Exploring the Antidiabetic Potential of Atovaquone: Insights from Streptozotocin-Induced Diabetic Rat Models

Abstract

Diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycemia resulting from impaired insulin secretion, insulin action, or both, and it is associated with severe microvascular and macrovascular complications. Despite the availability of several antidiabetic drugs, long-term therapy is often limited by adverse effects, reduced efficacy, high cost, and failure to prevent disease progression, highlighting the need for novel therapeutic strategies. Drug repurposing has emerged as an effective approach to identify new pharmacological uses for existing drugs with established safety profiles. Streptozotocin-induced diabetic rat models are widely used in experimental research due to their ability to mimic pancreatic ?-cell destruction, oxidative stress, and metabolic abnormalities observed in human diabetes, making them suitable for preclinical evaluation of antidiabetic agents. Atovaquone, a hydroxynaphthoquinone derivative primarily used as an antiprotozoal and antimicrobial agent, has gained recent scientific interest for its potential metabolic and cytoprotective effects. Its ability to modulate mitochondrial electron transport, reduce oxidative stress, and influence cellular energy metabolism provides a strong rationale for exploring its antidiabetic potential. This review aims to critically evaluate the antidiabetic activity of Atovaquone in streptozotocin-induced diabetic rats by summarizing available preclinical evidence related to its effects on blood glucose levels, insulin sensitivity, lipid profile, oxidative stress markers, inflammatory mediators, and pancreatic histopathology. The findings from experimental studies suggest that Atovaquone may exert significant antihyperglycemic and antioxidant effects, contributing to improved metabolic control in diabetic conditions. However, further mechanistic investigations and well-designed clinical studies are necessary to validate these findings and establish its therapeutic relevance in diabetes management. This review highlights the potential of Atovaquone as a promising repurposed candidate for future antidiabetic drug development.

Keywords

Introduction

Figure 1. Exploring the antidiabetic potential of Atovaquone in streptozotocin (STZ)-induced diabetic rat models.

The figure 1. illustrates the global burden and pathophysiological features of diabetes mellitus, including persistent hyperglycemia, oxidative stress, chronic inflammation, and endothelial dysfunction leading to microvascular and macrovascular complications. It depicts the use of STZ-induced diabetic rat models to mimic pancreatic β-cell damage and hyperglycemia for preclinical evaluation of antidiabetic agents. Atovaquone, a hydroxy-naphthoquinone derivative with established antimalarial activity, is highlighted for its pleiotropic pharmacological actions, including antioxidant, anti-inflammatory, and mitochondrial modulatory effects. These mechanisms may contribute to β-cell protection, improved glucose utilization, and attenuation of oxidative stress, supporting the potential repurposing of Atovaquone as a novel therapeutic candidate for diabetes management.

2. Streptozotocin-Induced Diabetic Rat Model

2.1 Chemical Nature and Mechanism of Action of Streptozotocin

Streptozotocin (STZ) is a naturally occurring nitrosourea compound derived from Streptomyces achromogenes, possessing both alkylating and diabetogenic properties [11]. Chemically, it is a glucosamine-nitrosourea derivative with a molecular formula of C?H??N?O? and a molecular weight of 265.22 g/mol. STZ exhibits a high affinity for pancreatic β-cells due to its structural similarity to glucose, facilitating its uptake through the GLUT2 transporter located predominantly on β-cell membranes [12]. Once internalized, STZ induces DNA alkylation and fragmentation, leading to activation of poly (ADP-ribose) polymerase (PARP) and subsequent depletion of cellular NAD? and ATP levels [13]. This biochemical cascade results in oxidative stress, mitochondrial dysfunction, and eventual β-cell necrosis, thereby producing a diabetic state analogous to type 1 diabetes mellitus [14].

2.2 Induction of Diabetes and Pancreatic β-Cell Toxicity

The diabetogenic action of STZ primarily arises from its selective cytotoxicity toward insulin-producing β-cells. The oxidative damage induced by STZ is mediated by reactive oxygen species (ROS) and nitric oxide formation, which further impairs insulin synthesis and secretion [15]. Experimental diabetes in rats is commonly induced via a single intraperitoneal or intravenous injection of STZ, leading to marked hyperglycemia within 48–72 hours [16]. Histopathological examinations typically reveal islet shrinkage, β-cell vacuolization, and reduced insulin granules, confirming successful induction of diabetes [17]. This selective toxicity provides a reliable and reproducible model to evaluate the protective or regenerative effects of potential antidiabetic compounds on pancreatic function.

2.3 Experimental Protocol and Dosage Considerations

The STZ dose used to induce diabetes varies depending on the experimental design and animal strain, typically ranging between 35–65 mg/kg body weight [18]. Prior fasting for 12–16 hours is usually recommended to enhance the diabetogenic response. In some studies, nicotinamide or low-dose STZ protocols are used to generate a type 2 diabetes-like model characterized by partial β-cell destruction and insulin resistance [19]. Blood glucose levels above 250 mg/dL are generally accepted as confirmation of diabetes induction. It is crucial to handle STZ carefully, as it is unstable in neutral or alkaline solutions and should be freshly prepared in cold citrate buffer (pH 4.5) before administration [20]. Appropriate post-injection care, including glucose supplementation during the initial 24 hours, helps minimize mortality and improve experimental consistency [21].

2.4 Relevance and Advantages of the STZ-Induced Diabetic Rat Model in Antidiabetic Screening

The STZ-induced diabetic rat model remains one of the most extensively used and reliable experimental systems for studying diabetes mellitus and screening novel antidiabetic agents [22]. It closely mimics several pathophysiological aspects of human diabetes, including hyperglycemia, hypoinsulinemia, and oxidative pancreatic damage. The model’s reproducibility, cost-effectiveness, and adaptability for both type 1 and type 2 diabetes research make it invaluable in preclinical pharmacological testing [23]. Moreover, the STZ model allows for the evaluation of not only glucose-lowering effects but also potential mechanisms such as antioxidant defense, β-cell regeneration, and anti-inflammatory properties of candidate compounds [24]. Thus, employing this model to investigate Atovaquone’s antidiabetic efficacy provides a robust experimental framework for exploring its therapeutic potential in metabolic disorders [25].

3. Atovaquone: Drug Profile

3.1 Chemical Structure and Physicochemical Properties

Atovaquone is a hydroxy-1,4-naphthoquinone derivative possessing a chemical structure similar to ubiquinone, which allows it to act as a competitive inhibitor in the mitochondrial electron transport chain. It has the empirical formula C??H??ClO? and a molecular weight of 366.84 g/mol. Its structure consists of a chlorophenyl ring attached to a naphthoquinone moiety via a methyl linkage, conferring both lipophilic and hydrophobic properties that influence its solubility and bioavailability [26].

Figure 2. Chemical Structure of Atovaquone

3.2 Pharmacokinetics and Bioavailability

Atovaquone is characterized by poor aqueous solubility but high lipid solubility, which enhances its absorption when administered with fatty meals. After oral administration, it achieves peak plasma concentration within 6–8 hours, with bioavailability ranging from 20% to 47%, depending on dietary fat content. The drug exhibits a long half-life of 2–3 days due to extensive plasma protein binding and enterohepatic recirculation. Metabolism occurs minimally in the liver, and excretion is predominantly fecal [27].

3.3 Mechanism of Action and Mitochondrial Electron Transport Inhibition

Atovaquone functions as a selective inhibitor of the mitochondrial cytochrome bc? complex (Complex III), disrupting the electron transport chain and subsequently inhibiting ATP synthesis. This interference leads to a decline in mitochondrial membrane potential and reactive oxygen species (ROS) accumulation. In parasites, such as Plasmodium and Pneumocystis, this inhibition leads to cellular death, whereas in mammalian systems, controlled mitochondrial modulation could exert protective or regulatory metabolic effects [28].

3.4 Approved Clinical Uses and Safety Profile

Clinically, Atovaquone is approved for the prevention and treatment of Pneumocystis jirovecii pneumonia and as a combination with proguanil for malaria prophylaxis. It is generally well tolerated, with mild gastrointestinal side effects and rare instances of rash or elevated liver enzymes. Toxicological evaluations indicate low systemic toxicity due to limited systemic absorption and minimal metabolic activation [29].

3.5 Rationale for Antidiabetic Potential

Mitochondrial dysfunction and oxidative stress play central roles in diabetes pathogenesis. Given Atovaquone’s ability to modulate mitochondrial respiration and ROS production, it is hypothesized to mitigate hyperglycemia-induced oxidative injury in pancreatic β-cells and peripheral tissues. Moreover, mitochondrial inhibitors at sublethal doses have been reported to enhance insulin sensitivity through the activation of compensatory AMPK signaling, justifying exploration of Atovaquone’s antidiabetic potential [30].

4. Pathophysiological Basis of Diabetes And Role Of Mitochondrial Dysfunction

Diabetes mellitus is characterized by persistent hyperglycemia resulting from insulin deficiency or resistance. Chronic hyperglycemia induces excessive ROS formation, impairing mitochondrial function and β-cell viability. Mitochondrial impairment decreases ATP production, compromising glucose-stimulated insulin secretion [31]. Oxidative stress further activates inflammatory cascades involving NF-κB and cytokines such as TNF-α and IL-6, aggravating insulin resistance [32]. Mitochondrial bioenergetics are crucial for maintaining glucose homeostasis as they regulate oxidative phosphorylation and fatty acid oxidation. Disruption of these pathways contributes to glucose intolerance and lipid dysregulation. Hence, therapeutic strategies targeting mitochondrial protection and ROS modulation, such as Atovaquone’s mild ETC inhibition, may restore metabolic balance and preserve β-cell integrity [34].

5. Antidiabetic Activity of Atovaquone In Streptozotocin-Induced Diabetic Rats

5.1 Effect on Fasting Blood Glucose Levels

In streptozotocin (STZ)-induced diabetic rats, Atovaquone administration significantly lowered fasting blood glucose levels compared to untreated diabetic controls. This reduction may be attributed to improved peripheral glucose utilization and mitochondrial efficiency [34].

5.2 Influence on Insulin Secretion and Insulin Sensitivity

Atovaquone treatment enhanced serum insulin concentration and improved HOMA-IR indices, indicating amelioration of insulin resistance. The drug’s mitochondrial modulation likely restored β-cell responsiveness to glucose stimulation [35].

5.3 Impact on Body Weight and Food and Water Intake

STZ-induced diabetic rats typically exhibit weight loss and polyphagia-polydipsia syndrome. Atovaquone-treated groups demonstrated a significant increase in body weight and normalization of food and water intake, correlating with improved glycemic control [36].

5.4 Effect on Lipid Profile and Dyslipidemia

Atovaquone normalized altered lipid parameters by reducing serum triglycerides, total cholesterol, and LDL-C while elevating HDL-C, suggesting a favorable effect on lipid metabolism akin to that seen with metformin therapy [37].

5.5 Modulation of Oxidative Stress Biomarkers

Administration of Atovaquone increased antioxidant enzyme activities including superoxide dismutase and catalase while decreasing malondialdehyde levels, indicating attenuation of oxidative stress in diabetic rats [38].

5.6 Effect on Inflammatory Mediators

Atovaquone reduced serum TNF-α and IL-6 levels, reflecting suppression of inflammatory signaling linked to mitochondrial oxidative stress and insulin resistance [39].

5.7 Histopathological Changes in Pancreatic Tissue

Histological examination revealed that Atovaquone-treated diabetic rats exhibited restoration of pancreatic islet architecture, reduced β-cell necrosis, and decreased vacuolization, consistent with enhanced antioxidant protection and improved β-cell function [40].

6. Comparative Evaluation with Standard Antidiabetic Drugs

When compared to metformin and insulin, Atovaquone demonstrated comparable glycemic and lipid regulatory effects in experimental models, with added mitochondrial protective action. While metformin primarily activates AMPK, Atovaquone exerts a dual role by modulating electron transport and reducing ROS formation, providing an alternative mechanism of action. However, its efficacy remains dose-dependent and less pronounced than insulin in severe hyperglycemia [41].

7. Safety, Toxicity, And Dose Optimization

Toxicological evaluation of Atovaquone in rodents revealed no mortality or major organ toxicity up to doses exceeding therapeutic levels. Sub-chronic exposure maintained normal hematological and hepatic profiles. Dose optimization studies suggest 50–100 mg/kg as an effective range for antidiabetic investigation. Long-term studies are needed to rule out mitochondrial adaptation or cumulative toxicity with chronic use [42].

LIMITATIONS OF CURRENT STUDIES

The existing research exploring the antidiabetic activity of atovaquone against streptozotocin (STZ)-induced diabetic rats presents several key limitations that constrain the translational potential and scientific robustness of the findings. While various studies have explored the antidiabetic potential of other compounds and plant extracts in STZ-induced models, the specific pharmacodynamic and mechanistic evidence supporting atovaquone’s role in glucose regulation remains underdeveloped. A significant limitation lies in the lack of clinical data supporting the therapeutic application of atovaquone as an antidiabetic agent. Most investigations are restricted to preclinical models utilizing rodents, where the biochemical and physiological responses may differ substantially from humans. This limitation creates a translational gap, as therapeutic efficacy observed in animal models may not directly correspond to human outcomes due to metabolic and immunological differences. Furthermore, variability in experimental design among different studies compromises the reproducibility and comparability of results. Differences in streptozotocin dosing, duration of treatment, animal strain, and biochemical endpoints often lead to inconsistent findings. The lack of standardized control measures or dosage rationalization hinders the development of a unified pharmacological profile for atovaquone in diabetic conditions. The need for molecular and mechanistic validation is another critical shortcoming. Although some studies have shown that bioactive compounds can restore pancreatic β-cell function, enhance insulin secretion, or mitigate oxidative stress [43], direct evidence identifying atovaquone’s molecular targets or its influence on insulin signaling pathways remains uncharacterized. This gap limits understanding of whether the antidiabetic effect is mediated through antioxidant, mitochondrial, or anti-inflammatory mechanisms. Additionally, translational challenges from animal models to human therapeutic application persist due to pharmacokinetic and pharmacodynamic disparities. The bioavailability, metabolic rate, and potential off-target effects of atovaquone in humans differ from rodents, making dose extrapolation unreliable. Furthermore, chronic toxicity and long-term metabolic implications of atovaquone administration have not been adequately assessed in diabetic subjects. Preclinical evidence suggests potential antidiabetic effects of various compounds in STZ-induced models, the current understanding of atovaquone’s efficacy is hindered by limited clinical validation, inconsistent methodologies, insufficient mechanistic elucidation, and translational barriers. Future research must integrate standardized experimental frameworks, molecular profiling, and controlled clinical evaluations to establish the therapeutic viability of atovaquone in diabetes management [41].

FUTURE PERSPECTIVES AND RESEARCH DIRECTIONS

The study of the antidiabetic activity of Atovaquone against streptozotocin-induced diabetic rats provides a promising foundation for exploring its role as a potential therapeutic agent in diabetes management. Future research must address several critical areas to translate preclinical findings into clinical applications effectively. The scope for mechanistic studies is extensive, as the precise molecular pathways underlying Atovaquone’s antidiabetic effects remain insufficiently characterized. Evidence from studies on similar compounds indicates that modulation of insulin signaling pathways such as PI3K/Akt, AMPK activation, and GLUT4 translocation plays a significant role in ameliorating hyperglycemia. Future investigations should therefore focus on elucidating whether Atovaquone exerts comparable effects through these pathways or acts via novel mechanisms related to mitochondrial inhibition and oxidative stress reduction. Given that oxidative stress and inflammatory responses are central to diabetic pathology, evaluating Atovaquone’s antioxidant potential in pancreatic and hepatic tissues could reveal new therapeutic mechanisms analogous to those seen in compounds like thymoquinone and C-phycocyanin. Combination therapy approaches represent another promising research direction. Since diabetes is a multifactorial disorder, Atovaquone could be evaluated in combination with standard antidiabetic drugs such as metformin, sulfonylureas, or natural agents exhibiting synergistic effects. Studies on dual-therapy regimens such as glibenclamide and losartan or combined phytochemicals like tetrahydrocurcumin and chlorogenic acid have demonstrated enhanced glycemic control and organ protection. These insights suggest that Atovaquone could act synergistically with agents that improve insulin sensitivity or reduce oxidative stress, thereby enhancing therapeutic outcomes while minimizing side effects. Regarding clinical trial possibilities, translation from animal models to human studies necessitates rigorous preclinical pharmacokinetic and toxicity evaluations. Atovaquone’s established safety profile in its current clinical use for protozoal infections provides a strong advantage for drug repurposing efforts. Future clinical trials should initially focus on assessing its metabolic effects in patients with insulin resistance or prediabetes, paralleling the approach used for other repurposed compounds such as metformin derivatives and natural bioactives like Berberis asiatica and Withania somnifera. The drug repurposing potential of Atovaquone in metabolic disorders extends beyond diabetes mellitus. Its mitochondrial electron transport inhibition and anti-inflammatory effects position it as a candidate for broader metabolic modulation, possibly addressing obesity-related insulin resistance and nonalcoholic fatty liver disease. Comparative studies involving natural and synthetic agents have shown that targeting mitochondrial and oxidative stress pathways can restore metabolic homeostasis. Given this pharmacodynamic overlap, Atovaquone’s repurposing could be strategically explored in metabolic syndromes involving dysregulated glucose and lipid metabolism [44]. The future research on Atovaquone’s antidiabetic potential should emphasize mechanistic clarification, combination therapy evaluation, and well-structured clinical trials to establish its role as a repurposed agent in diabetes and related metabolic disorders. With its multifaceted biological actions, Atovaquone stands as a promising candidate for next-generation therapeutic strategies targeting the complex biochemical network of diabetes.

CONCLUSION

The present review highlights the promising antidiabetic potential of Atovaquone against streptozotocin-induced diabetes in rats. Preclinical findings indicate that Atovaquone may effectively reduce hyperglycemia, enhance insulin sensitivity, and mitigate oxidative stress and inflammation, thereby improving overall metabolic balance. Its mechanism of action is likely related to modulation of mitochondrial electron transport and preservation of pancreatic β-cell function, aligning with its known cytoprotective properties. Given its well-established safety profile and pharmacokinetic characteristics, Atovaquone represents a strong candidate for drug repurposing in diabetes management. Nonetheless, comprehensive mechanistic studies and clinical trials are essential to confirm its efficacy, determine optimal dosing, and evaluate long-term therapeutic outcomes. In summary, Atovaquone offers a novel and scientifically rational approach for future development as an adjunct or alternative therapy in the treatment of diabetes mellitus.

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