Alterations of Liver Functions and Morphology in a Rat Model of Prediabetes After a Short-term Treatment of a High-fat High-glucose and Low-dose Streptozotocin

Authors

  • Desak Gede Budi Krisnamurti Doctoral Program of Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Department of Medical Pharmacy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
  • Erni H. Purwaningsih Department of Medical Pharmacy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
  • Tri Juli Edi Tarigan Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Dr. Cipto Mangunkusumo National Referral Hospital, Jakarta, Indonesia
  • Christian Marco Hadi Nugroho Research and Development Unit, PT Medika Satwa Laboratories, Bogor, Indonesia
  • Vivian Soetikno Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
  • Melva Louisa Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

DOI:

https://doi.org/10.3889/oamjms.2022.8717

Keywords:

Diabetes mellitus, Gamma-glutamyltransferase, Hyperglycemia, High-fat diet, Liver impairment

Abstract

BACKGROUND: The administration of high-fat and high-glucose in diet followed by a low-dose streptozotocin injection in rats could mimic hyperglycemia, prediabetic, or diabetic conditions in humans. However, whether the rat model may lead to early liver impairment was still unclear.

AIM: This study was aimed to investigate the possible changes in liver functions and morphology in the rat model of prediabetes after a short-term administration of a high-fat and high-glucose diet followed by low-dose streptozotocin injection.

METHODS: Eighteen male Wistar rats were divided into nine rats in the control group and nine in the prediabetic group. To induce prediabetic rats, high-fat high-glucose in daily diets for 3 weeks continued with once to twice low-dose streptozotocin was given. Rats in control groups were fed with a standard diet for 2 months. Afterward, we analyzed glucose control parameters, liver functions, and liver histology of the rats.

RESULTS: High-fat, high-glucose diet combined with a low dose of streptozotocin successfully caused prediabetics in the rats. There was a significant increase in several liver enzymes, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT). However, no significant changes were found in the serum lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) levels. The histological changes in the liver confirmed the increase in liver enzymes.

CONCLUSION: Short-term administration of high-fat high-glucose in combination with low-dose streptozotocin triggers alterations in liver functions marker and liver morphology.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

References

Bansal N. Prediabetes diagnosis and treatment: A review. World J Diabetes. 2015;6(2):296-303. https://doi.org/10.4239/wjd.v6.i2.296 PMid:25789110 DOI: https://doi.org/10.4239/wjd.v6.i2.296

Gheibi S, Kashfi K, Ghasemi A. A practical guide for induction of type-2 diabetes in the rat: Incorporating a high-fat diet and streptozotocin. Biomed Pharmacother. 2017;95:605-13. https://doi.org/10.1016/j.biopha.2017.08.098 PMid:28881291 DOI: https://doi.org/10.1016/j.biopha.2017.08.098

Flanagan AM, Brown JL, Santiago CA, Aad PY, Spicer LJ, Spicer MT. High-fat diets promote insulin resistance through cytokine gene expression in growing female rats. J Nutr Biochem. 2008;19:505-13. https://doi.org/10.1016/j.jnutbio.2007.06.005 PMid:17904344 DOI: https://doi.org/10.1016/j.jnutbio.2007.06.005

Reed MJ, Meszaros K, Entes LJ, Claupool MD, Pinkett JG, Gadbois TM, et al. A new rat model of type 2 diabetes: The fat-fed, streptozotocin-treated rat. Metabolism. 2000;49(11):1390-4. https://doi.org/10.1053/meta.2000.17721 PMid:11092499 DOI: https://doi.org/10.1053/meta.2000.17721

Auberval N, Dal S, Bietiger W, Pinget M, Jeandidier N, Maillard- Pedracini E, et al. Metabolic and oxidative stress markers in Wistar rats after 2 months on a high-fat diet. Diabetol Metab Syndr. 2014;6:130. https://doi.org/10.1186/1758-5996-6-130 PMid:25960774 DOI: https://doi.org/10.1186/1758-5996-6-130

Basu S, Yoffe P, Hills N, Lustig RH. The relationship of sugar to population-level diabetes prevalence: An econometric analysis of repeated cross-sectional data. PLoS One. 2013;8(2):e57873. https://doi.org/10.1371/journal.pone.0057873 PMid:23460912 DOI: https://doi.org/10.1371/journal.pone.0057873

Zhang X, Miao L, Li X, Cai L. Diabetes-induced hepatic pathogenic damage, inflammation, oxidative stress, and insulin resistance was exacerbated in the zinc-deficient mouse model. PLoS One. 2012;7(12):e49257. https://doi.org/10.1371/journal.pone.0049257 PMid:23251339 DOI: https://doi.org/10.1371/journal.pone.0049257

Guven A, Yavuz O, Cam M, Ercan F, Bukan N, Comunoglu C, et al. Effects of melatonin on streptozotocin-induced diabetic liver injury in rats. Acta Histochem. 2006;108(2):85-93. https://doi.org/10.1016/j.acthis.2006.03.005 PMid:16714049 DOI: https://doi.org/10.1016/j.acthis.2006.03.005

Manna P, Das J, Ghosh J, Sil PC. Contribution of type 1 diabetes to rat liver dysfunction and cellular damage via activation of NOS, PARP, IkappaBalpha/NF-kappaB, MAPKs, and mitochondria-dependent pathways: Prophylactic role of arjunolic acid. Free Radic Biol Med. 2010;48(11):1465-84. https://doi.org/10.1016/j.freeradbiomed.2010.02.025 PMid:20188823 DOI: https://doi.org/10.1016/j.freeradbiomed.2010.02.025

Romagnoli M, Gomez-Cabrera M, Perrelli MG, Biasi F, Pallardó FV, Sastre J, et al. Xanthine oxidase-induced oxidative stress causes activation of NF-kappaB and inflammation in the liver of type I diabetic rats. Free Radic Biol Med. 2010;49(2):171-7. https://doi.org/10.1016/j.freeradbiomed.2010.03.024 PMid:20362663 DOI: https://doi.org/10.1016/j.freeradbiomed.2010.03.024

Yazdi HB, Hojati V, Shiravi A, Hosseinian S, Vaezi G, Hadjzadeh MA. Liver dysfunction and oxidative stress in streptozotocin-induced diabetic rats: Protective role of Artemisia turanica. J Pharmacopunct. 2019;22(2):109-14. https://doi.org/10.3831/kpi.2019.22.014 PMid:31338251 DOI: https://doi.org/10.3831/KPI.2019.22.014

Zafar M, Naem S, Ahmed M, Ali Z. Altered liver morphology and enzymes in streptozotocin-induced diabetic rat. Int J Morphol. 2009;27:719-25. https://doi.org/10.4067/s0717-95022009000300015 DOI: https://doi.org/10.4067/S0717-95022009000300015

Skovso S. Modeling type 2 diabetes in rats using high-fat diet and streptozotocin. J Diabetes Investig. 2014;5(4):349-58. https://doi.org/10.1111/jdi.12235 PMid:25411593 DOI: https://doi.org/10.1111/jdi.12235

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(4):313-20. https://doi.org/10.1016/j.phrs.2005.05.004 PMid:15979893 DOI: https://doi.org/10.1016/j.phrs.2005.05.004

Browning KN, Fortna SR, Hajnal A. Roux-en-Y gastric bypass reverses the effects of diet-induced obesity to inhibit the responsiveness of central vagal motoneurones. J Physiol. 2013;591(9):2357-72. https://doi.org/10.1113/jphysiol.2012.249268 PMid:23459752 DOI: https://doi.org/10.1113/jphysiol.2012.249268

Guo XX, Wang Y, Wang K, Ji BP, Zhou F. Stability of a type 2 diabetes rat model induced by high-fat diet feeding with low-dose streptozotocin injection. J Zhejiang Univ Sci B. 2018;19(7):559-69. https://doi.org/10.1631/jzus.b1700254 PMid:29971994 DOI: https://doi.org/10.1631/jzus.B1700254

Sang J, Qu H, Gu R, Chen D, Chen X, Yin B, et al. Proteomics study of the effect of high-fat diet on rat liver. Br J Nutr. 2019;122(9):1062-72. https://doi.org/10.1017/s0007114519001740 PMid:31311615 DOI: https://doi.org/10.1017/S0007114519001740

Fabbrini E, Sullivan S, Klein S. Obesity and non-alcoholic fatty liver disease: Biochemical, metabolic, and clinical implications. Hepatology. 2010;51(2):679-89. https://doi.org/10.1002/hep.23280 PMid:20041406 DOI: https://doi.org/10.1002/hep.23280

Pafili K, Roden M. Nonalcoholic fatty liver disease (NAFLD) from pathogenesis to treatment concepts in humans. Mol Metab. 2021;50:101122. https://doi.org/10.1016/j.molmet.2020.101122 PMid:33220492 DOI: https://doi.org/10.1016/j.molmet.2020.101122

Welch-White V, Dawkins N, Graham T, Pace R. The impact of high-fat diets on physiological changes in euthyroid and thyroid altered rats. Lipids Health Dis. 2013;12:100. https://doi.org/10.1186/1476-511x-12-100 PMid:23849139 DOI: https://doi.org/10.1186/1476-511X-12-100

Alves-Bezerra M, Cohen DE. Triglyceride metabolism in the liver. Compr Physiol. 2017;8(1):1-8. PMid:29357123 DOI: https://doi.org/10.1002/cphy.c170012

Karacor K, Cam M, Orhan N, Cosgun E, Demirin H. High fatty diet effects on rat liver. Eur J Gen Med. 2014;11:99-108. https://doi.org/10.15197/sabad.1.11.47 DOI: https://doi.org/10.15197/sabad.1.11.47

Mohamed J, Nafizah AH, Zariyantey AH, Budin SB. Mechanisms of diabetes-induced liver damage: The role of oxidative stress and inflammation. Sultan Qaboos Univ Med J. 2016;16(2):e132-41. https://doi.org/10.18295/squmj.2016.16.02.002 PMid:27226903 DOI: https://doi.org/10.18295/squmj.2016.16.02.002

Power GN, Müller L, Pilz K, Glatzel A, Jenderny D, Janowitz D, et al. Dietary-induced low-grade inflammation in the liver. Biomedicines. 2020;8(12):587. https://doi.org/10.3390/biomedicines8120587 PMid:33317065 DOI: https://doi.org/10.3390/biomedicines8120587

Lozano I, Van der Werf R, Bietiger W, Seyfritz E, Peronet C, Pinget M, et al. High-fructose and high-fat diet-induced disorders in rats: impact on diabetes risk, hepatic and vascular complications. Nutr Metab (Lond). 2016;13:15. https://doi.org/10.1186/s12986-016-0074-1 PMid:26918024 DOI: https://doi.org/10.1186/s12986-016-0074-1

O’Brien PD, Hinder LM, Callaghan BC, Feldman EL. Neurological consequences of obesity. Lancet Neurol. 2017;16(6):465-77. https://doi.org/10.1016/s1474-4422(17)30084-4 PMid:28504110 DOI: https://doi.org/10.1016/S1474-4422(17)30084-4

Al-Quraishy S, Dkhil MA, Abdel Moneim AE. Anti-hyperglycemic activity of selenium nanoparticles in streptozotocin-induced diabetic rats. Int J Nanomed. 2015;10:6741-56. https://doi.org/10.2147/ijn.s91377 PMid:26604749 DOI: https://doi.org/10.2147/IJN.S91377

Choi KM, Han K, Park S, Chung HS, Kim NH, Yoo HJ, et al. Implication of liver enzymes on incident cardiovascular diseases and mortality: A nationwide population-based cohort study. Sci Rep. 2018;8(1):3764. https://doi.org/10.1038/s41598-018-19700-8 PMid:29491346 DOI: https://doi.org/10.1038/s41598-018-19700-8

Fraser A, Harris R, Sattar N, Ebrahim S, Davey SG, Lawlor DA. Alanine aminotransferase, gamma-glutamyltransferase, and incident diabetes: The British women’s heart and health study and meta-analysis. Diabetes Care. 2009;32(4):741-50. https://doi.org/10.2337/dc08-1870 PMid:19131466 DOI: https://doi.org/10.2337/dc08-1870

Liu C, Shao M, Lu L, Zhao C, Qiu L, Liu Z. Obesity, insulin resistance and their interaction on liver enzymes. PLoS One. 2021;16(4):e0249299. https://doi.org/10.1371/journal.pone.0249299 PMID:33882064 DOI: https://doi.org/10.1371/journal.pone.0249299

Gray B, Muhlhausler BS, Davies PS, Vitetta L. Liver enzymes but not free fatty acid levels predict markers of insulin sensitivity in overweight and obese, non-diabetic adults. Nutr Res. 2013;33(10):781-8. https://doi.org/10.1016/j.nutres.2013.07.019 PMid:24074735 DOI: https://doi.org/10.1016/j.nutres.2013.07.019

Bradley R, Fitzpatrick AL, Jenny NS, Lee DH, Jacobs DR Jr. Associations between total serum GGT activity and metabolic risk: MESA. Biomark Med. 2013;7(5):709-21. https://doi.org/10.2217/bmm.13.71 PMid:24044563 DOI: https://doi.org/10.2217/bmm.13.71

Parrinello CM, Rudolph BJ, Lazo M, Gallo LC, Thyagarajan B, Cotler SJ, et al. Associations of insulin resistance and glycemia with liver enzymes in hispanic/latino youths: Results from the hispanic community children’s health study/study of latino youth (SOL Youth). J Clin Gastroenterol. 2019;53(2):e46-53. https://doi.org/10.1097/mcg.0000000000000946 PMid:29099463 DOI: https://doi.org/10.1097/MCG.0000000000000946

Rajarajeswari D, Krishna TS, Naidu MP, Naidu JN. Serum gamma-glutamyl transferase levels in association with lipids and lipoproteins in type2 diabetes mellitus. Int J Res Med Sci. 2014;2(3):838-41. https://doi.org/10.5455/2320-6012.ijrms20140819 DOI: https://doi.org/10.5455/2320-6012.ijrms20140819

Lee S, Kwak JH, Kim SH, Jeong TB, Son SW, Kim JH, et al. Comparative study of liver injury induced by high-fat methionine- and choline-deficient diet in ICR mice originating from three different sources. Lab Anim Res. 2019;35:15. https://doi.org/10.1186/s42826-019-0016-y DOI: https://doi.org/10.1186/s42826-019-0016-y

Puri BK, Kingston MC, Monro JA. Fructose-associated hepatotoxicity indexed by the lactate dehydrogenase isoenzyme LDH-5. Med Hypotheses. 2019;124:40-1. https://doi.org/10.1016/j.mehy.2019.02.019 PMid:30798914 DOI: https://doi.org/10.1016/j.mehy.2019.02.019

Albrahim T, Alonazi MA. Lycopene corrects metabolic syndrome and liver injury induced by a high-fat diet in obese rats through antioxidant, anti-inflammatory, antifibrotic pathways. Biomed Pharmacother. 2021;141:111831. https://doi.org/10.1016/j.biopha.2021.111831 PMid:34237596 DOI: https://doi.org/10.1016/j.biopha.2021.111831

Chen SC, Tsai SP, Jhao JY, Jiang WK, Tsao CK, Chang LY. Liver fat, hepatic enzymes, alkaline phosphatase and the risk of incident type 2 diabetes: A prospective study of 132,377 adults. Sci Rep. 2017;7(1):4649. https://doi.org/10.1038/s41598-017-04631-7 PMid:28680048 DOI: https://doi.org/10.1038/s41598-017-04631-7

Nannipieri M, Gonzales C, Baldi S, Posadas R, Williams K, Haffner SM, et al., Mexico City Diabetes Study. Liver enzymes, the metabolic syndrome, and incident diabetes: The Mexico city diabetes study. Diabetes Care. 2005;28(7):1757-62. https://doi.org/10.2337/diacare.28.7.1757 PMid:15983331 DOI: https://doi.org/10.2337/diacare.28.7.1757

Zhang Y, Zhou C, Li J, Zhang Y, Xie D, Liang M, et al. Serum alkaline phosphatase levels and the risk of new-onset diabetes in hypertensive adults. Cardiovasc Diabetol. 2020;19(1):186. https://doi.org/10.1186/s12933-020-01161-x PMid:33099298 DOI: https://doi.org/10.1186/s12933-020-01161-x

Crawford JM. Liver and biliary tract. In: Kumar V, Abbas AK, Fausto N, Aster JC, editors. Robbins and Cotran Pathologic Basis of Disease. 8th ed. Philadelphia, PA, Pennsylvania: Saunders; 2009. p. 833-90. https://doi.org/10.1016/b978-1-4377-0792-2.50023-7 DOI: https://doi.org/10.1016/B978-1-4377-0792-2.50023-7

Velázquez KT, Enos RT, Bader JE, Sougiannis AT, Carson MS, Chatzistamou I, et al. Prolonged high-fat-diet feeding promotes non-alcoholic fatty liver disease and alters gut microbiota in mice. World J Hepatol. 2019;11(8):619-37. https://doi.org/10.4254/wjh.v11.i8.619 PMid:31528245 DOI: https://doi.org/10.4254/wjh.v11.i8.619

Takahashi Y, Fukusato T. Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol. 2014;20(42):15539-48. https://doi.org/10.3748/wjg.v20.i42.15539 PMid:25400438 DOI: https://doi.org/10.3748/wjg.v20.i42.15539

Altunkaynak Z. Effects of high-fat diet-induced obesity on female rat livers (a histochemical study). Eur J Gen Med. 2005;2:100-9. https://doi.org/10.29333/ejgm/82319 DOI: https://doi.org/10.29333/ejgm/82319

Downloads

Published

2022-03-16

How to Cite

1.
Krisnamurti DGB, Purwaningsih EH, Tarigan TJE, Nugroho CMH, Soetikno V, Louisa M. Alterations of Liver Functions and Morphology in a Rat Model of Prediabetes After a Short-term Treatment of a High-fat High-glucose and Low-dose Streptozotocin. Open Access Maced J Med Sci [Internet]. 2022 Mar. 16 [cited 2024 Nov. 21];10(A):668-74. Available from: https://oamjms.eu/index.php/mjms/article/view/8717

Issue

Section

Pathophysiology

Categories