Evaluation of The Antioxidant, Hypolipidemic, and Pancreatic Histological Alterations Effects of Tirzepatide in High-Fat Diet and Streptozotocin-Induced Type 2 Diabetic Rats

Authors

  • Shams Dhiaa Fakhir Department of Pharmacology and Toxicology, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq
  • Inam Sameh Arif Department of Pharmacology and Toxicology, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq
  • Sayed Mahmood Alqallaf Pharmacy program, College of Health Sciences, University of Bahrain, Kingdom of Bahrain
  • Huda Jaber Waheed Department of Pharmacology and Toxicology, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq

DOI:

https://doi.org/10.32947/ajps.v26i1.1347

Keywords:

Type 2 diabetes, High-Fat diet, Streptozocin, Tirzepatide, lipid profile, SOD

Abstract

Background: Type 2 diabetes mellitus (T2DM) is a complicated and multifaceted metabolic disease defined by insulin resistance, dyslipidemia, oxidative stress, and β-cell dysfunction.  Tirzepatide (TZP), a dual GIP and GLP-1 receptor agonist, offers potent glucose-lowering and weight-loss.

Objective: To assess the effect of different doses of TZP on lipid profile, SOD activity, and histopathological changes of the pancreas in a high-fat diet and streptozotocin-induced T2DM.

Methods: Thirty male Wistar rats were divided into five groups (n=6): Group I, control group, Groups II-V were induced with diabetes by feeding with a high-fat diet for six weeks with a single injection of streptozocin (35 mg/kg). Groups III- V were treated with TZP at three doses: low, medium, and high (0.44, 0.88, and 1.32 mg/kg) subcutaneously once weekly for 4 weeks. Blood and pancreas samples were then collected for biochemical and histopathological analyses.

Result: The results showed that all doses of TZP-treated groups significantly lowered (p<0.0001) cholesterol, TG, LDL, and VLDL, and increased SOD and HDL levels in a dose-response manner compared to the T2DM rats. while all doses of the TZP-treated groups revealed pronounced improvements in pancreatic architecture, especially at the higher doses.

Conclusion: Treatment of T2DM rats with TZP ameliorated their lipid profile, improving pancreatic architecture and augmenting antioxidant activity.

References

1- Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022;183:109119.

2- Goel S, Garg PK, Malhotra V, Madan J, Mitra S, Grover S. Dyslipidemia in Type II Diabetes Mellitus-An assessment of the main lipoprotein abnormalities. Bangladesh J Med Sci. 2016;15(1):99–102.

3- Bhatti JS, Sehrawat A, Mishra J, Sidhu IS, Navik U, Khullar N, et al. Oxidative stress in the pathophysiology of type 2 diabetes and related complications: Current therapeutics strategies and future perspectives. Free Radic Biol Med. 2022;184:114–34.

4- Sakamoto-Hojo ET, Lima J, Xavier D. Oxidative Stress, DNA Damage and Repair Pathways in Patients with Type 2 Diabetes Mellitus. In: Siderova M, editor. Rijeka: IntechOpen; 2019.

5- Omoruyi F, Sparks J, Stennett D, Dilworth L. Chapter 40 - Superoxide dismutase as a measure of antioxidant status and its application to diabetes. In: Preedy VRBTD (Second E, editor. Academic Press; 2020. p. 409–17.

6- Skovsø S. Modeling type 2 diabetes in rats using high fat diet and streptozotocin. J Diabetes Investig. 2014;5(4):349–58.

7- Willard FS, Douros JD, Gabe MBN, Showalter AD, Wainscott DB, Suter TM, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI insight. 2020;5(17).

8- Chavda VP, Ajabiya J, Teli D, Bojarska J, Apostolopoulos V. Tirzepatide, a new era of dual-targeted treatment for diabetes and obesity: a mini-review. Molecules. 2022;27(13):4315.

9- Binh DV, Dung NTK, Thao LTB, Nhi NB, Chi P V. Macro-and microvascular complications of diabetes induced by high-fat diet and low-dose streptozotocin injection in rats model. Int J Diabetes Res. 2013;2(3):50–5.

10- Guo X, Lei M, Zhao J, Wu M, Ren Z, Yang X, et al. Tirzepatide ameliorates spatial learning and memory impairment through modulation of aberrant insulin resistance and in fl ammation response in diabetic rats. 2023;(August):1–14.

11- Hegab II, El-Horany HE, Abd-Ellatif RN, Nasef NA, Okasha AH, Emam MN, et al. Adropin/Tirzepatide Combination Mitigates Cardiac Metabolic Aberrations in a Rat Model of Polycystic Ovarian Syndrome, Implicating the Role of the AKT/GSK3β/NF-κB/NLRP3 Pathway. Vol. 26, International Journal of Molecular Sciences. 2025.

12- Zatroch KK, Knight CG, Reimer JN, Pang DSJ. Refinement of intraperitoneal injection of sodium pentobarbital for euthanasia in laboratory rats (Rattus norvegicus). BMC Vet Res. 2017;13(1):60.

13- Pang D, Laferriere C. Review of Intraperitoneal Injection of Sodium Pentobarbital as a Method of Euthanasia in Laboratory Rodents. J Am Assoc Lab Anim Sci. 2020 May;59(3):346.

14- Knopfholz J, Disserol CCD, Pierin AJ, Schirr FL, Streisky L, Takito LL, et al. Validation of the friedewald formula in patients with metabolic syndrome. Cholesterol. 2014;2014:261878.

15- Obineche EN, Abdulle AM, Lakhani MS, Gillett MPT. Estimation of plasma very low density lipoprotein-cholesterol levels in uremia. Clin Exp Nephrol. 2002;6:38–42.

16- A protective effect of Ivermectin on vasculitis rat model: Histopathological study. Al Mustansiriyah J Pharm Sci. 2025 Oct;25(4 SE-Reviews):515–24.

17- Meyerholz DK, Beck AP. Fundamental Concepts for Semiquantitative Tissue Scoring in Translational Research. ILAR J. 2018 Dec;59(1):13–7.

18- Impact of Pyridoxine Supplement on Oxidative Stress in Type 2 Diabetic Patients. Al Mustansiriyah J Pharm Sci. 2024 Jan;24(1 SE-Articles):89–104.

19- Halande MP, Patil PA, Garge V, Dhar H. Anti-diabetic effects of a phytomedicinal formulation in streptozotocin and high-fat diet-induced diabetic nephropathy. Indian J Physiol Pharmacol. 68.

20- Naidu PB, Ponmurugan P, Begum MS, Mohan K, Meriga B, RavindarNaik R, et al. Diosgenin reorganises hyperglycaemia and distorted tissue lipid profile in high-fat diet–streptozotocin-induced diabetic rats. J Sci Food Agric. 2015 Dec;95(15):3177–82.

21- Pratiwi RY, Elya B, Setiawan H, Solawati A, Rosmalena. Alterations in Body Weight, Blood Glucose Levels, and Lipid Profiles in High-Fat Diet-Low Dose Streptozotocin-Induced Diabetic Rats. Pharmacogn J. 2021;13(6s).

22- Kurek JM, Król E, Krejpcio Z. Steviol Glycosides Supplementation Affects Lipid Metabolism in High-Fat Fed STZ-Induced Diabetic Rats. Nutrients. 2020 Dec;13(1):112.

23- Pandey KB, Mishra N, Rizvi SI. Protein oxidation biomarkers in plasma of type 2 diabetic patients. Clin Biochem. 2010;43(4–5):508–11.

24- Alathary AJ, Kadhim ZJ. Tirzepatide protects against hepatic oxidative stress in high-fat induced obesity in male rats. Maaen J Med Sci. 2024;3(3):6.

25- Lv X, Wang H, Chen C, Zhao Y, Li K, Wang Y, et al. The effect of tirzepatide on weight, lipid metabolism and blood pressure in overweight/obese patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes, Metab Syndr Obes. 2024;701–14.

26- Kanbay M, Copur S, Siriopol D, Yildiz AB, Gaipov A, van Raalte DH, et al. Effect of tirzepatide on blood pressure and lipids: A meta-analysis of randomized controlled trials. Diabetes, Obes Metab. 2023 Dec;25(12):3766–78.

27- Kim SJ, Nian C, Karunakaran S, Clee SM, Isales CM, McIntosh CHS. GIP-Overexpressing Mice Demonstrate Reduced Diet-Induced Obesity and Steatosis, and Improved Glucose Homeostasis. PLoS One. 2012 Jul;7(7):e40156.

28- Schofield JD, Liu Y, Rao-Balakrishna P, Malik RA, Soran H. Diabetes Dyslipidemia. Diabetes Ther Res Treat Educ diabetes Relat Disord. 2016 Jun;7(2):203–19.

29- Hammadi NA, Waheed HJ. Nebivolol effect on oxidative biomarkers in Tamoxifen-Induced Hepatotoxicity in Female White Albino Rats: In Vivo Study. Al Mustansiriyah J Pharm Sci. 2025;25(2):203–11.

30- Mendoza-Pérez JA, Fregoso-Aguilar TA, Hernandez Navarro BCC. Endogenous Antioxidants: A Review of their Role in Oxidative Stress. In: Morales-Gonzalez JA, Morales-González A, Madrigal-Santillan EO, editors. Rijeka: IntechOpen; 2016.

31- Gilani SJ, Bin-Jumah MN, Al-Abbasi FA, Nadeem MS, Afzal M, Sayyed N, et al. Fustin Ameliorates Elevated Levels of Leptin, Adiponectin, Serum TNF-α, and Intracellular Oxidative Free Radicals in High-Fat Diet and Streptozotocin-Induced Diabetic Rats. ACS Omega. 2021 Oct;6(40):26098–107.

32- Das S, Behera JP, Rojaramani Y, Mohanty RR. Effects of resveratrol on oxidative stress in high fat diet /streptozocin induced diabetic wistar albino rats. Int J Basic Clin Pharmacol. 2019 Feb;8(3 SE-Original Research Articles):482–7.

33- Kumawat M, Sharma TK, Singh I, Singh N, Ghalaut VS, Vardey SK, et al. Antioxidant Enzymes and Lipid Peroxidation in Type 2 Diabetes Mellitus Patients with and without Nephropathy. N Am J Med Sci. 2013 Mar;5(3):213–9.

34- Yang Y, Wang Y, Zhou Y, Deng J, Wu L. Tirzepatide alleviates oxidative stress and inflammation in diabetic nephropathy via IL-17 signaling pathway. Mol Cell Biochem. 2025;480(2):1241–54.

35- Tian Y, Tian R, Juan H, Guo Y, Yan P, Cheng Y, et al. GLP-1/GIP dual agonist tirzepatide normalizes diabetic nephropathy via PI3K/AKT mediated suppression of oxidative stress. Int Immunopharmacol. 2025 Jan;146:113877.

36- Batiha GES, Al-Kuraishy HM, Al-Gareeb AI, Ashour NA, Negm WA. Potential role of tirzepatide towards Covid-19 infection in diabetic patients: a perspective approach. Inflammopharmacology. 2023 Aug;31(4):1683–93.

37- Iwamoto Y, Kimura T, Dan K, Iwamoto H, Sanada J, Fushimi Y, et al. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor agonist, exhibits favourable effects on pancreatic β-cells and hepatic steatosis in obese type 2 diabetic db/db mice. Diabetes, Obes Metab. 2024 Dec;26(12):5982–94.

Downloads

Published

2026-03-31

How to Cite

Evaluation of The Antioxidant, Hypolipidemic, and Pancreatic Histological Alterations Effects of Tirzepatide in High-Fat Diet and Streptozotocin-Induced Type 2 Diabetic Rats. (2026). Al Mustansiriyah Journal of Pharmaceutical Sciences, 26(1), 66-79. https://doi.org/10.32947/ajps.v26i1.1347

Similar Articles

31-40 of 299

You may also start an advanced similarity search for this article.

Most read articles by the same author(s)

1 2 > >>