Histopathological and functional liver changes in diabetic rats intervened goat’s milk kefir and randu honey
Abstract
ABSTRAK
Latar Belakang: Kejadian diabetes secara global diperkirakan meningkat 19,74% pada tahun 2030, sehingga memerlukan intervensi yang komprehensif. Hiperglikemia kronis berpotensi menyebabkan komplikasi kerusakan jaringan pada organ hati yang bisa dipicu stres oksidatif. Kefir merupakan produk kaya antioksidan yang berpotensi mengurangi stres oksidatif pada penderita DM dengan kerusakan hati yang diindikasi oleh kadar AST dan ALT. Oleh karena itu, konsumsi kefir pada dosis tertentu berkontribusi pada perbaikan kerusakan jaringan hati.
Tujuan: Mengamati perbedaan kadar AST, ALT, dan histopatologi hati pada tikus diabetes yang diintervensi kefir susu kambing yang dikombinasikan dengan madu randu.
Metode: Studi klinis dengan desain pre-post test menggunakan 42 ekor tikus jantan Sprague dawley (120-150 g) yang diintervensi selama 21 hari. Sampel terdiri dari 6 kelompok yaitu Ks (kontrol sehat), KN (kontrol negatif), K1 (quercetin 15 mg/kg BB), K2 (metformin 62.5 mg/kg BB), P1 (Kefir 1.8 ml/200g BB), dan P2 (preventif). Fungsi hati diukur menggunakan metode spektrofotometri kinetik dan histopatologi menggunakan mikroskop. Kemudian analisis data menggunakan One Way ANOVA dan Kruskal-Wallis.
Hasil: Pemberian kefir madu randu selama 21 hari menunjukkan perbedaan signifikan kadar ALT pre dan post test (p=0.001), dan menurunkan rerata ALT menjadi 31.22 ± 2,86 U/L pada kelompok P1, tetapi belum efektif menurunkan kadar AST (P=0.058). Terdapat hasil signifikan perbaikan kerusakan jaringan hati akibat penumpukan lemak pada kelompok P1 dan P2.
Kesimpulan: Kefir madu randu menurunkan kadar ALT serta memperbaiki kerusakan jaringan hati akibat penumpukan lemak.
ABSTRACT
Background: The prevalence of diabetes is projected to increase globally by 19.74% by 2030, which necessitates comprehensive interventions. Chronic hyperglycemia-induced oxidative stress contributes to hepatic tissue damage. Kefir is a product rich in antioxidants that has the potential to reduce oxidative stress in diabetic patients with liver damage as indicated by AST and ALT levels. Therefore, consuming kefir at certain doses contributes to the repair of liver tissue damage.
Objectives: To observe the differences in AST, ALT levels, and liver histopathology in diabetic rats intervened with goat's milk kefir combined with randu honey.
Methods: A clinical study with a pre-post test design using 42 male rats of the Sprague Dawley strain (120-150 g) was conducted for 21 days. The samples consisted of 6 groups: Ks (healthy control), KN (diabetic control), K1 (quercetin 15 mg/kg BW), K2 (metformin 62.5 mg/kg BW), P1 (Kefir 1.8 ml/200g BW), and P2 (preventive). Liver function was measured using the kinetic spectrophotometry method and histopathology using a microscope. Then analyze the data using One-Way ANOVA and Kruskal-Wallis.
Results: Administration of randu honey kefir for 21 days showed that there was a significant difference in ALT pre and post test (p=0.001), and reduced ALT levels to 31.22 ± 2.86 U/L in P1 group. There were significant results of improvement in liver tissue damage due to fat accumulation in the P1 and P2 groups.
Conclusions: Randu honey kefir reduces ALT levels and repairs liver tissue damage due to fat accumulation.
References
1. International Diabetes Federation. [Internet]. 2021. IDF Diabetes Atlas, 10th edn. [cited 2024 Sep 10]. Available from: https://www.diabetesatlas.org
2. International Diabetes Federation. IDF DIABETES ATLAS: Ninth edition 2019. 2019 [cited 2024 Dec 10]; Available from: https://diabetesatlas.org/media/uploads/sites/3/2025/02/IDF-Atlas-9th-Edition-EN.pdf
3. Shi G-J, Shi G-R, Zhou J, Zhang W, Gao C, Jiang Y, et al. Involvement of growth factors in diabetes mellitus and its complications: A general review. Biomedicine & Pharmacotherapy. 2018;101:510–27. https://doi.org/10.1016/j.biopha.2018.02.105
4. Saeedi P, Salpea P, Karuranga S, Petersohn I, Malanda B, Gregg EW, et al. Mortality attributable to diabetes in 20–79 years old adults, 2019 estimates: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2020;162:108086. https://doi.org/10.1016/j.diabres.2020.108086
5. Mobasheri L, Ahadi M, Beheshti Namdar A, Alavi MS, Bemidinezhad A, Moshirian Farahi SM, et al. Pathophysiology of diabetic hepatopathy and molecular mechanisms underlying the hepatoprotective effects of phytochemicals. Biomedicine and Pharmacotherapy. Elsevier Masson s.r.l.; 2023;167. https://doi.org/10.1016/j.biopha.2023.115502
6. Teshome G, Ambachew S, Fasil A, Abebe M. Prevalence of Liver Function Test Abnormality and Associated Factors in Type 2 Diabetes Mellitus: A Comparative Cross-Sectional Study. The Journal of the International Federation of Clinical Chemistry and Laboratory Medicine. 2019;30(3):303–16.
7. El-Sayed MH, Thabet RA, Hamza MT, Hussein MS, El Saeed MM. Liver disease in children and adolescents with type 1 diabetes mellitus: A link between glycemic control and hepatopathy. Diabetes Res Clin Pract. 2020;170:108458. https://doi.org/10.1016/j.diabres.2020.108458
8. Schwartz SS, Epstein S, Corkey BE, Grant SFA, Gavin JR, Aguilar RB. The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the β-Cell–Centric Classification Schema. Diabetes Care. 2016;39(2):179–86. https://doi.org/10.2337/dc15-1585
9. Mohamed J, H. NNA, H. ZA, B. BS. Mechanisms of Diabetes-Induced Liver Damage: The role of oxidative stress and inflammation. Sultan Qaboos Univ Med J. 2016;16(2):e132-141. https://doi.org/10.18295/squmj.2016.16.02.002
10. Putri FASE. Pengaruh Vitamin D Terhadap Ekspresi mRNA NF-Kappa B dan Gambaran Histopatologik Makrofag CD68 pada Hepar Tikus Model Diabetes Mellitus [Skripsi]. Universitas Gadjah Mada; 2023.
11. Kumar V, Gill KD. To Determine Alanine and Aspartate Transaminase Activity in Serum. In: Basic Concepts in Clinical Biochemistry: A Practical Guide. Singapore: Springer Singapore; 2018. https://doi.org/10.1007/978-981-10-8186-6_25
12. Tyagi S, Jain P, Wani CP. Elevation Of Liver Enzymes and Its Correlation with Type 2 Diabetes Mellitus in A Tertiary Care Hospital. European Journal of Cardiovascular Medicine. 2025;15(6):209–12. https://doi.org/10.5083/ejcm/25-06-40
13. Parmar K, Singh G, Gupta G, Pathak T, Nayak S. Evaluation of De Ritis ratio in liver-associated diseases. Int J Med Sci Public Health. ScopeMed; 2016;5(9):1783. https://doi.org/10.5455/ijmsph.2016.24122015322
14. Mohamed J, Nazratun Nafizah AH, Zariyantey AH, Budin SB. Mechanisms of diabetes-induced liver damage: The role of oxidative stress and inflammation. Sultan Qaboos Univ Med J. Sultan Qaboos University; 2016;16(2):132–41. https://doi.org/10.18295/squmj.2016.16.02.002
15. London A, Lundsgaard A-M, Kiens B, Bojsen-Møller KN. The Role of Hepatic Fat Accumulation in Glucose and Insulin Homeostasis—Dysregulation by the Liver. J Clin Med. 2021;10(3):390. https://doi.org/10.3390/jcm10030390
16. Mohamed J, H. NNA, H. ZA, B. BS. Mechanisms of Diabetes-Induced Liver Damage: The role of oxidative stress and inflammation. Sultan Qaboos Univ Med J. 2016;16(2):e132-141. https://doi.org/10.18295/squmj.2016.16.02.002
17. Yuniartha R, Arfian N, Setyaningsih WAW, Kencana SMS, Sari DCR. Accelerated Senescence and Apoptosis in the Rat Liver during the Progression of Diabetic Complications. Malaysian Journal of Medical Sciences. Penerbit Universiti Sains Malaysia; 2022;29(6):46–59. https://doi.org/10.21315/mjms2022.29.6.5
18. Azizi NF, Kumar MR, Yeap SK, Abdullah JO, Khalid M, Omar AR, et al. Kefir and its biological activities. Foods. MDPI AG; 2021;10(6). https://doi.org/10.3390/foods10061210
19. Farag MA, Jomaa SA, El-wahed AA, El-seedi HR. The many faces of kefir fermented dairy products: Quality characteristics, flavour chemistry, nutritional value, health benefits, and safety. Nutrients. MDPI AG; 2020;12(2):1. https://doi.org/10.3390/nu12020346
20. Rosa DD, Dias MMS, Grześkowiak ŁM, Reis SA, Conceição LL, Peluzio MDCG. Milk kefir: Nutritional, microbiological and health benefits. Nutr Res Rev. Cambridge University Press; 2017;30(1):82–96. https://doi.org/10.1017/S0954422416000275
21. Rukmi DL, Fitri ZE, Sahenda LN. Characteristics of kefir based on goat’s milk with different starter combinations. IOP Conf Ser Earth Environ Sci. 2023;1168(1). https://doi.org/10.1088/1755-1315/1168/1/012031
22. Hammam ARA, Salman SM, Elfaruk MS, Alsaleem KA. Goat milk: compositional, technological, nutritional, and ther-apeutic aspects. 2021; https://doi.org/10.20944/preprints202108.0097.v1
23. Petherick A. International Milk Genomics Consortium [Internet]. 2018. Goat’s Milk: An Easily Digestible and Hypoallergenic Option [cited 2025 Dec 31]. Available from: https://www.milkgenomics.org/?splash=goats-milk-an-easily-digestible-and-hypoallergic-option
24. Hardiansyah A, Hadi Kusuma H. Optimalisasi Kualitas Organoleptik dan Aktivitas Antioksidan Kefir Susu Kambing dengan Penambahan Madu Lokal Bunga Randu. Journal of Nutrition College. 2022;11(4):278–84. https://doi.org/10.14710/jnc.v11i4.34506
25. Rao PV, Krishnan KT, Salleh N, Gan SH. Biological and therapeutic effects of honey produced by honey bees and stingless bees: a comparative review. Revista Brasileira de Farmacognosia. 2016;26(5):657–64. https://doi.org/10.1016/j.bjp.2016.01.012
26. Mortensen MB, Dzaye O, Bøtker HE, Jensen JM, Maeng M, Bentzon JF, et al. Low-Density Lipoprotein Cholesterol Is Predominantly Associated With Atherosclerotic Cardiovascular Disease Events in Patients With Evidence of Coronary Atherosclerosis: The Western Denmark Heart Registry. Circulation. Lippincott Williams and Wilkins; 2023;147(14):1053–63. https://doi.org/10.1161/circulationaha.122.061010
27. Björkegren JLM, Lusis AJ. Atherosclerosis: Recent developments. Cell. 2022;185(10):1630–45. https://doi.org/10.1016/j.cell.2022.04.004
28. Rusmini H, Febriani D, Risandy D. Pengaruh Madu Ceiba Pentandra Terhadap Kadar LDL Tikus Rattus Norvegicus Yang Diberi Diet Tinggi Lemak. Jurnal Ilmiah Kesehatan Sandi Husada. 2020;11(1):479–89. https://doi.org/10.35816/jiskh.v10i2.331
29. Sulistyianingsih, Poernomo AT, Primaharinastiti R. Physicochemical Properties and Antioxidant Activity of Three Types of Monofloral Honey from Indonesia. Jurnal Farmasi dan Ilmu Kefarmasian Indonesia. Universitas Airlangga; 2022;9(3):290–7. https://doi.org/10.20473/jfiki.v9i32022.290-297
30. Wan Mohammad WMZ. Sample Size Calculation in Animal Studies Using Resource Equation Approach. Malaysian Journal of Medical Sciences. 2017;24(5):101–5. https://doi.org/10.21315/mjms2017.24.5.11
31. Mutiarahmi CN, Hartady T, Lesmana R. Use of Mice as Experimental Animals in Laboratories that Refer to The Principles of Animal Welfare: A Literature Review. Indonesia Medicus Veterinus. 2021;10(1):134–45. https://doi.org/10.19087/imv.2020.10.1.134
32. Khairani D, Ilyas S, Yurnadi. Prinsip dan Praktik Hewan Percobaan Mencit (Mus musculus) [Internet]. Medan: USU Press; 2024 [cited. Available from: https://www.researchgate.net/publication/378012780
33. Saputra MM. Analisis Bakteri Asam Laktat (BAL), Organoleptik, dan Daya Simpan Kefir Susu Kambing dengan Penambahan Madu Bunga Randu (Ceiba pentandra I.) [Skripsi]. Semarang: Universitas Islam Negeri Walisongo; 2023.
34. Hardiansyah A. Identifikasi Nilai Gizi dan Potensi Manfaat Kefir Susu Kambing Kaligesing. Journal of Nutrition College. 2020;9(3):208–14. https://doi.org/10.14710/jnc.v9i3.27308
35. Firdaus. Peran Ekstrak Nutrasetikal Galohgor Untuk Mengatasi Resistensi Insulin pada Tikus Diabetes yang Diinduksi Streptozotocin (STZ). Institut Pertanian Bogor; 2016.
36. Ghasemi A, Jeddi S. Streptozotocin as a Tool for Induction of Rat Models of Diabetes: A Practical Guide. EXCLI J. Leibniz Research Centre for Working Environment and Human Factors; 2023;22:274–94. https://doi.org/10.17179/excli2022-5720
37. Shi G-J, Li Y, Cao Q-H, Wu H-X, Tang X-Y, Gao X-H, et al. In vitro and in vivo evidence that quercetin protects against diabetes and its complications: A systematic review of the literature. Biomedicine & Pharmacotherapy. 2019;109:1085–99. https://doi.org/10.1016/j.biopha.2018.10.130
38. Rahmawati FC, Djamiatun K, Suci N. Pengaruh yogurt sinbiotik pisang terhadap kadar glukosa dan insulin tikus sindrom metabolik. Jurnal Gizi Klinik Indonesia. 2017;14(1):10. https://doi.org/10.22146/ijcn.19379
39. Ahrens Kress AP, Zhang Y, Kaiser-Vry AR, Sauer MB. A Comparison of Blood Collection Techniques in Mice and their Effects on Welfare. Journal of the American Association for Laboratory Animal Science. American Association for Laboratory Animal Science; 2022;61(3):287–95. https://doi.org/10.30802/AALAS-JAALAS-21-000129
40. C. Loomis M. NYU Langone Medical Center [Internet]. 2016. Experimental Pathology Research Laboratory [cited 2025 Jan 3]. Available from: https://share.google/8BJcSuLKjOHBl7HgL
41. Al-Sabaawy HB, Rahawi AM, Al-Mahmood SS. Standard techniques for formalin-fixed paraffin-embedded tissue: A Pathologist’s perspective. Iraqi Journal of Veterinary Sciences. 2021;35(Supplement I-III):127–35. https://doi.org/10.33899/ijvs.2021.131918.2023
42. Octary N, Sari I, Aristoteles. Liver Tissue Examination of Mice Using 10% BNF Fixation For 6 Hours And 16 Hours. Jurnal Analis Laboratorium Medik. 2022;7(2):104–9. https://doi.org/10.51544/jalm.v7i2.3457
43. Abidov M, Sokolova K, Danilova I, Baykenova M, Gette I, Mychlynina E, et al. Hepatic insulin synthesis increases in rat models of diabetes mellitus type 1 and 2 differently. PLoS One. Public Library of Science; 2023;18(11). https://doi.org/10.1371/journal.pone.0294432
44. Pradnyawati N, Lestari AAW, Subawa A, Oka T. Analisis Kadar Albumin Serum terhadap Aspartate Transaminase (AST), Alanine Transaminase (ALT) dan Rasio De Ritis pada Pasien Hepatitis B di RSUP Sanglah, Denpasar. E-Jurnal Medika. 2018;7(6).
45. Yuneldi RF, Saraswati TR, Yuniwarti EYW. Profile of SGPT and SGOT on Male Rats (Rattus norvegicus) Hyperglycemic After Giving Insulin Leaf Extract (Tithonia diversifolia). Biosaintifika: Journal of Biology & Biology Education. 2018;10(3):519–25. https://doi.org/10.15294/biosaintifika.v10i3.5516
46. Sah H, Gülmez N, Söyler G, Sayıner S, Sehirli AÖ, Kükner A. Effect of Kefir on Increased Apoptosis in Liver and Kidney in Cisplatin Toxicity. International Journal of Morphology. 2022;40(2):480. https://doi.org/10.4067/S0717-95022022000200480
47. Guo X xuan, Wang Y, Wang K, Ji B ping, 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. Zhejiang University Press; 2018;19(7):559–69. https://doi.org/10.1631/jzus.B1700254
48. Bagaméry F, Varga K, Kecsmár K, Vincze I, Szökő É, Tábi T. Lack of insulin resistance in response to streptozotocin treatment in neuronal SH-SY5Y cell line. J Neural Transm. 2020;127(1):71–80. https://doi.org/10.1007/s00702-019-02118-5
49. Gheibi S, Kashfi K, Ghasemi A. A practical guide for induction of type-2 diabetes in rat: Incorporating a high-fat diet and streptozotocin. Biomedicine & Pharmacotherapy. 2017;95:605–13. https://doi.org/10.1016/j.biopha.2017.08.098
50. 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. Scientific Foundation SPIROSKI; 2022;10(A):668–74. https://doi.org/10.3889/oamjms.2022.8717
51. OD A. “Liver Function Status of Diabetic Wistar Rats Treated with Ethanol Extract of Cucumis Sativus Fruit.” Biomed J Sci Tech Res. Biomedical Research Network, LLC; 2023;51(2). https://doi.org/ 10.26717/bjstr.2023.51.008065
52. Fitriani RN, Sitasiwi AJ, Isdadiyanto S. Struktur Hepar dan Rasio Bobot Hepar Terhadap Bobot Tubuh Mencit (Mus Musculus L.) Jantan Setelah Pemberian Ekstrak Etanol Daun Mimba (Azadirachta Indica A.Juss). Buletin Anatomi dan Fisiologi. 2020;5(1):75–83. https://doi.org/10.14710/baf.5.1.2020.75-83
53. Salah N, Eissa S, Mansour A, El Magd NMA, Hasanin AH, El Mahdy MM, et al. Evaluation of the role of kefir in management of non-alcoholic steatohepatitis rat model via modulation of NASH linked mRNA-miRNA panel. Sci Rep. Nature Research; 2023;13(1). https://doi.org/10.1038/s41598-022-27353-x
54. Saulahirwan R, Sinay H, Karuwal RL. Transaminase Enzyme and Liver Histopatological Structure of Mice Facing to Smoke Cigarettes After Administerred with Enhalus acoroides Peel Extract. Biosaintifika: Journal of Biology & Biology Education. 2023;15(1):97–104. https://doi.org/10.15294/biosaintifika.v15i1.40725
55. Pramita MI. Perbaikan Kerusakan Sel-Sel Hepatosit Mencit (Mus musculus L.) yang Diinduksi Karbon Tetraklorida (CCl4) oleh Ekstrak Etanol Daun Bungur (Lagerstroemia speciosa L.) [Skripsi]. Bandar Lampung: Universitas Lampung; 2023.
56. Richard Hendarto D, Putri Handayani A, Esterelita E, Aji Handoko Y. Mekanisme Biokimiawi dan Optimalisasi Lactobacillus bulgaricus dan Streptococcus thermophilus dalam Pengolahan Yoghurt yang Berkualitas. Jurnal Sains Dasar. 2021;8(1):13–9. https://doi.org/ 10.21831/jsd.v8i1.24261
57. Setiawati L, Rizqiati H, Susanti S. Analisis Rendemen, Kadar Alkohol, Nilai pH dan Total BAL pada Kefir Whey Susu Kambing dengan Lama Fermentasi yang Berbeda. Jurnal Teknologi Pangan. 2019;3(1):142–6. https://doi.org/10.14710/jtp.2019.23771
58. Kim D-H, Kim H, Jeong D, Kang I-B, Chon J-W, Kim H-S, et al. Kefir alleviates obesity and hepatic steatosis in high-fat diet-fed mice by modulation of gut microbiota and mycobiota: targeted and untargeted community analysis with correlation of biomarkers. J Nutr Biochem. 2017;44:35–43. https://doi.org/10.1016/j.jnutbio.2017.02.014
59. Karni I. Ulasan Ilmiah: Karakteristik Mutu Nutrisi, Organoleptik dan Mikrobiologis Kefir Susu Kambing. Jurnal Teknologi dan Mutu Pangan. 2023;2(1):29–44. https://doi.org/10.30812/jtmp.v2i1.3060
60. Wang H, Zhou X, Sun Y, Sun X, Guo M. Differences in Protein Profiles of Kefir Grains from Different Origins When Subcultured in Goat Milk. J Agric Food Chem. 2022;70(24):7515–24. https://doi.org/10.1021/acs.jafc.2c01391
61. Rachmani NH, Taufik E, Apriantini A, Yuni Cahya Endrawati. Kualitas Kefir Susu Sapi dengan Tambahan Madu Hutan Selama Penyimpanan Suhu Rendah. Jurnal Ilmu Pertanian Indonesia. 2022;28(1):78–82. https://doi.org/10.18343/jipi.28.1.78
62. Ben Taheur F, Mansour C, Mechri S, Laaouar H, Safta Skhiri S, Bouricha M, et al. Protective effects of dietary Kefir against aflatoxin B1‐induced hepatotoxicity in Nile tilapia fish, Oreochromis niloticus. Food Sci Nutr. 2022;10(7):2300–11. https://doi.org/10.1002/fsn3.2838
63. Adalina Y, Heryati Y, Yuniati D. Quality of kapok honey in some areas of Apis mellifera honey cultivation in Central Java and East Java Province. IOP Conf Ser Earth Environ Sci. 2019;394(1):012049. https://doi.org/10.1088/1755-1315/394/1/012049
64. Wardani NP, Primaharinastiti R, Poernomo AT, Khatib A. A Comparative Study of Randu Honey Antimicrobial Activity from Several Regions in Java. Jurnal Farmasi dan Ilmu Kefarmasian Indonesia. 2024;11(2):147–55. https://doi.org/10.20473/jfiki.v11i22024.147-155
65. Ustadi U, Radiati L, Thohari I. Bioactive Components of Rubber Tree Honey (Hevea Brasiliensis) and Calliandra (Calliandra Callothyrsus) and Kapok Honey (Ceiba Pentandra). Jurnal Ilmu dan Teknologi Hasil Ternak. 2017;12(2):97–102. https://doi.org/10.21776/ub.jitek.2017.012.02.6
66. Almasaudi S. The antibacterial activities of honey. Saudi J Biol Sci. 2021;28(4):2188–96. https://doi.org/10.1016/j.sjbs.2020.10.017
67. Mohammadi F, Razmjooei N, Mohsenpour MA, Nejati MA, Eftekhari MH, Hejazi N. The effects of kefir drink on liver aminotransferases and metabolic indicators in patients with nonalcoholic fatty liver disease: a randomized controlled trial. BMC Nutr. 2025;11(3):1–11. https://doi.org/10.1186/s40795-024-00989-w
68. Koodathil J, Venkatachalam G, Bhaskaran K. In vitro and in vivo antidiabetic activity of bitter honey in streptozotocin-nicotinamide-induced diabetic Wistar rats. J Med Life. Carol Davila University Press; 2023;2023(1):91–100. https://doi.org/10.25122/jml-2022-0099
69. Liu M, Tan J, He Z, He X, Hou D-X, He J, et al. Inhibitory effect of blue honeysuckle extract on high-fat-diet-induced fatty liver in mice. Animal Nutrition. 2018;4(3):288–93. https://doi.org/10.1016/j.aninu.2018.06.001
70. Lori G, Cecchi L, Mulinacci N, Melani F, Caselli A, Cirri P, et al. Honey extracts inhibit PTP1B, upregulate insulin receptor expression, and enhance glucose uptake in human HepG2 cells. Biomedicine & Pharmacotherapy. 2019;113:108752. https://doi.org/10.1016/j.biopha.2019.108752
71. Samarghandian S, Azimi-Nezhad M, Samini F, Farkhondeh T. Chrysin treatment improves diabetes and its complications in liver, brain, and pancreas in streptozotocin-induced diabetic rats. Can J Physiol Pharmacol. 2016;94(4):388–93. https://doi.org/10.1139/cjpp-2014-0412
72. Susanti S, Nurwantoro N, Elto JJ, Nugroho T, Suryani AE, Rizqiati H. Preclinical study of goat milk kefir as an antihyperglycemic food. Functional Foods in Health and Disease. 2022;12(12):705. https://doi.org/10.31989/ffhd.v12i12.987
73. ÖZSOY ŞY. Karbon Tetraklorüre Bağlı Ratların Karaciğerinde Oluşan Histopatolojik Değişikliklere Karşı Kefirin Koruyucu Etkisi. Kafkas Univ Vet Fak Derg. 2016; https://doi.org/10.9775/kvfd.2015.14825
74. Ozsoy B, Cantekin Z, Yalcin S, Bayraktar HS. Effects of kefir on blood parameters and intestinal microflora in rats: An experimental study. Kafkas Univ Vet Fak Derg. Veteriner Fakultesi Dergisi; 2021;27(1):111–5. https://doi.org/10.9775/kvfd.2020.24855
2. International Diabetes Federation. IDF DIABETES ATLAS: Ninth edition 2019. 2019 [cited 2024 Dec 10]; Available from: https://diabetesatlas.org/media/uploads/sites/3/2025/02/IDF-Atlas-9th-Edition-EN.pdf
3. Shi G-J, Shi G-R, Zhou J, Zhang W, Gao C, Jiang Y, et al. Involvement of growth factors in diabetes mellitus and its complications: A general review. Biomedicine & Pharmacotherapy. 2018;101:510–27. https://doi.org/10.1016/j.biopha.2018.02.105
4. Saeedi P, Salpea P, Karuranga S, Petersohn I, Malanda B, Gregg EW, et al. Mortality attributable to diabetes in 20–79 years old adults, 2019 estimates: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2020;162:108086. https://doi.org/10.1016/j.diabres.2020.108086
5. Mobasheri L, Ahadi M, Beheshti Namdar A, Alavi MS, Bemidinezhad A, Moshirian Farahi SM, et al. Pathophysiology of diabetic hepatopathy and molecular mechanisms underlying the hepatoprotective effects of phytochemicals. Biomedicine and Pharmacotherapy. Elsevier Masson s.r.l.; 2023;167. https://doi.org/10.1016/j.biopha.2023.115502
6. Teshome G, Ambachew S, Fasil A, Abebe M. Prevalence of Liver Function Test Abnormality and Associated Factors in Type 2 Diabetes Mellitus: A Comparative Cross-Sectional Study. The Journal of the International Federation of Clinical Chemistry and Laboratory Medicine. 2019;30(3):303–16.
7. El-Sayed MH, Thabet RA, Hamza MT, Hussein MS, El Saeed MM. Liver disease in children and adolescents with type 1 diabetes mellitus: A link between glycemic control and hepatopathy. Diabetes Res Clin Pract. 2020;170:108458. https://doi.org/10.1016/j.diabres.2020.108458
8. Schwartz SS, Epstein S, Corkey BE, Grant SFA, Gavin JR, Aguilar RB. The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the β-Cell–Centric Classification Schema. Diabetes Care. 2016;39(2):179–86. https://doi.org/10.2337/dc15-1585
9. Mohamed J, H. NNA, H. ZA, B. BS. Mechanisms of Diabetes-Induced Liver Damage: The role of oxidative stress and inflammation. Sultan Qaboos Univ Med J. 2016;16(2):e132-141. https://doi.org/10.18295/squmj.2016.16.02.002
10. Putri FASE. Pengaruh Vitamin D Terhadap Ekspresi mRNA NF-Kappa B dan Gambaran Histopatologik Makrofag CD68 pada Hepar Tikus Model Diabetes Mellitus [Skripsi]. Universitas Gadjah Mada; 2023.
11. Kumar V, Gill KD. To Determine Alanine and Aspartate Transaminase Activity in Serum. In: Basic Concepts in Clinical Biochemistry: A Practical Guide. Singapore: Springer Singapore; 2018. https://doi.org/10.1007/978-981-10-8186-6_25
12. Tyagi S, Jain P, Wani CP. Elevation Of Liver Enzymes and Its Correlation with Type 2 Diabetes Mellitus in A Tertiary Care Hospital. European Journal of Cardiovascular Medicine. 2025;15(6):209–12. https://doi.org/10.5083/ejcm/25-06-40
13. Parmar K, Singh G, Gupta G, Pathak T, Nayak S. Evaluation of De Ritis ratio in liver-associated diseases. Int J Med Sci Public Health. ScopeMed; 2016;5(9):1783. https://doi.org/10.5455/ijmsph.2016.24122015322
14. Mohamed J, Nazratun Nafizah AH, Zariyantey AH, Budin SB. Mechanisms of diabetes-induced liver damage: The role of oxidative stress and inflammation. Sultan Qaboos Univ Med J. Sultan Qaboos University; 2016;16(2):132–41. https://doi.org/10.18295/squmj.2016.16.02.002
15. London A, Lundsgaard A-M, Kiens B, Bojsen-Møller KN. The Role of Hepatic Fat Accumulation in Glucose and Insulin Homeostasis—Dysregulation by the Liver. J Clin Med. 2021;10(3):390. https://doi.org/10.3390/jcm10030390
16. Mohamed J, H. NNA, H. ZA, B. BS. Mechanisms of Diabetes-Induced Liver Damage: The role of oxidative stress and inflammation. Sultan Qaboos Univ Med J. 2016;16(2):e132-141. https://doi.org/10.18295/squmj.2016.16.02.002
17. Yuniartha R, Arfian N, Setyaningsih WAW, Kencana SMS, Sari DCR. Accelerated Senescence and Apoptosis in the Rat Liver during the Progression of Diabetic Complications. Malaysian Journal of Medical Sciences. Penerbit Universiti Sains Malaysia; 2022;29(6):46–59. https://doi.org/10.21315/mjms2022.29.6.5
18. Azizi NF, Kumar MR, Yeap SK, Abdullah JO, Khalid M, Omar AR, et al. Kefir and its biological activities. Foods. MDPI AG; 2021;10(6). https://doi.org/10.3390/foods10061210
19. Farag MA, Jomaa SA, El-wahed AA, El-seedi HR. The many faces of kefir fermented dairy products: Quality characteristics, flavour chemistry, nutritional value, health benefits, and safety. Nutrients. MDPI AG; 2020;12(2):1. https://doi.org/10.3390/nu12020346
20. Rosa DD, Dias MMS, Grześkowiak ŁM, Reis SA, Conceição LL, Peluzio MDCG. Milk kefir: Nutritional, microbiological and health benefits. Nutr Res Rev. Cambridge University Press; 2017;30(1):82–96. https://doi.org/10.1017/S0954422416000275
21. Rukmi DL, Fitri ZE, Sahenda LN. Characteristics of kefir based on goat’s milk with different starter combinations. IOP Conf Ser Earth Environ Sci. 2023;1168(1). https://doi.org/10.1088/1755-1315/1168/1/012031
22. Hammam ARA, Salman SM, Elfaruk MS, Alsaleem KA. Goat milk: compositional, technological, nutritional, and ther-apeutic aspects. 2021; https://doi.org/10.20944/preprints202108.0097.v1
23. Petherick A. International Milk Genomics Consortium [Internet]. 2018. Goat’s Milk: An Easily Digestible and Hypoallergenic Option [cited 2025 Dec 31]. Available from: https://www.milkgenomics.org/?splash=goats-milk-an-easily-digestible-and-hypoallergic-option
24. Hardiansyah A, Hadi Kusuma H. Optimalisasi Kualitas Organoleptik dan Aktivitas Antioksidan Kefir Susu Kambing dengan Penambahan Madu Lokal Bunga Randu. Journal of Nutrition College. 2022;11(4):278–84. https://doi.org/10.14710/jnc.v11i4.34506
25. Rao PV, Krishnan KT, Salleh N, Gan SH. Biological and therapeutic effects of honey produced by honey bees and stingless bees: a comparative review. Revista Brasileira de Farmacognosia. 2016;26(5):657–64. https://doi.org/10.1016/j.bjp.2016.01.012
26. Mortensen MB, Dzaye O, Bøtker HE, Jensen JM, Maeng M, Bentzon JF, et al. Low-Density Lipoprotein Cholesterol Is Predominantly Associated With Atherosclerotic Cardiovascular Disease Events in Patients With Evidence of Coronary Atherosclerosis: The Western Denmark Heart Registry. Circulation. Lippincott Williams and Wilkins; 2023;147(14):1053–63. https://doi.org/10.1161/circulationaha.122.061010
27. Björkegren JLM, Lusis AJ. Atherosclerosis: Recent developments. Cell. 2022;185(10):1630–45. https://doi.org/10.1016/j.cell.2022.04.004
28. Rusmini H, Febriani D, Risandy D. Pengaruh Madu Ceiba Pentandra Terhadap Kadar LDL Tikus Rattus Norvegicus Yang Diberi Diet Tinggi Lemak. Jurnal Ilmiah Kesehatan Sandi Husada. 2020;11(1):479–89. https://doi.org/10.35816/jiskh.v10i2.331
29. Sulistyianingsih, Poernomo AT, Primaharinastiti R. Physicochemical Properties and Antioxidant Activity of Three Types of Monofloral Honey from Indonesia. Jurnal Farmasi dan Ilmu Kefarmasian Indonesia. Universitas Airlangga; 2022;9(3):290–7. https://doi.org/10.20473/jfiki.v9i32022.290-297
30. Wan Mohammad WMZ. Sample Size Calculation in Animal Studies Using Resource Equation Approach. Malaysian Journal of Medical Sciences. 2017;24(5):101–5. https://doi.org/10.21315/mjms2017.24.5.11
31. Mutiarahmi CN, Hartady T, Lesmana R. Use of Mice as Experimental Animals in Laboratories that Refer to The Principles of Animal Welfare: A Literature Review. Indonesia Medicus Veterinus. 2021;10(1):134–45. https://doi.org/10.19087/imv.2020.10.1.134
32. Khairani D, Ilyas S, Yurnadi. Prinsip dan Praktik Hewan Percobaan Mencit (Mus musculus) [Internet]. Medan: USU Press; 2024 [cited. Available from: https://www.researchgate.net/publication/378012780
33. Saputra MM. Analisis Bakteri Asam Laktat (BAL), Organoleptik, dan Daya Simpan Kefir Susu Kambing dengan Penambahan Madu Bunga Randu (Ceiba pentandra I.) [Skripsi]. Semarang: Universitas Islam Negeri Walisongo; 2023.
34. Hardiansyah A. Identifikasi Nilai Gizi dan Potensi Manfaat Kefir Susu Kambing Kaligesing. Journal of Nutrition College. 2020;9(3):208–14. https://doi.org/10.14710/jnc.v9i3.27308
35. Firdaus. Peran Ekstrak Nutrasetikal Galohgor Untuk Mengatasi Resistensi Insulin pada Tikus Diabetes yang Diinduksi Streptozotocin (STZ). Institut Pertanian Bogor; 2016.
36. Ghasemi A, Jeddi S. Streptozotocin as a Tool for Induction of Rat Models of Diabetes: A Practical Guide. EXCLI J. Leibniz Research Centre for Working Environment and Human Factors; 2023;22:274–94. https://doi.org/10.17179/excli2022-5720
37. Shi G-J, Li Y, Cao Q-H, Wu H-X, Tang X-Y, Gao X-H, et al. In vitro and in vivo evidence that quercetin protects against diabetes and its complications: A systematic review of the literature. Biomedicine & Pharmacotherapy. 2019;109:1085–99. https://doi.org/10.1016/j.biopha.2018.10.130
38. Rahmawati FC, Djamiatun K, Suci N. Pengaruh yogurt sinbiotik pisang terhadap kadar glukosa dan insulin tikus sindrom metabolik. Jurnal Gizi Klinik Indonesia. 2017;14(1):10. https://doi.org/10.22146/ijcn.19379
39. Ahrens Kress AP, Zhang Y, Kaiser-Vry AR, Sauer MB. A Comparison of Blood Collection Techniques in Mice and their Effects on Welfare. Journal of the American Association for Laboratory Animal Science. American Association for Laboratory Animal Science; 2022;61(3):287–95. https://doi.org/10.30802/AALAS-JAALAS-21-000129
40. C. Loomis M. NYU Langone Medical Center [Internet]. 2016. Experimental Pathology Research Laboratory [cited 2025 Jan 3]. Available from: https://share.google/8BJcSuLKjOHBl7HgL
41. Al-Sabaawy HB, Rahawi AM, Al-Mahmood SS. Standard techniques for formalin-fixed paraffin-embedded tissue: A Pathologist’s perspective. Iraqi Journal of Veterinary Sciences. 2021;35(Supplement I-III):127–35. https://doi.org/10.33899/ijvs.2021.131918.2023
42. Octary N, Sari I, Aristoteles. Liver Tissue Examination of Mice Using 10% BNF Fixation For 6 Hours And 16 Hours. Jurnal Analis Laboratorium Medik. 2022;7(2):104–9. https://doi.org/10.51544/jalm.v7i2.3457
43. Abidov M, Sokolova K, Danilova I, Baykenova M, Gette I, Mychlynina E, et al. Hepatic insulin synthesis increases in rat models of diabetes mellitus type 1 and 2 differently. PLoS One. Public Library of Science; 2023;18(11). https://doi.org/10.1371/journal.pone.0294432
44. Pradnyawati N, Lestari AAW, Subawa A, Oka T. Analisis Kadar Albumin Serum terhadap Aspartate Transaminase (AST), Alanine Transaminase (ALT) dan Rasio De Ritis pada Pasien Hepatitis B di RSUP Sanglah, Denpasar. E-Jurnal Medika. 2018;7(6).
45. Yuneldi RF, Saraswati TR, Yuniwarti EYW. Profile of SGPT and SGOT on Male Rats (Rattus norvegicus) Hyperglycemic After Giving Insulin Leaf Extract (Tithonia diversifolia). Biosaintifika: Journal of Biology & Biology Education. 2018;10(3):519–25. https://doi.org/10.15294/biosaintifika.v10i3.5516
46. Sah H, Gülmez N, Söyler G, Sayıner S, Sehirli AÖ, Kükner A. Effect of Kefir on Increased Apoptosis in Liver and Kidney in Cisplatin Toxicity. International Journal of Morphology. 2022;40(2):480. https://doi.org/10.4067/S0717-95022022000200480
47. Guo X xuan, Wang Y, Wang K, Ji B ping, 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. Zhejiang University Press; 2018;19(7):559–69. https://doi.org/10.1631/jzus.B1700254
48. Bagaméry F, Varga K, Kecsmár K, Vincze I, Szökő É, Tábi T. Lack of insulin resistance in response to streptozotocin treatment in neuronal SH-SY5Y cell line. J Neural Transm. 2020;127(1):71–80. https://doi.org/10.1007/s00702-019-02118-5
49. Gheibi S, Kashfi K, Ghasemi A. A practical guide for induction of type-2 diabetes in rat: Incorporating a high-fat diet and streptozotocin. Biomedicine & Pharmacotherapy. 2017;95:605–13. https://doi.org/10.1016/j.biopha.2017.08.098
50. 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. Scientific Foundation SPIROSKI; 2022;10(A):668–74. https://doi.org/10.3889/oamjms.2022.8717
51. OD A. “Liver Function Status of Diabetic Wistar Rats Treated with Ethanol Extract of Cucumis Sativus Fruit.” Biomed J Sci Tech Res. Biomedical Research Network, LLC; 2023;51(2). https://doi.org/ 10.26717/bjstr.2023.51.008065
52. Fitriani RN, Sitasiwi AJ, Isdadiyanto S. Struktur Hepar dan Rasio Bobot Hepar Terhadap Bobot Tubuh Mencit (Mus Musculus L.) Jantan Setelah Pemberian Ekstrak Etanol Daun Mimba (Azadirachta Indica A.Juss). Buletin Anatomi dan Fisiologi. 2020;5(1):75–83. https://doi.org/10.14710/baf.5.1.2020.75-83
53. Salah N, Eissa S, Mansour A, El Magd NMA, Hasanin AH, El Mahdy MM, et al. Evaluation of the role of kefir in management of non-alcoholic steatohepatitis rat model via modulation of NASH linked mRNA-miRNA panel. Sci Rep. Nature Research; 2023;13(1). https://doi.org/10.1038/s41598-022-27353-x
54. Saulahirwan R, Sinay H, Karuwal RL. Transaminase Enzyme and Liver Histopatological Structure of Mice Facing to Smoke Cigarettes After Administerred with Enhalus acoroides Peel Extract. Biosaintifika: Journal of Biology & Biology Education. 2023;15(1):97–104. https://doi.org/10.15294/biosaintifika.v15i1.40725
55. Pramita MI. Perbaikan Kerusakan Sel-Sel Hepatosit Mencit (Mus musculus L.) yang Diinduksi Karbon Tetraklorida (CCl4) oleh Ekstrak Etanol Daun Bungur (Lagerstroemia speciosa L.) [Skripsi]. Bandar Lampung: Universitas Lampung; 2023.
56. Richard Hendarto D, Putri Handayani A, Esterelita E, Aji Handoko Y. Mekanisme Biokimiawi dan Optimalisasi Lactobacillus bulgaricus dan Streptococcus thermophilus dalam Pengolahan Yoghurt yang Berkualitas. Jurnal Sains Dasar. 2021;8(1):13–9. https://doi.org/ 10.21831/jsd.v8i1.24261
57. Setiawati L, Rizqiati H, Susanti S. Analisis Rendemen, Kadar Alkohol, Nilai pH dan Total BAL pada Kefir Whey Susu Kambing dengan Lama Fermentasi yang Berbeda. Jurnal Teknologi Pangan. 2019;3(1):142–6. https://doi.org/10.14710/jtp.2019.23771
58. Kim D-H, Kim H, Jeong D, Kang I-B, Chon J-W, Kim H-S, et al. Kefir alleviates obesity and hepatic steatosis in high-fat diet-fed mice by modulation of gut microbiota and mycobiota: targeted and untargeted community analysis with correlation of biomarkers. J Nutr Biochem. 2017;44:35–43. https://doi.org/10.1016/j.jnutbio.2017.02.014
59. Karni I. Ulasan Ilmiah: Karakteristik Mutu Nutrisi, Organoleptik dan Mikrobiologis Kefir Susu Kambing. Jurnal Teknologi dan Mutu Pangan. 2023;2(1):29–44. https://doi.org/10.30812/jtmp.v2i1.3060
60. Wang H, Zhou X, Sun Y, Sun X, Guo M. Differences in Protein Profiles of Kefir Grains from Different Origins When Subcultured in Goat Milk. J Agric Food Chem. 2022;70(24):7515–24. https://doi.org/10.1021/acs.jafc.2c01391
61. Rachmani NH, Taufik E, Apriantini A, Yuni Cahya Endrawati. Kualitas Kefir Susu Sapi dengan Tambahan Madu Hutan Selama Penyimpanan Suhu Rendah. Jurnal Ilmu Pertanian Indonesia. 2022;28(1):78–82. https://doi.org/10.18343/jipi.28.1.78
62. Ben Taheur F, Mansour C, Mechri S, Laaouar H, Safta Skhiri S, Bouricha M, et al. Protective effects of dietary Kefir against aflatoxin B1‐induced hepatotoxicity in Nile tilapia fish, Oreochromis niloticus. Food Sci Nutr. 2022;10(7):2300–11. https://doi.org/10.1002/fsn3.2838
63. Adalina Y, Heryati Y, Yuniati D. Quality of kapok honey in some areas of Apis mellifera honey cultivation in Central Java and East Java Province. IOP Conf Ser Earth Environ Sci. 2019;394(1):012049. https://doi.org/10.1088/1755-1315/394/1/012049
64. Wardani NP, Primaharinastiti R, Poernomo AT, Khatib A. A Comparative Study of Randu Honey Antimicrobial Activity from Several Regions in Java. Jurnal Farmasi dan Ilmu Kefarmasian Indonesia. 2024;11(2):147–55. https://doi.org/10.20473/jfiki.v11i22024.147-155
65. Ustadi U, Radiati L, Thohari I. Bioactive Components of Rubber Tree Honey (Hevea Brasiliensis) and Calliandra (Calliandra Callothyrsus) and Kapok Honey (Ceiba Pentandra). Jurnal Ilmu dan Teknologi Hasil Ternak. 2017;12(2):97–102. https://doi.org/10.21776/ub.jitek.2017.012.02.6
66. Almasaudi S. The antibacterial activities of honey. Saudi J Biol Sci. 2021;28(4):2188–96. https://doi.org/10.1016/j.sjbs.2020.10.017
67. Mohammadi F, Razmjooei N, Mohsenpour MA, Nejati MA, Eftekhari MH, Hejazi N. The effects of kefir drink on liver aminotransferases and metabolic indicators in patients with nonalcoholic fatty liver disease: a randomized controlled trial. BMC Nutr. 2025;11(3):1–11. https://doi.org/10.1186/s40795-024-00989-w
68. Koodathil J, Venkatachalam G, Bhaskaran K. In vitro and in vivo antidiabetic activity of bitter honey in streptozotocin-nicotinamide-induced diabetic Wistar rats. J Med Life. Carol Davila University Press; 2023;2023(1):91–100. https://doi.org/10.25122/jml-2022-0099
69. Liu M, Tan J, He Z, He X, Hou D-X, He J, et al. Inhibitory effect of blue honeysuckle extract on high-fat-diet-induced fatty liver in mice. Animal Nutrition. 2018;4(3):288–93. https://doi.org/10.1016/j.aninu.2018.06.001
70. Lori G, Cecchi L, Mulinacci N, Melani F, Caselli A, Cirri P, et al. Honey extracts inhibit PTP1B, upregulate insulin receptor expression, and enhance glucose uptake in human HepG2 cells. Biomedicine & Pharmacotherapy. 2019;113:108752. https://doi.org/10.1016/j.biopha.2019.108752
71. Samarghandian S, Azimi-Nezhad M, Samini F, Farkhondeh T. Chrysin treatment improves diabetes and its complications in liver, brain, and pancreas in streptozotocin-induced diabetic rats. Can J Physiol Pharmacol. 2016;94(4):388–93. https://doi.org/10.1139/cjpp-2014-0412
72. Susanti S, Nurwantoro N, Elto JJ, Nugroho T, Suryani AE, Rizqiati H. Preclinical study of goat milk kefir as an antihyperglycemic food. Functional Foods in Health and Disease. 2022;12(12):705. https://doi.org/10.31989/ffhd.v12i12.987
73. ÖZSOY ŞY. Karbon Tetraklorüre Bağlı Ratların Karaciğerinde Oluşan Histopatolojik Değişikliklere Karşı Kefirin Koruyucu Etkisi. Kafkas Univ Vet Fak Derg. 2016; https://doi.org/10.9775/kvfd.2015.14825
74. Ozsoy B, Cantekin Z, Yalcin S, Bayraktar HS. Effects of kefir on blood parameters and intestinal microflora in rats: An experimental study. Kafkas Univ Vet Fak Derg. Veteriner Fakultesi Dergisi; 2021;27(1):111–5. https://doi.org/10.9775/kvfd.2020.24855
Authors
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.