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ORIGINAL ARTICLE

Sex-based differences in streptozotocin-induced type 2 diabetes rat models

Ugljesa Malicevic1,2,3 ,  Jacob Smith1 ,  Devendra K. Agrawal1 ,  Vikrant Rai1*
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1 Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California, United States of America
2 Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
3 Department of Pathophysiology, Pharmacology, Toxicology, and Clinical Pharmacology, Faculty of Medicine, University of Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
JCTR, 025170020 https://doi.org/10.36922/JCTR025170020
Received: 26 April 2025 | Revised: 16 August 2025 | Accepted: 9 October 2025 | Published online: 28 October 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
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Abstract

Background: Diabetic foot ulcers (DFUs) are a severe complication of diabetes mellitus, leading to chronic infections, amputations, and increased mortality despite existing treatments. More effective therapeutics are urgently needed, and animal models provide a critical platform for investigating the molecular mechanisms underlying DFUs. Streptozotocin (STZ)—administered at a low dose to induce type 2 diabetes (T2D) and at a high dose to induce type 1 diabetes—is commonly used in mice and rats in DFU research. Aim: The objective of this study is to highlight the importance of including male and female rats in DFU research. Methods: Both male and female Sprague–Dawley rats, 6–8 weeks old, were fed a high-fat diet for 9 weeks. STZ (25 mg/kg intraperitoneally) was administered weekly from the 6th week to induce T2D. Results: Female rats required a higher dose of STZ compared to male rats. The induction of T2D correlated positively with weight gain, which was greater in males than in females. Conclusion: The findings suggest that in addition to gender and weight, other factors may influence the induction of T2D in rats. Most studies in the literature do not use both sexes in DFU research. The distinct responses to STZ and weight gain observed emphasize the need to include both sexes and employ a more detailed approach in preclinical studies to enhance the understanding of DFU wound healing and translate the findings into potential treatments. Relevance for patients: The multifactorial effect on diabetes development, which differs in males and females, suggests the need to consider etiological, physiological, and demographic factors, such as body weight, gender, age, and body mass index, in the prevention and treatment of diabetes. This will also help in planning the individualized treatment for DFUs.

Graphical abstract
Keywords
Diabetic foot ulcer
Animal model
Type 2 diabetes
Streptozotocin
Gender
Funding
The research was supported by a grant (25270C) from GMS Capitals LLC.
Conflict of interest
Vikrant Rai is an Editorial Board Member of this journal but was not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. Separately, other authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
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