The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지
DOI QR코드

DOI QR Code

Chronic Alcohol Consumption Results in Greater Damage to the Pancreas Than to the Liver in the Rats

  • Lee, Seong-Su (Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Bucheon St. Mary’s Hospital, The Catholic University of Korea) ;
  • Hong, Oak-Kee (Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Bucheon St. Mary’s Hospital, The Catholic University of Korea) ;
  • Ju, Anes (Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Gottingen, Germany DFG Center for Nanoscale Microscopy & Molecular Physiology of the Brain (CNMPB)) ;
  • Kim, Myung-Jun (Department of Physiology, College of Medicine, The Catholic University of Korea) ;
  • Kim, Bong-Jo (Division of Structural and Functional Genomics, Center for Genome Science, National Institute of Health) ;
  • Kim, Sung-Rae (Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Bucheon St. Mary’s Hospital, The Catholic University of Korea) ;
  • Kim, Won-Ho (Division of Metabolic Disease, Center for Biomedical Sicence, National Institutes of Health) ;
  • Cho, Nam-Han (Department in Preventive Medicine, Ajou University School of Medicine) ;
  • Kang, Moo-Il (Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea) ;
  • Kang, Sung-Koo (Division of Endocrinology and Metabolism, Department of Internal Medicine, Soonchunhyang University College of Medicine) ;
  • Kim, Dai-Jin (Department of Psychiatry, College of Medicine, The Catholic University of Korea) ;
  • Yoo, Soon-Jib (Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Bucheon St. Mary’s Hospital, The Catholic University of Korea)
  • Received : 2015.01.07
  • Accepted : 2015.05.06
  • Published : 2015.07.01
Download PDF
⟨ Previous Next ⟩

Abstract

Alcohol consumption increases the risk of type 2 diabetes. However, its effects on prediabetes or early diabetes have not been studied. We investigated endoplasmic reticulum (ER) stress in the pancreas and liver resulting from chronic alcohol consumption in the prediabetes and early stages of diabetes. We separated Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a type-2 diabetic animal model, into two groups based on diabetic stage: prediabetes and early diabetes were defined as occurrence between the ages of 11 to 16 weeks and 17 to 22 weeks, respectively. The experimental group received an ethanol-containing liquid diet for 6 weeks. An intraperitoneal glucose tolerance test was conducted after 16 and 22 weeks for the prediabetic and early diabetes groups, respectively. There were no significant differences in body weight between the control and ethanol groups. Fasting and 120-min glucose levels were lower and higher, respectively, in the ethanol group than in the control group. In prediabetes rats, alcohol induced significant expression of ER stress markers in the pancreas; however, alcohol did not affect the liver. In early diabetes rats, alcohol significantly increased most ER stress-marker levels in both the pancreas and liver. These results indicate that chronic alcohol consumption increased the risk of diabetes in prediabetic and early diabetic OLETF rats; the pancreas was more susceptible to damage than was the liver in the early diabetic stages, and the adaptive and proapoptotic pathway of ER stress may play key roles in the development and progression of diabetes affected by chronic alcohol ingestion.

Keywords

References

  1. Research Society on Alcoholism. Impact of Alcoholism and Alcohol Induced Disease on America. In: Alcoholism RSo, editor. Research Society on Alcoholism: Research Society on Alcoholism; 2011. p.1-6.
  2. World Health Organization. Global strategy to reduce the harmful use of alcohol. [Accessed May 21 2010] Available from: http://www.who.int/substance_abuse/activities/gsrhua/en/
  3. Wechsler H, Lee JE, Kuo M, Seibring M, Nelson TF, Lee H. Trends in college binge drinking during a period of increased prevention efforts. Findings from 4 Harvard School of Public Health College Alcohol Study surveys: 1993-2001. J Am Coll Health. 2002;50:203-217. https://doi.org/10.1080/07448480209595713
  4. Chung SS, Joung KH. Risk factors of heavy episodic drinking among Korean adolescents. J Psychiatr Ment Health Nurs. 2013;20:665-671. https://doi.org/10.1111/j.1365-2850.2012.01954.x
  5. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgon C, Glimcher LH, Hotamisligil GS. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004;306:457-461. https://doi.org/10.1126/science.1103160
  6. Ji C. Mechanisms of alcohol-induced endoplasmic reticulum stress and organ injuries. Biochem Res Int. 2012;2012:216450.
  7. Marciniak SJ, Ron D. Endoplasmic reticulum stress signaling in disease. Physiol Rev. 2006;86:1133-1149. https://doi.org/10.1152/physrev.00015.2006
  8. Bernales S, Papa FR, Walter P. Intracellular signaling by the unfolded protein response. Annu Rev Cell Dev Biol. 2006;22:487-508. https://doi.org/10.1146/annurev.cellbio.21.122303.120200
  9. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8:519-529. https://doi.org/10.1038/nrm2199
  10. Zhang K, Kaufman RJ. From endoplasmic-reticulum stress to the inflammatory response. Nature. 2008;454:455-462. https://doi.org/10.1038/nature07203
  11. Minamino T, Komuro I, Kitakaze M. Endoplasmic reticulum stress as a therapeutic target in cardiovascular disease. Circ Res. 2010;107:1071-1082. https://doi.org/10.1161/CIRCRESAHA.110.227819
  12. Hendershot LM. The ER function BiP is a master regulator of ER function. Mt Sinai J Med. 2004;71:289-297.
  13. Ron D. Translational control in the endoplasmic reticulum stress response. J Clin Invest. 2002;110:1383-1388. https://doi.org/10.1172/JCI0216784
  14. Rasheva VI, Domingos PM. Cellular responses to endoplasmic reticulum stress and apoptosis. Apoptosis. 2009;14:996-1007. https://doi.org/10.1007/s10495-009-0341-y
  15. Xu C, Bailly-Maitre B, Reed JC. Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest. 2005;115:2656-2664. https://doi.org/10.1172/JCI26373
  16. Kawano K, Hirashima T, Mori S, Natori T. OLETF (Otsuka Long-Evans Tokushima Fatty) rat: a new NIDDM rat strain. Diabetes Res Clin Pract. 1994;24 Suppl:S317-320. https://doi.org/10.1016/0168-8227(94)90269-0
  17. Moran TH, Katz LF, Plata-Salaman CR, Schwartz GJ. Disordered food intake and obesity in rats lacking cholecystokinin A receptors. Am J Physiol. 1998;274:R618-625.
  18. Seo E, Park EJ, Park MK, Kim DK, Lee HJ, Hong SH. Differential expression of metabolism-related genes in liver of diabetic obese rats. Korean J Physiol Pharmacol. 2010;14:99-103. https://doi.org/10.4196/kjpp.2010.14.2.99
  19. Kloner RA, Rezkalla SH. To drink or not to drink? That is the question. Circulation. 2007;116:1306-1317. https://doi.org/10.1161/CIRCULATIONAHA.106.678375
  20. Grauvogel J, Daemmrich TD, Ryschich E, Gebhard MM, Werner J. Chronic alcohol intake increases the severity of pancreatitis induced by acute alcohol administration, hyperlipidemia and pancreatic duct obstruction in rats. Pancreatology. 2010;10:603-612. https://doi.org/10.1159/000288707
  21. de la M Hall P, Lieber CS, DeCarli LM, French SW, Lindros KO, Jarvelainen H, Bode C, Parlesak A, Bode JC. Models of alcoholic liver disease in rodents: a critical evaluation. Alcohol Clin Exp Res. 2001;25(5 Suppl ISBRA):254S-261S. https://doi.org/10.1111/j.1530-0277.2001.tb02405.x
  22. Baliunas DO, Taylor BJ, Irving H, Roerecke M, Patra J, Mohapatra S, Rehm J. Alcohol as a risk factor for type 2 diabetes: A systematic review and meta-analysis. Diabetes Care. 2009;32:2123-2132. https://doi.org/10.2337/dc09-0227
  23. Lieber CS, DeCarli LM. The feeding of alcohol in liquid diets: two decades of applications and 1982 update. Alcohol Clin Exp Res. 1982;6:523-531. https://doi.org/10.1111/j.1530-0277.1982.tb05017.x
  24. Lieber CS, DeCarli LM, Sorrell MF. Experimental methods of ethanol administration. Hepatology. 1989;10:501-510. https://doi.org/10.1002/hep.1840100417
  25. Tang SM, Gabelaia L, Gauthier TW, Brown LA. N-acetylcysteine improves group B streptococcus clearance in a rat model of chronic ethanol ingestion. Alcohol Clin Exp Res. 2009;33:1197-1201. https://doi.org/10.1111/j.1530-0277.2009.00943.x
  26. Kim MK, Park KG. Endoplasmic reticulum stress and diabetes. J Korean Endocr Soc. 2008;23:1-8. https://doi.org/10.3803/jkes.2008.23.1.1
  27. Ji C, Mehrian-Shai R, Chan C, Hsu YH, Kaplowitz N. Role of CHOP in hepatic apoptosis in the murine model of intragastric ethanol feeding. Alcohol Clin Exp Res. 2005;29:1496-1503. https://doi.org/10.1097/01.alc.0000174691.03751.11
  28. Harding HP, Zeng H, Zhang Y, Jungries R, Chung P, Plesken H, Sabatini DD, Ron D. Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. Mol Cell. 2001;7:1153-1163. https://doi.org/10.1016/S1097-2765(01)00264-7
  29. Seo HY, Kim YD, Lee KM, Min AK, Kim MK, Kim HS, Won KC, Park JY, Lee KU, Choi HS, Park KG, Lee IK. Endoplasmic reticulum stress-induced activation of activating transcription factor 6 decreases insulin gene expression via up-regulation of orphan nuclear receptor small heterodimer partner. Endocrinology. 2008;149:3832-3841. https://doi.org/10.1210/en.2008-0015
  30. Arky RA, Veverbrants E, Abramson EA. Irreversible hypoglycemia. A complication of alcohol and insulin. JAMA. 1968;206:575-578. https://doi.org/10.1001/jama.1968.03150030031006
  31. Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature. 2002;415:92-96. https://doi.org/10.1038/415092a
  32. Allagnat F, Christulia F, Ortis F, Pirot P, Lortz S, Lenzen S, Eizirik DL, Cardozo AK. Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis. Diabetologia. 2010;53:1120-1130. https://doi.org/10.1007/s00125-010-1699-7
  33. Kato H, Nakajima S, Saito Y, Takahashi S, Katoh R, Kitamura M. mTORC1 serves ER stress-triggered apoptosis via selective activation of the IRE1-JNK pathway. Cell Death Differ. 2012;19:310-320. https://doi.org/10.1038/cdd.2011.98
  34. Tan TC, Crawford DH, Jaskowski LA, Subramaniam VN, Clouston AD, Crane DI, Bridle KR, Anderson GJ, Fletcher LM. Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat diet-induced liver injury. Lab Invest. 2013;93:1295-1312. https://doi.org/10.1038/labinvest.2013.121
  35. Zhang K, Wang S, Malhotra J, Hassler JR, Back SH, Wang G, Chang L, Xu W, Miao H, Leonardi R, Chen YE, Jackowski S, Kaufman RJ. The unfolded protein response transducer IRE1 prevents ER stress-induced hepatic steatosis. EMBO J. 2011;30:1357-1375. https://doi.org/10.1038/emboj.2011.52
  36. Kaneto H, Nakatani Y, Kawamori D, Miyatsuka T, Matsuoka TA, Matsuhisa M, Yamasaki Y. Role of oxidative stress, endoplasmic reticulum stress, and c-Jun N-terminal kinase in pancreatic beta-cell dysfunction and insulin resistance. Int J Biochem Cell Biol. 2005;37:1595-1608. https://doi.org/10.1016/j.biocel.2005.04.003
  37. Kaneto H, Matsuoka TA, Nakatani Y, Kawamori D, Miyatsuka T, Matsuhisa M, Yamasaki Y. Oxidative stress, ER stress, and the JNK pathway in type 2 diabetes. J Mol Med (Berl). 2005;83:429-439. https://doi.org/10.1007/s00109-005-0640-x
  38. Kim JY, Lee DY, Lee YJ, Park KJ, Kim KH, Kim JW, Kim WH. Chronic alcohol consumption potentiates the development of diabetes through pancreatic ${\beta}$-cell dysfunction. World J Biol Chem. 2015;6:1-15. https://doi.org/10.4331/wjbc.v6.i1.1
  39. Cullinan SB, Diehl JA. Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway. Int J Biochem Cell Biol. 2006;38:317-332. https://doi.org/10.1016/j.biocel.2005.09.018
  40. Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 2010;140:900-917. https://doi.org/10.1016/j.cell.2010.02.034
  41. Dembele K, Nguyen KH, Hernandez TA, Nyomba BL. Effects of ethanol on pancreatic beta-cell death: interaction with glucose and fatty acids. Cell Biol Toxicol. 2009;25:141-152. https://doi.org/10.1007/s10565-008-9067-9
  42. Ji C. Dissection of endoplasmic reticulum stress signaling in alcoholic and non-alcoholic liver injury. J Gastroenterol Hepatol. 2008;23 Suppl 1:S16-24. https://doi.org/10.1111/j.1440-1746.2007.05276.x
  43. Ji C. New Insights into the Pathogenesis of alcohol-induced ER stress and liver diseases. Int J Hepatol. 2014;2014:513787.
  44. Esfandiari F, Villanueva JA, Wong DH, French SW, Halsted CH. Chronic ethanol feeding and folate deficiency activate hepatic endoplasmic reticulum stress pathway in micropigs. Am J Physiol Gastrointest Liver Physiol. 2005;289:G54-63. https://doi.org/10.1152/ajpgi.00542.2004
  45. Hamelet J, Demuth K, Paul JL, Delabar JM, Janel N. Hyperhomocysteinemia due to cystathionine beta synthase deficiency induces dysregulation of genes involved in hepatic lipid homeostasis in mice. J Hepatol. 2007;46:151-159. https://doi.org/10.1016/j.jhep.2006.07.028
  46. van der Kallen CJ, van Greevenbroek MM, Stehouwer CD, Schalkwijk CG. Endoplasmic reticulum stress-induced apoptosis in the development of diabetes: is there a role for adipose tissue and liver? Apoptosis. 2009;14:1424-1434. https://doi.org/10.1007/s10495-009-0400-4
  47. Werstuck GH, Lentz SR, Dayal S, Hossain GS, Sood SK, Shi YY, Zhou J, Maeda N, Krisans SK, Malinow MR, Austin RC. Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. J Clin Invest. 2001;107:1263-1273. https://doi.org/10.1172/JCI11596
  48. Ji C, Kaplowitz N. Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice. Gastroenterology. 2003;124:1488-1499. https://doi.org/10.1016/S0016-5085(03)00276-2

Cited by

  1. Alcoholic Beverage Consumption and Chronic Diseases vol.13, pp.6, 2015, https://doi.org/10.3390/ijerph13060522
  2. Joint and separate exposure to alcohol and ∆9-tetrahydrocannabinol produced distinct effects on glucose and insulin homeostasis in male rats vol.9, pp.1, 2015, https://doi.org/10.1038/s41598-019-48466-w
  3. Chronic binge alcohol and ovariectomy-mediated impaired insulin responsiveness in SIV-infected female rhesus macaques vol.321, pp.5, 2015, https://doi.org/10.1152/ajpregu.00159.2021