The Korean journal of internal medicine

  • 제32권2호
  • /
  • Pages.314-322
  • /
  • 2017
  • /
  • 1226-3303(pISSN)
  • /
  • 2005-6648(eISSN)
대한내과학회 (The Korean Association of Internal Medicine)
권호 표지
DOI QR코드

DOI QR Code

Effects of metformin on hyperglycemia in an experimental model of tacrolimus- and sirolimus-induced diabetic rats

  • Jin, Jian (Transplant Research Center, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea) ;
  • Lim, Sun Woo (Transplant Research Center, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea) ;
  • Jin, Long (Transplant Research Center, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea) ;
  • Yu, Ji Hyun (Transplant Research Center, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea) ;
  • Kim, Hyun Seon (Transplant Research Center, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea) ;
  • Chung, Byung Ha (Convergent Research Consortium for Immunologic Disease, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea) ;
  • Yang, Chul Woo (Transplant Research Center, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea)
  • 투고 : 2015.12.08
  • 심사 : 2016.02.09
  • 발행 : 2017.03.01
⟨ 이전 논문 다음 논문 ⟩

초록

Background/Aims: Metformin (MET) is a first-line drug for type 2 diabetes mellitus (DM); its effect on new-onset diabetes after transplantation caused by immunosuppressant therapy is unclear. We compared the effects of MET on DM caused by tacrolimus (TAC) or sirolimus (SRL). Methods: DM was induced by injection of TAC (1.5 mg/kg) or SRL (0.3 mg/kg) for 2 weeks in rats, and MET (200 mg/kg) was injected for 2 more weeks. The effects of MET on DM caused by TAC or SRL were evaluated using an intraperitoneal glucose tolerance test (IPGTT) and by measuring plasma insulin concentration, islet size, and glucose-stimulated insulin secretion (GSIS). The effects of MET on the expression of adenosine monophosphate-activated protein kinase (AMPK), a pharmacological target of MET, were compared between TAC- and SRL-treated islets. Results: IPGTT showed that both TAC and SRL induced hyperglycemia and reduced plasma insulin concentration compared with vehicle. These changes were reversed by addition of MET to SRL but not to TAC. Pancreatic islet cell size was decreased by TAC but not by SRL, but addition of MET did not affect pancreatic islet cell size in either group. MET significantly increased GSIS in SRL- but not in TAC-treated rats. AMPK expression was not affected by TAC but was significantly decreased in SRL-treated islets. Addition of MET restored AMPK expression in SRL-treated islets but not in TAC-treated islets. Conclusions: MET has different effects on hyperglycemia caused by TAC and SRL. The discrepancy between these drugs is related to their different mechanisms causing DM.

키워드

과제정보

연구 과제 주관 기관 : Ministry for Health and Welfare

참고문헌

  1. Hjelmesaeth J, Flyvbjerg A, Jenssen T, et al. Hypoadiponectinemia is associated with insulin resistance and glucose intolerance after renal transplantation: impact of immunosuppressive and antihypertensive drug therapy. Clin J Am Soc Nephrol 2006;1:575-582. https://doi.org/10.2215/CJN.01471005
  2. Bee YM, Tan HC, Tay TL, Kee TY, Goh SY, Kek PC. Incidence and risk factors for development of new-onset diabetes after kidney transplantation. Ann Acad Med Singapore 2011;40:160-167.
  3. Cosio FG, Pesavento TE, Kim S, Osei K, Henry M, Ferguson RM. Patient survival after renal transplantation: IV. Impact of post-transplant diabetes. Kidney Int 2002;62:1440-1446. https://doi.org/10.1111/j.1523-1755.2002.kid582.x
  4. Luan FL, Steffick DE, Ojo AO. New-onset diabetes mellitus in kidney transplant recipients discharged on steroid-free immunosuppression. Transplantation 2011;91:334-341. https://doi.org/10.1097/TP.0b013e318203c25f
  5. Rodrigo E, Fernandez-Fresnedo G, Valero R, et al. New-onset diabetes after kidney transplantation: risk factors. J Am Soc Nephrol 2006;17(12 Suppl 3):S291-S295. https://doi.org/10.1681/ASN.2006080929
  6. Montori VM, Basu A, Erwin PJ, Velosa JA, Gabriel SE, Kudva YC. Posttransplantation diabetes: a systematic review of the literature. Diabetes Care 2002;25:583-592. https://doi.org/10.2337/diacare.25.3.583
  7. Israni AK, Zaun D, Rosendale JD, Snyder JJ, Kasiske BL. OPTN/SRTR 2012 annual data report: deceased organ donation. Am J Transplant 2014;14 Suppl 1:167-183. https://doi.org/10.1111/ajt.12585
  8. Larson TS, Dean PG, Stegall MD, et al. Complete avoidance of calcineurin inhibitors in renal transplantation: a randomized trial comparing sirolimus and tacrolimus. Am J Transplant 2006;6:514-522. https://doi.org/10.1111/j.1600-6143.2005.01177.x
  9. Wullschleger S, Loewith R, Oppliger W, Hall MN. Molecular organization of target of rapamycin complex 2. J Biol Chem 2005;280:30697-30704. https://doi.org/10.1074/jbc.M505553200
  10. Johnston O, Rose CL, Webster AC, Gill JS. Sirolimus is associated with new-onset diabetes in kidney transplant recipients. J Am Soc Nephrol 2008;19:1411-1418. https://doi.org/10.1681/ASN.2007111202
  11. Yang SB, Tien AC, Boddupalli G, Xu AW, Jan YN, Jan LY. Rapamycin ameliorates age-dependent obesity associated with increased mTOR signaling in hypothalamic POMC neurons. Neuron 2012;75:425-436. https://doi.org/10.1016/j.neuron.2012.03.043
  12. Ratner RE, Maggs D, Nielsen LL, et al. Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with type 2 diabetes mellitus. Diabetes Obes Metab 2006;8:419-428. https://doi.org/10.1111/j.1463-1326.2006.00589.x
  13. Sharif A, Baboolal K. Complications associated with new-onset diabetes after kidney transplantation. Nat Rev Nephrol 2012;8:34-42. https://doi.org/10.1038/nrneph.2011.174
  14. Kurian B, Joshi R, Helmuth A. Effectiveness and longterm safety of thiazolidinediones and metformin in renal transplant recipients. Endocr Pract 2008;14:979-984. https://doi.org/10.4158/EP.14.8.979
  15. Hwang H, Ghee JY, Song JH, Piao S, Yang CW. Comparison of adverse drug reaction profiles of two tacrolimus formulations in rats. Immunopharmacol Immunotoxicol 2012;34:434-442. https://doi.org/10.3109/08923973.2011.618135
  16. Song HK, Han DH, Song JH, et al. Influence of sirolimus on cyclosporine-induced pancreas islet dysfunction in rats. Am J Transplant 2009;9:2024-2033. https://doi.org/10.1111/j.1600-6143.2009.02751.x
  17. Cheng JT, Huang CC, Liu IM, Tzeng TF, Chang CJ. Novel mechanism for plasma glucose-lowering action of metformin in streptozotocin-induced diabetic rats. Diabetes 2006;55:819-825. https://doi.org/10.2337/diabetes.55.03.06.db05-0934
  18. Shivaswamy V, Bennett RG, Clure CC, Larsen JL, Hamel FG. Metformin improves immunosuppressant induced hyperglycemia and exocrine apoptosis in rats. Transplantation 2013;95:280-284. https://doi.org/10.1097/TP.0b013e318275a322
  19. Choi YH, Kim SG, Lee MG. Dose-independent pharmacokinetics of metformin in rats: hepatic and gastrointestinal first-pass effects. J Pharm Sci 2006;95:2543-2552. https://doi.org/10.1002/jps.20744
  20. Quaile MP, Melich DH, Jordan HL, et al. Toxicity and toxicokinetics of metformin in rats. Toxicol Appl Pharmacol 2010;243:340-347. https://doi.org/10.1016/j.taap.2009.11.026
  21. Jin L, Lim SW, Doh KC, et al. Dipeptidyl peptidase IV inhibitor MK-0626 attenuates pancreatic islet injury in tacrolimus-induced diabetic rats. PLoS One 2014;9:e100798. https://doi.org/10.1371/journal.pone.0100798
  22. Lim SW, Jin L, Piao SG, Chung BH, Yang CW. Inhibition of dipeptidyl peptidase IV protects tacrolimus-induced kidney injury. Lab Invest 2015;95:1174-1185. https://doi.org/10.1038/labinvest.2015.93
  23. Piao SG, Bae SK, Lim SW, et al. Drug interaction between cyclosporine and mTOR inhibitors in experimental model of chronic cyclosporine nephrotoxicity and pancreatic islet dysfunction. Transplantation 2012;93:383-389. https://doi.org/10.1097/TP.0b013e3182421604
  24. Shivaswamy V, Bennett RG, Clure CC, et al. Tacrolimus and sirolimus have distinct effects on insulin signaling in male and female rats. Transl Res 2014;163:221-231. https://doi.org/10.1016/j.trsl.2013.12.002
  25. Pernicova I, Korbonits M. Metformin: mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol 2014;10:143-156. https://doi.org/10.1038/nrendo.2013.256
  26. Akkan AG, Malaisse WJ. Insulinotropic action of AICA riboside. I. Insulin release by isolated islets and the perfused pancreas. Diabetes Res 1994;25:13-23.
  27. Leclerc I, Viollet B, da Silva Xavier G, Kahn A, Rutter GA. Role of AMP-activated protein kinase in the regulation of gene transcription. Biochem Soc Trans 2002;30:307-311. https://doi.org/10.1042/bst0300307
  28. Saeedi R, Parsons HL, Wambolt RB, et al. Metabolic actions of metformin in the heart can occur by AMPK-independent mechanisms. Am J Physiol Heart Circ Physiol 2008;294:H2497-H2506. https://doi.org/10.1152/ajpheart.00873.2007
  29. Lim SW, Jin JZ, Jin L, Jin J, Li C. Role of dipeptidyl peptidase-4 inhibitors in new-onset diabetes after transplantation. Korean J Intern Med 2015;30:759-770. https://doi.org/10.3904/kjim.2015.30.6.759
  30. Jeong YK, Kim MS, Lee JY, Kim EH, Ha H. Metformin radiosensitizes p53-deficient colorectal cancer cells through induction of G2/M arrest and inhibition of DNA repair proteins. PLoS One 2015;10:e0143596. https://doi.org/10.1371/journal.pone.0143596
  31. Jang EK, Kim WG, Kwon H, et al. Metformin is associated with a favorable outcome in diabetic patients with cervical lymph node metastasis of differentiated thyroid cancer. Eur Thyroid J 2015;4:181-188. https://doi.org/10.1159/000437365

피인용 문헌

  1. Ginseng extract reduces tacrolimus-induced oxidative stress by modulating autophagy in pancreatic beta cells vol.97, pp.11, 2017, https://doi.org/10.1038/labinvest.2017.75
  2. Effect of Empagliflozin on Tacrolimus‐Induced Pancreas Islet Dysfunction and Renal Injury vol.17, pp.10, 2017, https://doi.org/10.1111/ajt.14316
  3. Therapeutic potential of coenzyme Q 10 in mitochondrial dysfunction during tacrolimus-induced beta cell injury vol.9, pp.None, 2019, https://doi.org/10.1038/s41598-019-44475-x
  4. The effects of addition of coenzyme Q10 to metformin on sirolimus-induced diabetes mellitus vol.34, pp.2, 2019, https://doi.org/10.3904/kjim.2017.004
  5. Influence of Tacrolimus on Depressive-Like Behavior in Diabetic Rats Through Brain-Derived Neurotrophic Factor Regulation in the Hippocampus vol.36, pp.2, 2017, https://doi.org/10.1007/s12640-019-00062-6
  6. Shen-Kang protects against tacrolimus-induced renal injury vol.34, pp.5, 2017, https://doi.org/10.3904/kjim.2017.276
  7. FXR activation alleviates tacrolimus-induced post-transplant diabetes mellitus by regulating renal gluconeogenesis and glucose uptake vol.17, pp.1, 2017, https://doi.org/10.1186/s12967-019-02170-5
  8. Diabetes Mellitus and Osteoporosis Correlation: Challenges and Hopes vol.16, pp.None, 2017, https://doi.org/10.2174/1573399816666200324152517
  9. The safety, immunological benefits, and efficacy of ginseng in organ transplantation vol.44, pp.3, 2017, https://doi.org/10.1016/j.jgr.2020.02.001
  10. The therapeutic efficacy of water-soluble coenzyme Q10 in an experimental model of tacrolimus-induced diabetes mellitus vol.35, pp.6, 2017, https://doi.org/10.3904/kjim.2019.269
  11. Novel complementary coloprotective effects of metformin and MCC950 by modulating HSP90/NLRP3 interaction and inducing autophagy in rats vol.29, pp.1, 2017, https://doi.org/10.1007/s10787-020-00730-6
  12. Vitamin D3 potentiates the nephroprotective effects of metformin in a rat model of metabolic syndrome: role of AMPK/SIRT1 activation and DPP-4 inhibition vol.99, pp.6, 2017, https://doi.org/10.1139/cjpp-2020-0435
  13. Tacrolimus Decreases Cognitive Function by Impairing Hippocampal Synaptic Balance: a Possible Role of Klotho vol.58, pp.11, 2017, https://doi.org/10.1007/s12035-021-02499-3