Metabolic and structural hepatic changes in diabetes and intracerebral haemorrhage: Comparative study of lipid-lowering and antidiabetic drugs
Abstract
Type 2 diabetes is a major global health problem frequently accompanied by hepatic metabolic disturbances. An exper i mental model of streptozotocin-induced type 2 diabetes complicated by intracerebral haemorrhage was established in rats. Pha r macological correction was performed using rosuvastatin, metformin, or vitamin D. Liver morphology was assessed by histolo g ical examination, while lipid and biochemical parameters were evaluated using spectrometric methods. Streptozotocin-induced type 2 diabetes was associated with significant dysregulation of glucose metabolism, hepatic cholesterol and triglyceride levels, and aminotransferase activity. The addition of intracerebral haemorrhage resulted in pronounced macrovesicular steatosis, deter i oration of the hepatic lipid profile, diapedesis haemorrhage, perivascular oedema, and marked lymphocytic infiltration. Rosuvastatin demonstrated the most pronounced corrective effect, leading to near-complete regression of steatosis, normalisation of lipid parameters, prevention of necrotic and haemorrhagic changes, and restoration of lobular liver architecture. Metformin and vitamin D produced moderate improvements in hepatic morphology and lipid metabolism without full normalisation. Intracerebral haemorrhage markedly aggravates hepatic morphofunctional disturbances in streptozotocin-induced type 2 diabetes, promoting the development of macrovesicular steatosis. Among the agents investigated, rosuvastatin exhibited the greatest hepatoprotective potential, whereas metformin and vitamin D showed moderate corrective effects. These findings support diffe r entiated pharmacological approaches and suggest potential benefits of combination therapy in diabetic hepatopathy. From a research perspective, further work should focus on identifying effective combinations of the drugs studied in this experimental model.References
Christiansen, L. B., Dohlmann, T. L., Ludvigsen, T. P., Parfieniuk, E., Ciborowski, M., Szczerbinski, L., Kretowski, A., Desler, C., Tiano, L., Orlando, P., Martinussen, T., Olsen, L. H., & Larsen, S. (2021). Atorvastatin impairs liver mitochondrial function in obese Göttingen minipigs but heart and skeletal muscle are not affected. Scientific Reports, 11(1), 2167.
Corsini, A., & Bortolini, M. (2013). Drug-induced liver injury: The role of drug metabolism and transport. Journal of Clinical Pharmacology, 53(5), 463–474.
Dall'Agnese, A., Platt, J. M., Zheng, M. M., Friesen, M., Dall'Agnese, G., Blaise, A. M., Spinelli, J. B., Henninger, J. E., Tevonian, E. N., Hannett, N. M., Lazaris, C., Drescher, H. K., Bartsch, L. M., Kilgore, H. R., Jaenisch, R., Griffith, L. G., Cisse, I. I., Jeppesen, J. F., Lee, T. I., & Young, R. A. (2022). The dynamic clustering of the insulin receptor underlies its signalling and is disrupted in insulin resistance. Nature Communications, 13(1), 7522.
Du, T., Xiang, L., Zhang, J., Yang, C., Zhao, W., Li, J., Zhou, Y., & Ma, L. (2023). Vitamin D improves hepatic steatosis in NAFLD via regulation of fatty acid uptake and β-oxidation. Frontiers in Endocrinology, 14, 1138078.
Dutta, S., Shah, R. B., Singhal, S., Dutta, S. B., Bansal, S., Sinha, S., & Haque, M. (2023). Metformin: A review of potential mechanisms and therapeutic utility beyond diabetes. Drug Design, Development and Therapy, 17, 1907–1932.
Dyomshyna, O. O., & Kyrychenko, S. V. (2020). Hepatotoksychnistʹ likarsʹkykh zasobiv [Hepatotoxicity of drugs]. Dnipro National University, Dnipro (in Ukrainian).
Dyomshyna, O., & Reziapov, A. (2021). Formuvannya korelyatsiynykh zv’yazkiv mizh biokhimichnymy parametramy tsukrovoho diabetu typu 2 ta zakhvoryuvan’ pechinky, yak markeriv pechinkovoyi insulinorezystentnosti [Formation of a correlation between biochemical parameters of type 2 diabetes mellitus and liver diseases, such as insulin resistance markers]. Biology and Ecology, 6(1–2), 82–91 (in Ukrainian).
Dziubak, A., Wójcicka, G., Wojtak, A., & Bełtowski, J. (2018). Metabolic effects of metformin in the failing heart. International Journal of Molecular Sciences, 19(10), 2869.
El Messaoudi, S., Rongen, G. A., de Boer, R. A., & Riksen, N. P. (2011). The cardioprotective effects of metformin. Current Opinion in Lipidology, 22(6), 445–453.
Etuk, E. U. (2010). Animal models for studying diabetes mellitus. Global Journal of Medical Sciences, 1(2), 130–135.
Fahmy, M. I. M., Sayed, R. H., El-Yamany, M. F., El-Naggar, R., & A Eliwa, H. (2022). Rosuvastatin and co-enzyme Q10 improve high-fat and high-fructose diet-induced metabolic syndrome in rats via ameliorating the inflammatory and oxidative burden. Biomedicine and Pharmacotherapy, 153, 113526.
Farrash, W. F., Idris, S., Elzubier, M. E., Khidir, E. B. A., Aslam, A., Mujalli, A., Almaimani, R. A., Obaid, A. A., El-Readi, M. Z., Alobaidy, M. A., Salaka, A., Shakoori, A. M., Saleh, A. M., Minshawi, F., Samkari, J. A., Alshehre, S. M., & Refaat, B. (2024). Enhanced hepatoprotective effects of empagliflozin and vitamin D dual therapy against metabolic dysfunction-associated steatohepatitis in mice by boosted modulation of metabolic, oxidative stress, and inflammatory pathways. International Journal of Experimental Pathology, 105(6), 219–234.
Frias, J. P., Wynne, A. G., Matyjaszek-Matuszek, B., Bartaskova, D., Cox, D. A., Woodward, B., Li, Y. G., Tham, L. S., & Milicevic, Z. (2019). Efficacy and safety of an expanded dulaglutide dose range: A phase 2, placebo-controlled trial in patients with type 2 diabetes using metformin. Diabetes, Obesity and Metabolism, 21(9), 2048–2057.
Furman, B. L. (2021). Streptozotocin-induced diabetic models in mice and rats. Current Protocols, 1, e78.
Ghasemi, A., Khalifi, S., & Jedi, S. (2014). Streptozotocin-nicotinamide-induced rat model of type 2 diabetes (review). Acta Physiologica Hungarica, 101(4), 408–412.
Goel, S., Singh, R., Singh, V., Singh, H., Kumari, P., Chopra, H., Sharma, R., Nepovimova, E., Valis, M., Kuca, K., & Emran, T. B. (2022). Metformin: Activation of 5′ AMP-activated protein kinase and its emerging potential beyond anti-hyperglycemic action. Frontiers in Genetics, 13, 1022739.
Grievink, H., Kuzmina, N., Chevion, M., & Drenger, B. (2019). Sevoflurane postconditioning is not mediated by ferritin accumulation and cannot be rescued by simvastatin in isolated streptozotocin-induced diabetic rat hearts. PLoS One, 14(1), e0211238.
Heeba, G. H., & Hamza, A. A. (2015). Rosuvastatin ameliorates diabetes-induced reproductive damage via suppression of oxidative stress, inflammatory and apoptotic pathways in male rats. Life Sciences, 141, 13–19.
Kim, D. Y., Kim, S. H., Kim, E. J., Han, S. J., Park, J. Y., Youn, J. C., Kim, H. S., Jeong, J. E., & Ryu, K. H. (2025). Rosulord® safety for patients with dyslipidemia study: A non-interventional, multicenter, prospective, observational study in South Korea. Cardiology and Therapy, 14(1), 17–29.
Kim, G. H., Jeong, H. J., Lee, Y. J., Park, H. Y., Koo, S. K., & Lim, J. H. (2024). Vitamin D ameliorates age-induced nonalcoholic fatty liver disease by increasing the mitochondrial contact site and cristae organising system (MICOS) 60 level. Experimental and Molecular Medicine, 56, 142–155.
Kishore, L., Kajal, A., & Kaur, N. (2017). Role of nicotinamide in streptozotocin-induced diabetes in animal models. Journal of Applied Pharmaceutical Science Research, 2(1), 1–4.
Lee, W. H., Najjar, S. M., Kahn, C. R., & Hinds Jr., T. D. (2023). Hepatic insulin receptor: New views on the mechanisms of liver disease. Metabolism, 145, 155607.
Li, H., Zhang, J., Shi, Y., Zhao, G., Xu, H., Cai, M., Gao, J., & Wang, H. (2022). Mechanism of INSR clustering with insulin activation and resistance revealed by super-resolution imaging. Nanoscale, 14, 7747–7755.
Li, T. T., An, J. X., Xu, J. Y., & Tuo, B. G. (2019). Overview of organic anion transporters and organic anion transporter polypeptides and their roles in the liver. World Journal of Clinical Cases, 7(23), 3915–3933.
MacLellan, C. L., Silasi, G., Auriat, A. M., & Colbourne, F. (2010). Rodent models of intracerebral cerebral haemorrhage injury. Stroke, 41(10), 95–98.
Marek, K., Cichoń, N., Saluk-Bijak, J., Bijak, M., & Miller, E. (2022). The role of vitamin D in stroke prevention and the effects of its supplementation for post-stroke rehabilitation: A narrative review. Nutrients, 14(13), 2761.
Marino, F., Salerno, N., Scalise, M., Salerno, L., Torella, A., Molinaro, C., Chiefalo, A., Filardo, A., Siracusa, C., Panuccio, G., Ferravante, C., Giurato, G., Rizzo, F., Torella, M., Donniacuo, M., De Angelis, A., Viglietto, G., Urbanek, K., Weisz, A., Torella, D., … Cianflone, E. (2023). Streptozotocin-induced type 1 and 2 diabetes mellitus mouse models show different functional, cellular and molecular patterns of diabetic cardiomyopathy. International Journal of Molecular Sciences, 24(2), 1132.
Massimino, M., Monea, G., Marinaro, G., Rubino, M., Mancuso, E., Mannino, G. C., & Andreozzi, F. (2022). The triglycerides and glucose (TyG) index are associated with 1-hour glucose levels during an OGTT. International Journal of Environmental Research and Public Health, 20(1), 787.
Nagata, H., & Einama, T. (2020). A patient with a pancreatic neuroendocrine tumour and multiple liver metastases achieved a long-term partial response to third-line streptozocin treatment. International Cancer Conference Journal, 9(1), 45–49.
Neri, A. A., Dontas, I. A., Iliopoulos, D. C., & Karatzas, T. (2020). Pathophysiological changes during ischemia-reperfusion injury in rodent hepatic steatosis. In Vivo, 34(3), 953–964.
Ning, C., Liu, L., Lv, G., Yang, Y., Zhang, Y., Yu, R., Wang, Y., & Zhu, J. (2015). Lipid metabolism and inflammation modulated by vitamin D in type 2 diabetic rat liver. Lipids in Health and Disease, 14, 1–12.
Papanagnou, P., Stivarou, T., & Tsironi, M. (2016). Unexploited antineoplastic effects of commercially available anti-diabetic drugs. Pharmaceuticals, 9(2), 24.
Pfisterer, N., Schwarz, M., Schwarz, C., Putre, F., Ritt, L., Riedl, F., Hartl, L., Jachs, M., Mandorfer, M., Madl, C., Trauner, M., & Reiberger, T. (2024). Statins, metformin, and RAS inhibitors did not reduce variceal bleeding risk and mortality in a large, real-life cohort of patients with cirrhosis. PLoS One, 19(6), e0302811.
Ravaioli, F., Pivetti, A., Di Marco, L., Chrysanthi, C., Frassanito, G., Pambianco, M., Sicuro, C., Gualandi, N., Guasconi, T., Pecchini, M., & Colecchia, A. (2022). Role of vitamin D in liver disease and complications of advanced chronic liver disease. International Journal of Molecular Sciences, 23(16), 9016.
Reda, D., Elshopakey, G. E., Albukhari, T. A., Almehmadi, S. J., Refaat, B., Risha, E. F., Mahgoub, H. A., El-Boshy, M. E., & Abdelhamid, F. M. (2023). Vitamin D3 alleviates nonalcoholic fatty liver disease in rats by inhibiting hepatic oxidative stress and inflammation via the SREBP-1c/PPARα-NF-κB/IRS-2 signalling pathway. Frontiers in Pharmacology, 14, 1164512.
Rondi, S., Peddolla, R., & Venisetty, R. K. (2014). Neuro, cardio, and renal protective activities of rosuvastatin in streptozotocin-induced type 2 diabetic rats undergoing treatment with metformin and glimepiride. Journal of Advanced Pharmaceutical Technology and Research, 5(2), 78–83.
Sakurai, Y., Kubota, N., Yamauchi, T., & Kadowaki, T. (2021). Role of insulin resistance in MAFLD. International Journal of Molecular Sciences, 22(8), 4156.
Shymanskyi, I., Lisakovska, O., Veliky, M., Mezhenska, O., Bilous, V., Siromolot, A., Khomenko, A., Labudzynskyi, D., Horidko, T., & Pasichna, E. (2025). Vitamin D3 affects liver expression of pro- and anti-inflammatory cytokines and nitric oxide synthases in type 2 diabetes. Experimental Biology and Medicine, 250, 10456.
Silvares, R. R., Pereira, E. N., Flores, E. E., Estato, V., Reis, P. A., Silva, I. J., Machado, M. P., Neto, H. C., Tibiriça, E., & Daliry, A. (2016). Combined therapy with metformin and insulin attenuates systemic and hepatic alterations in a model of high-fat diet/streptozotocin-induced diabetes. International Journal of Experimental Pathology, 97(3), 266–277.
Sporea, I., Mare, R., Popescu, A., Nistorescu, S., Baldea, V., Sirli, R., Braha, A., Sima, A., Timar, R., & Lupusoru, R. (2020). Screening for liver fibrosis and steatosis in a large cohort of patients with type 2 diabetes using vibration-controlled transient elastography and controlled attenuation parameter. Journal of Clinical Medicine, 9(4), 1032.
Steinberg, G. R., Valvano, C. M., De Nardo, W., & Watt, M. J. (2025). Integrative metabolism in MASLD and MASH: Pathophysiology and emerging mechanisms. Journal of hepatology, 83(2), 584–595.
Sulaieva, O., Yerokhovych, V., Zemskov, S., Komisarenko, I., Gurianov, V., Pankiv, V., Tovkai, O., Yuzvenko, T., Yuzvenko, V., Tovkai, A., Shaienko, Z., Falalyeyeva, T., Skrypnyk, N., Romaniv, T., Pasyechko, N., Krytskyy, T., Danyliuk, S., Klantsa, A., Krasnienkov, D., Gurbych, O., … Kobyliak, N. (2024). The impact of war on people with type 2 diabetes in Ukraine: A survey study. eClinicalMedicine, 79, 103008.
Veluthakal, R., Esparza, D., Hoolachan, J. M., Balakrishnan, R., Ahn, M., Oh, E., Jayasena, C. S., & Thurmond, D. C. (2024). Mitochondrial dysfunction, oxidative stress, and inter-organ miscommunications in T2D progression. International Journal of Molecular Sciences, 25(3), 1504.
Wang, C., Deng, H., & Xu, Y. (2022). Literature review of the clinical characteristics of metformin-induced hepatotoxicity. Frontiers in Pharmacology, 13, 969505.
Wieckowski, M. R., Giorgi, C., Lebiedzinska, M., Duszynski, J., & Pinton, P. (2009). Isolation of mitochondria-associated membranes and mitochondria from animal tissues and cells. Nature Protocols, 4(10), 1582–1590.
Zhang, J. Y., Bai, Q. K., & Zhang, Y. D. (2018). Pretreatment with simvastatin upregulates expression of BK-2R and CD11b in the ischemic penumbra of rats. Journal of Biomedical Research, 32(5), 354–360.
Zhyliuk, V. I., Lievykh, A. E., Shevtsova, A. I., Tkachenko, V. A., & Kharchenko, Y. V. (2021b). The impact of perindopril and metformin on the markers of endothelial dysfunction in rats with acute intracerebral haemorrhage and type 2 diabetes mellitus. Medicni Perspektivi, 26(4), 15.
Zhyliuk, V., Levykh, A., Shevtsova, A., Tkachenko, V. A., Kharchenko, Y. V., & Myronenko, A. H. (2021a). The impact of metformin and rosuvastatin on the markers of oxidative stress, glycemic control, and lipid profile in rats with streptozotocin-nicotinamide-induced diabetes after acute intracerebral cerebral haemorrhage injury. Problems of Endocrine Pathology, 78(4), 87–93.
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons «Attribution» 4.0 License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.


