.

    Konturek PC, Dembinski A, Warzecha Z, Burnat G, Ceranowicz P, Hahn EG, et al. Pioglitazone, a specific ligand of peroxisome proliferator-activated receptor-gamma, protects pancreas against acute cerulein-induced pancreatitis. World J Gastroenterol. 2005;28(11):6322–9.

    Article  Google Scholar 

  29. 29.

    Xu G, Kaneto H, Lopez-Avalos MD, Weir GC, Bonner-Weir S. GLP-1/exendin-4 facilitates beta-cell neogenesis in rat and human pancreatic ducts. Diabetes Res Clin Pract. 2006;73:107–10.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Kanda Y, Shimoda M, Hamamoto S, Tawaramoto K, Kawasaki F, Hashiramoto M, et al. Molecular mechanism by which pioglitazone preserves pancreatic beta-cells in obese diabetic mice: evidence for acute and chronic actions as a PPARgamma agonist. Am J Physiol Endocrinol Metab. 2010;298:E278–86.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  31. 31.

    Chiang YT, Ip W, Jin T. The role of the Wnt signaling pathway in incretin hormone production and function. Front Physiol. 2012;3:273.

    PubMed Central  Article  PubMed  Google Scholar 

  32. 32.

    Portha B, Tourrel-Cuzin C, Movassat J. Activation of the GLP-1 receptor signalling pathway: a relevant strategy to repair a deficient beta-cell mass. Exp Diabetes Res. 2011:376509

  33. 33.

    Liu Z, Habener JF. Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic beta cell proliferation. J Biol Chem. 2008;283:8723–35.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  34. 34.

    Lenhard JM, Croom DK, Minnick DT. Reduced serum dipeptidyl peptidase-IV after metformin and pioglitazone treatments. Biochem Biophys Res Commun. 2004;5(324):92–7.

    Article  Google Scholar 

  35. 35.

    Kim M-H, Lee M-S, Kim K-W, Hur KY, Kim JH, Lee MK. Metfomin stimulates glucagon-like peptide (GLP-1) synthesis and secretion via Wnt signaling. 2010; 278.

  36. 36.

    Heller C, Kühn MC, Mülders-Opgenoorth B, Schott M, Willenberg HS, Scherbaum WA, et al. Exendin-4 upregulates the expression of Wnt-4, a novel regulator of pancreatic β-cell proliferation. Am J Physiol Endocrinol Metab. 2011;301:E864–72.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Hammarstedt A, Isakson P, Gustafson B, Smith U. Wnt-signaling is maintained and adipogenesis inhibited by TNFalpha but not MCP-1 and resistin. Biochem Biophys Res Commun. 2007;357:700–6.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Takatani T, Minagawa M, Takatani R, Kinoshita K, Kohno Y. AMP-activated protein kinase attenuates Wnt/β-catenin signaling in human osteoblastic Saos-2 cells. Mol Cell Endocrinol. 2011;339:114–9.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Siveke JT, Lubeseder-Martellato C, Lee M, Mazur PK, Nakhai H, Radtke F, et al. Notch signaling is required for exocrine regeneration after acute pancreatitis. Gastroenterology. 2008;134:544–55.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Figeac F, Uzan B, Faro M, Chelali N, Portha B, Movassat J. Neonatal growth and regeneration of beta-cells are regulated by the Wnt/beta-catenin signaling in normal and diabetic rats. Am J Physiol Endocrinol Metab. 2010;298:E245–56.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Dessimoz J, Bonnard C, Huelsken J, Grapin-Botton A. Pancreas-specific deletion of beta-catenin reveals Wnt-dependent and Wnt-independent functions during development. Curr Biol. 2005;15:1677–83.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Chocarro-Calvo A, García-Martínez JM, Ardila-González S, De la Vieja A, García-Jiménez C. Glucose-induced β-catenin acetylation enhances Wnt signaling in cancer. Mol Cell. 2012;49:474–86.

    Article  PubMed  Google Scholar 

  43. 43.

    Shimasaki T, Kitano A, Motoo Y, Minamoto T. Aberrant glycogen synthase kinase 3β in the development of pancreatic cancer. J Carcinog. 2012;11:15.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  44. 44.

    Abiola M, Favier M, Christodoulou-Vafeiadou E, Pichard AL, Martelly I, Guillet-Deniau I. Activation of Wnt/beta-catenin signaling increases insulin sensitivity through a reciprocal regulation of Wnt10b and SREBP-1c in skeletal muscle cells. PLoS One. 2009;4(12):e8509.

    PubMed Central  Article  PubMed  Google Scholar 

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Acknowledgments

This project was funded by the Deanship of Scientific Research (DSR), King Abdulaziz University (KAU), Jeddah, under grant number 195/828/1432. The authors, therefore, acknowledge with thanks DSR technical and financial support.

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Correspondence to Hussam A. S. Murad.

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Murad, H.A.S., Saleh, H.A., Abdulaziz, G.S. et al. Effect of metformin and pioglitazone on β-catenin and biochemical markers in sitagliptin-induced pancreatitis in diabetic rats. Int J Diabetes Dev Ctries 35, 332–339 (2015). https://doi.org/10.1007/s13410-014-0278-8

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Keywords

  • Metformin
  • Pancreatitis
  • Pioglitazone
  • Sitagliptin
  • Wnt/β-catenin pathway