The possible mechanisms of high-fructose diet-induced pancreatic disturbances

GÜNEY, Ceren; Akar, Fatma

doi:10.29228/jrp.357

The possible mechanisms of high-fructose diet-induced pancreatic disturbances

Ceren GÜNEY, (Gazi Üniversitesi, Eczacılık Fakültesi, Eczacılık Anabilim Dalı, Ankara, Türkiye)

Fatma AKAR (Gazi Üniversitesi, Eczacılık Fakültesi, Eczacılık Anabilim Dalı, Ankara, Türkiye)

Journal of research in pharmacy (online)

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Yıl: 2023 Cilt: 27 Sayı: 2 Sayfa Aralığı: 753 - 761 Metin Dili: İngilizce DOI: 10.29228/jrp.357 İndeks Tarihi: 31-05-2023

The possible mechanisms of high-fructose diet-induced pancreatic disturbances

Öz:

Excess fructose consumption in the regular human diet causes several health problems. The main source of dietary fructose is sugar-sweetened beverages, which are especially consumed by children and teenagers. High- fructose intake is one of the major responsible factors of the increased prevalence of metabolic syndrome and type 2 diabetes worldwide. The dietary high-fructose-induced metabolic syndrome was evidenced by hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertension, fatty liver disease, central adiposity, and inflammation. Molecular findings indicated that there was a suppression of insulin signaling and activation of oxidative stress in different tissues including the liver, blood vessels, adipose tissue, and kidney in the excess intake of fructose. However, there is a limited mechanistic study on the pancreatic disturbances induced by dietary high-fructose. The hyperglycemic condition in the consumption of high-fructose may lead to morphologic and pathological changes to increase the capacity of insulin secretion in the pancreas. High-fructose can activate the mitogenic and apoptotic pathways, thus probably inducing hyperplasia in β-cells. The overactivation of β-cells can trigger oxidative and endoplasmic reticulum stress as well as inflammation in the pancreas. In conclusion, high-fructose consumption may cause pancreatic disturbance possibly through stimulation of cellular oxidative stress, inflammation, mitogenesis, and apoptosis. Pancreas is one of the first organs affected by metabolic abnormalities, therefore, elucidation of potential mechanisms underlying high-fructose diet-induced pancreatic pathologies would be valuable in the prevention and treatment of the metabolic syndrome as well as type 2 diabetes.

Anahtar Kelime:

Belge Türü: Makale Makale Türü: Derleme Erişim Türü: Erişime Açık

[1] Jensen T, Abdelmalek MF, Sullivan S, Nadeau KJ, Green M, Roncal C, Nakagawa T, Kuwabara M, Sato Y, Kang DH, Tolan DR, Sanchez-Lozada LG, Rosen HR, Lanaspa MA, Diehl AM, Johnson RJ. Fructose and sugar: A major mediator of non-alcoholic fatty liver disease. J Hepatol. 2018 May;68(5):1063-1075. http://doi.org/10.1016/j.jhep.2018.01.019.
[2] Softic S, Stanhope KL, Boucher J, Divanovic S, Lanaspa MA, Johnson RJ, Kahn CR. Fructose and hepatic insulin resistance. Crit Rev Clin Lab Sci. 2020 Aug;57(5):308-322. http://doi.org/10.1080/10408363.2019.1711360.
[3] International Diabetes Federation, IDF Diabetes Atlas, tenth ed., 2021.
[4] Brown MS, Goldstein JL. Selective versus total insulin resistance: a pathogenic paradox. Cell Metab. 2008 Feb;7(2):95-6. http://doi.org/10.1016/j.cmet.2007.12.009.
[5] Shimobayashi M, Albert V, Woelnerhanssen B, Frei IC, Weissenberger D, Meyer-Gerspach AC, Clement N, Moes S, Colombi M, Meier JA, Swierczynska MM, Jenö P, Beglinger C, Peterli R, Hall MN. Insulin resistance causes inflammation in adipose tissue. J Clin Invest. 2018 Apr 2;128(4):1538-1550. http://doi.org/10.1172/JCI96139.
[6] Dinić S, Arambašić Jovanović J, Uskoković A, Mihailović M, Grdović N, Tolić A, Rajić J, Đorđević M, Vidaković M. Oxidative stress-mediated beta cell death and dysfunction as a target for diabetes management. Front Endocrinol (Lausanne). 2022 Sep 23;13:1006376. http://doi.org/10.3389/fendo.2022.1006376.
[7] Liu Y, Han J, Zhou Z, Li D. Paeoniflorin protects pancreatic β cells from STZ-induced damage through inhibition of the p38 MAPK and JNK signaling pathways. Eur J Pharmacol. 2019 Jun 15;853:18-24. http://doi.org/10.1016/j.ejphar.2019.03.025.
[8] Babacanoglu C, Yildirim N, Sadi G, Pektas MB, Akar F. Resveratrol prevents high-fructose corn syrup-induced vascular insulin resistance and dysfunction in rats. Food Chem Toxicol. 2013 Oct;60:160-7. http://doi.org/10.1016/j.fct.2013.07.026.
[9] Sadi G, Ergin V, Yilmaz G, Pektas MB, Yildirim OG, Menevse A, Akar F. High-fructose corn syrup-induced hepatic dysfunction in rats: improving effect of resveratrol. Eur J Nutr. 2015 Sep;54(6):895-904. http://doi.org/10.1007/s00394-014-0765-1.
[10] Korkmaz OA, Sumlu E, Koca HB, Pektas MB, Kocabas A, Sadi G, Akar F. Effects of Lactobacillus Plantarum and Lactobacillus Helveticus on Renal Insulin Signaling, Inflammatory Markers, and Glucose Transporters in High- Fructose-Fed Rats. Medicina (Kaunas). 2019 May 24;55(5):207. http://doi.org/10.3390/medicina55050207.
[11] Sumlu E, Bostancı A, Sadi G, Alçığır ME, Akar F. Lactobacillus plantarum improves lipogenesis and IRS- 1/AKT/eNOS signalling pathway in the liver of high-fructose-fed rats. Arch Physiol Biochem. 2022 Jun;128(3):786- 794. http://doi.org/10.1080/13813455.2020.1727527.
[12] Akar F, Sumlu E, Alçığır ME, Bostancı A, Sadi G. Potential mechanistic pathways underlying intestinal and hepatic effects of kefir in high-fructose-fed rats. Food Res Int. 2021 May;143:110287. http://doi.org/10.1016/j.foodres.2021.110287.
[13] Akar F, Yildirim OG, Yucel Tenekeci G, Tunc AS, Demirel MA, Sadi G. Dietary high-fructose reduces barrier proteins and activates mitogenic signalling in the testis of a rat model: Regulatory effects of kefir supplementation. Andrologia. 2022 Apr;54(3):e14342. http://doi.org/10.1111/and.14342.
[14] Pektas MB, Yücel G, Koca HB, Sadi G, Yıldırım OG, Öztürk G, Akar F. Dietary Fructose-Induced Hepatic Injury in Male and Female Rats: Influence of Resveratrol. Drug Res (Stuttg). 2017 Feb;67(2):103-110. http://doi.org/10.1055/s- 0042-118386.
[15] Pektas MB, Koca HB, Sadi G, Akar F. Dietary Fructose Activates Insulin Signaling and Inflammation in Adipose Tissue: Modulatory Role of Resveratrol. Biomed Res Int. 2016;2016:8014252. http://doi.org/10.1155/2016/8014252.
[16] Yildirim OG, Sumlu E, Aslan E, Koca HB, Pektas MB, Sadi G, Akar F. High-fructose in drinking water initiates activation of inflammatory cytokines and testicular degeneration in rat. Toxicol Mech Methods. 2019 Mar;29(3):224- 232. http://doi.org/10.1080/15376516.2018.1543745.
[17] Balakumar M, Raji L, Prabhu D, Sathishkumar C, Prabu P, Mohan V, Balasubramanyam M. High-fructose diet is as detrimental as high-fat diet in the induction of insulin resistance and diabetes mediated by hepatic/pancreatic endoplasmic reticulum (ER) stress. Mol Cell Biochem. 2016 Dec;423(1-2):93-104. http://doi.org/10.1007/s11010-016- 2828-5.
[18] Izadi MS, Eskandari F, Binayi F, Salimi M, Rashidi FS, Hedayati M, Dargahi L, Ghanbarian H, Zardooz H. Oxidative and endoplasmic reticulum stress develop adverse metabolic effects due to the high-fat high-fructose diet consumption from birth to young adulthood. Life Sci. 2022 Nov 15;309:120924. http://doi.org/10.1016/j.lfs.2022.120924.
[19] Weir GC, Gaglia J, Bonner-Weir S. Inadequate β-cell mass is essential for the pathogenesis of type 2 diabetes. Lancet Diabetes Endocrinol. 2020 Mar;8(3):249-256. http://doi.org/10.1016/S2213-8587(20)30022-X.
[20] Chen C, Cohrs CM, Stertmann J, Bozsak R, Speier S. Human beta cell mass and function in diabetes: Recent advances in knowledge and technologies to understand disease pathogenesis. Mol Metab. 2017 Jul 8;6(9):943-957. http://doi.org/10.1016/j.molmet.2017.06.019.
[21] Esser N, Utzschneider KM, Kahn SE. Early beta cell dysfunction vs insulin hypersecretion as the primary event in the pathogenesis of dysglycaemia. Diabetologia. 2020 Oct;63(10):2007-2021. http://doi.org/10.1007/s00125-020-05245-x.
[22] Giri B, Dey S, Das T, Sarkar M, Banerjee J, Dash SK. Chronic hyperglycemia mediated physiological alteration and metabolic distortion leads to organ dysfunction, infection, cancer progression and other pathophysiological consequences: An update on glucose toxicity. Biomed Pharmacother. 2018 Nov;107:306-328. http://doi.org/10.1016/j.biopha.2018.07.157.
[23] Giblin MJ, Ontko CD, Penn JS. Effect of cytokine-induced alterations in extracellular matrix composition on diabetic retinopathy-relevant endothelial cell behaviors. Sci Rep. 2022 Jul 28;12(1):12955. http://doi.org/10.1038/s41598-022- 12683-7.
[24] Keane KN, Cruzat VF, Carlessi R, de Bittencourt PI Jr, Newsholme P. Molecular Events Linking Oxidative Stress and Inflammation to Insulin Resistance and β -Cell Dysfunction. Oxid Med Cell Longev. 2015;2015:181643. http://doi.org/10.1155/2015/181643.
[25] Malin SK, Kirwan JP, Sia CL, González F. Pancreatic β -cell dysfunction in polycystic ovary syndrome: role of hyperglycemia-induced nuclear factor-κB activation and systemic inflammation. Am J Physiol Endocrinol Metab. 2015 May 1;308(9):E770-7. http://doi.org/10.1152/ajpendo.00510.2014.
[26] Horii T, Fujita Y, Ishibashi C, Fukui K, Eguchi H, Kozawa J, Shimomura I. Islet inflammation is associated with pancreatic fatty infiltration and hyperglycemia in type 2 diabetes. BMJ Open Diabetes Res Care. 2020 Aug;8(1):e001508. http://doi.org/10.1136/bmjdrc-2020-001508.
[27] Zhou X, Han D, Xu R, Li S, Wu H, Qu C, Wang F, Wang X, Zhao Y. A model of metabolic syndrome and related diseases with intestinal endotoxemia in rats fed a high fat and high sucrose diet. PLoS One. 2014 Dec 11;9(12):e115148. http://doi.org/10.1371/journal.pone.0115148.
[28] Pokrywczynska M, Flisinski M, Jundzill A, Krzyzanowska S, Brymora A, Deptula A, Bodnar M, Kloskowski T, Stefanska A, Marszalek A, Manitius J, Drewa T. Impact of fructose diet and renal failure on the function of pancreatic islets. Pancreas. 2014 Jul;43(5):801-8. http://doi.org/10.1097/MPA.0000000000000111.
[29] Asghar ZA, Cusumano A, Yan Z, Remedi MS, Moley KH. Reduced islet function contributes to impaired glucose homeostasis in fructose-fed mice. Am J Physiol Endocrinol Metab. 2017 Feb 1;312(2):E109-E116. http://doi.org/10.1152/ajpendo.00279.2016.
[30] Barrière DA, Noll C, Roussy G, Lizotte F, Kessai A, Kirby K, Belleville K, Beaudet N, Longpré JM, Carpentier AC, Geraldes P, Sarret P. Combination of high-fat/high-fructose diet and low-dose streptozotocin to model long-term type-2 diabetes complications. Sci Rep. 2018 Jan 11;8(1):424. http://doi.org/10.1038/s41598-017-18896-5.
[31] Chansela P, Potip B, Weerachayaphorn J, Kangwanrangsan N, Chukijrungroat N, Saengsirisuwan V. Morphological alteration of the pancreatic islet in ovariectomized rats fed a high-fat high-fructose diet. Histochem Cell Biol. 2022 Apr;157(4):427-442. http://doi.org/10.1007/s00418-021-02062-0.
[32] Zhao Y, Wang QY, Zeng LT, Wang JJ, Liu Z, Fan GQ, Li J, Cai JP. Long-Term High-Fat High-Fructose Diet Induces Type 2 Diabetes in Rats through Oxidative Stress. Nutrients. 2022 May 24;14(11):2181. http://doi.org/10.3390/nu14112181.
[33] Gerber PA, Rutter GA. The Role of Oxidative Stress and Hypoxia in Pancreatic Beta-Cell Dysfunction in Diabetes Mellitus. Antioxid Redox Signal. 2017 Apr 1;26(10):501-518. http://doi.org/10.1089/ars.2016.6755.
[34] Fiorentino TV, Prioletta A, Zuo P, Folli F. Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases. Curr Pharm Des. 2013;19(32):5695-703. http://doi.org/10.2174/1381612811319320005.
[35] Suryavanshi SV, Kulkarni YA. NF-κβ: A Potential Target in the Management of Vascular Complications of Diabetes. Front Pharmacol. 2017 Nov 7;8:798. http://doi.org/10.3389/fphar.2017.00798.
[36] Wang S, Ding L, Ji H, Xu Z, Liu Q, Zheng Y. The Role of p38 MAPK in the Development of Diabetic Cardiomyopathy. Int J Mol Sci. 2016 Jun 30;17(7):1037. http://doi.org/10.3390/ijms17071037.
[37] Yuan T, Yang T, Chen H, Fu D, Hu Y, Wang J, Yuan Q, Yu H, Xu W, Xie X. New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis. Redox Biol. 2019 Jan;20:247-260. http://doi.org/10.1016/j.redox.2018.09.025.
[38] Baumel-Alterzon S, Katz LS, Brill G, Jean-Pierre C, Li Y, Tse I, Biswal S, Garcia-Ocaña A, Scott DK. Nrf2 Regulates β- Cell Mass by Suppressing β -Cell Death and Promoting β -Cell Proliferation. Diabetes. 2022 May 1;71(5):989-1011. http://doi.org/10.2337/db21-0581.
[39] Yagishita Y, Fukutomi T, Sugawara A, Kawamura H, Takahashi T, Pi J, Uruno A, Yamamoto M. Nrf2 protects pancreatic β -cells from oxidative and nitrosative stress in diabetic model mice. Diabetes. 2014 Feb;63(2):605-18. http://doi.org/10.2337/db13-0909.
[40] Tian YF, He CT, Chen YT, Hsieh PS. Lipoic acid suppresses portal endotoxemia-induced steatohepatitis and pancreatic inflammation in rats. World J Gastroenterol. 2013 May 14;19(18):2761-71. http://doi.org/10.3748/wjg.v19.i18.2761.
[41] Topsakal S, Ozmen O, Cankara FN, Yesilot S, Bayram D, Genç Özdamar N, Kayan S. Alpha lipoic acid attenuates high-fructose-induced pancreatic toxicity. Pancreatology. 2016 May-Jun;16(3):347-52. http://doi.org/10.1016/j.pan.2016.03.001.
[42] Chen YR, Fang SR, Fu YC, Zhou XH, Xu MY, Xu WC. Calorie restriction on insulin resistance and expression of SIRT1 and SIRT4 in rats. Biochem Cell Biol. 2010 Aug;88(4):715-22. http://doi.org/10.1139/O10-010.
[43] Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MP, Gygi SP, Sinclair DA, Alt FW, Greenberg ME. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004 Mar 26;303(5666):2011-5. http://doi.org/10.1126/science.1094637.
[44] Moynihan KA, Grimm AA, Plueger MM, Bernal-Mizrachi E, Ford E, Cras-Méneur C, Permutt MA, Imai S. Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. Cell Metab. 2005 Aug;2(2):105-17. http://doi.org/10.1016/j.cmet.2005.07.001.
[45] Caton PW, Kieswich J, Yaqoob MM, Holness MJ, Sugden MC. Nicotinamide mononucleotide protects against pro- inflammatory cytokine-mediated impairment of mouse islet function. Diabetologia. 2011 Dec;54(12):3083-92. http://doi.org/10.1007/s00125-011-2288-0.
[46] Chen YR, Lai YL, Lin SD, Li XT, Fu YC, Xu WC. SIRT1 interacts with metabolic transcriptional factors in the pancreas of insulin-resistant and calorie-restricted rats. Mol Biol Rep. 2013 Apr;40(4):3373-80. http://doi.org/10.1007/s11033- 012-2412-3.
[47] Zarzuelo MJ, López-Sepúlveda R, Sánchez M, Romero M, Gómez-Guzmán M, Ungvary Z, Pérez-Vizcaíno F, Jiménez R, Duarte J. SIRT1 inhibits NADPH oxidase activation and protects endothelial function in the rat aorta: implications for vascular aging. Biochem Pharmacol. 2013 May 1;85(9):1288-96. http://doi.org/10.1016/j.bcp.2013.02.015.
[48] Román CL, Flores LE, Maiztegui B, Raschia MA, Del Zotto H, Gagliardino JJ. Islet NADPH oxidase activity modulates β-cell mass and endocrine function in rats with fructose-induced oxidative stress. Biochim Biophys Acta. 2014 Dec;1840(12):3475-82. http://doi.org/10.1016/j.bbagen.2014.09.011.
[49] Oh YS, Bae GD, Baek DJ, Park EY, Jun HS. Fatty Acid-Induced Lipotoxicity in Pancreatic Beta-Cells During Development of Type 2 Diabetes. Front Endocrinol (Lausanne). 2018 Jul 16;9:384. http://doi.org/10.3389/fendo.2018.00384.
[50] Burgos-Morón E, Abad-Jiménez Z, Marañón AM, Iannantuoni F, Escribano-López I, López-Domènech S, Salom C, Jover A, Mora V, Roldan I, Solá E, Rocha M, Víctor VM. Relationship Between Oxidative Stress, ER Stress, and Inflammation in Type 2 Diabetes: The Battle Continues. J Clin Med. 2019 Sep 4;8(9):1385. http://doi.org/10.3390/jcm8091385.
[51] Volchuk A, Ron D. The endoplasmic reticulum stress response in the pancreatic β-cell. Diabetes Obes Metab. 2010 Oct;12 Suppl 2:48-57. http://doi.org/10.1111/j.1463-1326.2010.01271.x.
[52] Kalpana K, Priyadarshini E, Sreeja S, Jagan K, Anuradha CV. Scopoletin intervention in pancreatic endoplasmic reticulum stress induced by lipotoxicity. Cell Stress Chaperones. 2018 Sep;23(5):857-869. http://doi.org/10.1007/s12192-018-0893-2.
[53] Li H, Meng Y, He S, Tan X, Zhang Y, Zhang X, Wang L, Zheng W. Macrophages, Chronic Inflammation, and Insulin Resistance. Cells. 2022 Sep 26;11(19):3001. http://doi.org/10.3390/cells11193001.
[54] Berchtold LA, Prause M, Størling J, Mandrup-Poulsen T. Cytokines and Pancreatic β-Cell Apoptosis. Adv Clin Chem. 2016;75:99-158. http://doi.org/10.1016/bs.acc.2016.02.001.
[55] Zhao T, Ma J, Li L, Teng W, Tian Y, Ma Y, Wang W, Yan W, Jiao P. MKP-5 Relieves Lipotoxicity-Induced Islet β-Cell Dysfunction and Apoptosis via Regulation of Autophagy. Int J Mol Sci. 2020 Sep 28;21(19):7161. http://doi.org/10.3390/ijms21197161.
[56] Sendler M, Dummer A, Weiss FU, Krüger B, Wartmann T, Scharffetter-Kochanek K, van Rooijen N, Malla SR, Aghdassi A, Halangk W, Lerch MM, Mayerle J. Tumour necrosis factor α secretion induces protease activation and acinar cell necrosis in acute experimental pancreatitis in mice. Gut. 2013 Mar;62(3):430-9. http://doi.org/10.1136/gutjnl-2011- 300771.
[57] Lanuza-Masdeu J, Arévalo MI, Vila C, Barberà A, Gomis R, Caelles C. In vivo JNK activation in pancreatic β-cells leads to glucose intolerance caused by insulin resistance in pancreas. Diabetes. 2013 Jul;62(7):2308-17. http://doi.org/10.2337/db12-1097.
[58] Chen J, Chen J, Wang X, Wang C, Cao W, Zhao Y, Zhang B, Cui M, Shi Q, Zhang G. Ligustrazine alleviates acute pancreatitis by accelerating acinar cell apoptosis at early phase via the suppression of p38 and Erk MAPK pathways. Biomed Pharmacother. 2016 Aug;82:1-7. http://doi.org/10.1016/j.biopha.2016.04.048.
[59] Yang J, Zhou Y, Shi J. Cordycepin protects against acute pancreatitis by modulating NF-κB and NLRP3 inflammasome activation via AMPK. Life Sci. 2020 Jun 15;251:117645. http://doi.org/10.1016/j.lfs.2020.117645.
[60] Wang Y, Qi W, Song G, Pang S, Peng Z, Li Y, Wang P. High-Fructose Diet Increases Inflammatory Cytokines and Alters Gut Microbiota Composition in Rats. Mediators Inflamm. 2020 Nov 30;2020:6672636. http://doi.org/10.1155/2020/6672636.
[61] Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev. 2011 Mar;75(1):50-83. http://doi.org/10.1128/MMBR.00031-10.
[62] Fukuda K, Tesch GH, Yap FY, Forbes JM, Flavell RA, Davis RJ, Nikolic-Paterson DJ. MKK3 signalling plays an essential role in leukocyte-mediated pancreatic injury in the multiple low-dose streptozotocin model. Lab Invest. 2008 Apr;88(4):398-407. http://doi.org/10.1038/labinvest.2008.10.
[63] Govindaraj J, Sorimuthu Pillai S. Rosmarinic acid modulates the antioxidant status and protects pancreatic tissues from glucolipotoxicity mediated oxidative stress in high-fat diet: streptozotocin-induced diabetic rats. Mol Cell Biochem. 2015 Jun;404(1-2):143-59. http://doi.org/10.1007/s11010-015-2374-6.
[64] He X, Gao F, Hou J, Li T, Tan J, Wang C, Liu X, Wang M, Liu H, Chen Y, Yu Z, Yang M. Metformin inhibits MAPK signaling and rescues pancreatic aquaporin 7 expression to induce insulin secretion in type 2 diabetes mellitus. J Biol Chem. 2021 Aug;297(2):101002. http://doi.org/10.1016/j.jbc.2021.101002.
[65] Hasnan J, Yusof MI, Damitri TD, Faridah AR, Adenan AS, Norbaini TH. Relationship between apoptotic markers (Bax and Bcl-2) and biochemical markers in type 2 diabetes mellitus. Singapore Med J. 2010 Jan;51(1):50-5. https://www.ncbi.nlm.nih.gov/pubmed/20200776.
[66] Kung CP, Murphy ME. The role of the p53 tumor suppressor in metabolism and diabetes. J Endocrinol. 2016 Nov;231(2):R61-R75. http://doi.org/10.1530/JOE-16-0324.
[67] McIlwain DR, Berger T, Mak TW. Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol. 2013 Apr 1;5(4):a008656. http://doi.org/10.1101/cshperspect.a008656.
[68] Minamino T, Orimo M, Shimizu I, Kunieda T, Yokoyama M, Ito T, Nojima A, Nabetani A, Oike Y, Matsubara H, Ishikawa F, Komuro I. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat Med. 2009 Sep;15(9):1082-7. http://doi.org/10.1038/nm.2014.
[69] Feng ZC, Riopel M, Li J, Donnelly L, Wang R. Downregulation of Fas activity rescues early onset of diabetes in c- Kit(Wv/+) mice. Am J Physiol Endocrinol Metab. 2013 Mar 15;304(6):E557-65. http://doi.org/10.1152/ajpendo.00453.2012.
[70] Alipour MR, Naderi R, Alihemmati A, Sheervalilou R, Ghiasi R. Swimming training attenuates pancreatic apoptosis through miR-34a/Sirtu in1/P53 Axis in high-fat diet and Streptozotocin-induced Type-2 diabetic rats. J Diabetes Metab Disord. 2020 Oct 29;19(2):1439-1446. http://doi.org/10.1007/s40200-020-00670-6.
[71] Lustig RH, Mulligan K, Noworolski SM, Tai VW, Wen MJ, Erkin-Cakmak A, Gugliucci A, Schwarz JM. Isocaloric fructose restriction and metabolic improvement in children with obesity and metabolic syndrome. Obesity (Silver Spring). 2016 Feb;24(2):453-60. http://doi.org/10.1002/oby.21371.
[72] Schwarz JM, Noworolski SM, Erkin-Cakmak A, Korn NJ, Wen MJ, Tai VW, Jones GM, Palii SP, Velasco-Alin M, Pan K, Patterson BW, Gugliucci A, Lustig RH, Mulligan K. Effects of Dietary Fructose Restriction on Liver Fat, De Novo Lipogenesis, and Insulin Kinetics in Children With Obesity. Gastroenterology. 2017 Sep;153(3):743-752. http://doi.org/10.1053/j.gastro.2017.05.043.

APA	GÜNEY C, Akar F (2023). The possible mechanisms of high-fructose diet-induced pancreatic disturbances. , 753 - 761. 10.29228/jrp.357
Chicago	GÜNEY Ceren,Akar Fatma The possible mechanisms of high-fructose diet-induced pancreatic disturbances. (2023): 753 - 761. 10.29228/jrp.357
MLA	GÜNEY Ceren,Akar Fatma The possible mechanisms of high-fructose diet-induced pancreatic disturbances. , 2023, ss.753 - 761. 10.29228/jrp.357
AMA	GÜNEY C,Akar F The possible mechanisms of high-fructose diet-induced pancreatic disturbances. . 2023; 753 - 761. 10.29228/jrp.357
Vancouver	GÜNEY C,Akar F The possible mechanisms of high-fructose diet-induced pancreatic disturbances. . 2023; 753 - 761. 10.29228/jrp.357
IEEE	GÜNEY C,Akar F "The possible mechanisms of high-fructose diet-induced pancreatic disturbances." , ss.753 - 761, 2023. 10.29228/jrp.357
ISNAD	GÜNEY, Ceren - Akar, Fatma. "The possible mechanisms of high-fructose diet-induced pancreatic disturbances". (2023), 753-761. https://doi.org/10.29228/jrp.357

APA	GÜNEY C, Akar F (2023). The possible mechanisms of high-fructose diet-induced pancreatic disturbances. Journal of research in pharmacy (online), 27(2), 753 - 761. 10.29228/jrp.357
Chicago	GÜNEY Ceren,Akar Fatma The possible mechanisms of high-fructose diet-induced pancreatic disturbances. Journal of research in pharmacy (online) 27, no.2 (2023): 753 - 761. 10.29228/jrp.357
MLA	GÜNEY Ceren,Akar Fatma The possible mechanisms of high-fructose diet-induced pancreatic disturbances. Journal of research in pharmacy (online), vol.27, no.2, 2023, ss.753 - 761. 10.29228/jrp.357
AMA	GÜNEY C,Akar F The possible mechanisms of high-fructose diet-induced pancreatic disturbances. Journal of research in pharmacy (online). 2023; 27(2): 753 - 761. 10.29228/jrp.357
Vancouver	GÜNEY C,Akar F The possible mechanisms of high-fructose diet-induced pancreatic disturbances. Journal of research in pharmacy (online). 2023; 27(2): 753 - 761. 10.29228/jrp.357
IEEE	GÜNEY C,Akar F "The possible mechanisms of high-fructose diet-induced pancreatic disturbances." Journal of research in pharmacy (online), 27, ss.753 - 761, 2023. 10.29228/jrp.357
ISNAD	GÜNEY, Ceren - Akar, Fatma. "The possible mechanisms of high-fructose diet-induced pancreatic disturbances". Journal of research in pharmacy (online) 27/2 (2023), 753-761. https://doi.org/10.29228/jrp.357