Cardioprotective Activity of Propionic Acid in High-Fat Diet/ Streptozotocin-Induced Cardiotoxicity in Diabetic Rats Model

Oluwatosin Okunlola, Folasade Omobolanle Ajao*, Noheem Olaoluwa Kalejaiye, Damilola Ayodeji Balogun, Marcus Olaoye Iyedupe

Physiology Department, Faculty of Basic Medical Science, College of Health Science, Ladoke Akintola University of Technology, P.M.B. 4000, Ogbomoso, Oyo State, Nigeria

*Corresponding Author’s Email: foajao@lautech.edu.ng

Abstract

Background: The healthcare sector is increasingly focusing on the discovery of toxic-free natural medicines to treat diabetes-related complications. The current study investigated the cardioprotective efficacy of propionic acid (PA) in a type 2 diabetic rat model. Methods: Twenty-five Wistar rats (200– 300 g) were used. The rats were fed a high-fat diet for 8 weeks, and streptozotocin (30 mg/kg b.wt) was injected intraperitoneally to induce diabetes. The animals were divided into 5 groups (n = 5) and treated for 4 weeks. Group 1: normal control; Group 2: normal control + PA (60 mg/kg b.wt); Group 3: diabetic; Group 4: diabetic + PA (60 mg/kg b.wt); Group 5: diabetic + metformin (200 mg/kg b.wt). Serum and supernatant plasma retrieved from blood samples, along with heart tissue homogenate after centrifugation, were used to determine biochemical parameters. Results: Propionic acid administration significantly (p < 0.05) reduced serum insulin, fasting blood glucose, oral glucose tolerance, cardiac creatine kinase-myoglobin, troponin-I, Lactate dehydrogenase, brain natriuretic peptide, caspase-3, triglycerides, total cholesterol, low-density lipoprotein cholesterol, oxidative malondialdehyde, tumor necrosis factor-α, interleukin-1β, interleukin-6, heart rate, blood pressure, QT and QTc intervals, QRS interval, PR interval, and food and water intake. It also significantly increased cardiac B-cell lymphoma- 2, superoxide dismutase, catalase, reduced glutathione, high-density lipoprotein cholesterol, P-wave, and body and heart weight in diabetic rats. Conclusion: Propionic acid lowered hyperglycemia and prevented cardiac injury by suppressing elevated cardiac injury markers, oxidative stress, and inflammation. Propionic acid may be useful as a natural medication for treating cardiac ailments in diabetes.

Keywords: Cardiac; Diabetes Mellitus; Inflammation; Oxidative Stress; Propionic Acid

Introduction

Diabetes mellitus (DM) is globally ranked as the fourth largest metabolic disease, and its prevalence continues to rise every year (Singh et al., 2025). In 2019, DM was the eighth leading cause of death and disability (Ong et al., 2023). Current estimates from the International Diabetes Federation predict that approximately 783 million adults will be living with diabetes by 2045 (Migdalis, 2024).

DM, a non-communicable metabolic disorder, is characterized by chronic hyperglycemia due to alterations in the metabolism of carbohydrates, fats, and proteins resulting from insulin secretion deficiency from pancreatic beta cells, insulin resistance, or both (Sini et al., 2025). Chronic hyperglycemia affects multiple organs, leading to microvascular and macrovascular complications such as diabetic retinopathy, nephropathy, neuropathy, and cardiovascular diseases including atherosclerosis, myocardial infarction, and coronary artery disease (Wang et al., 2024).

Cardiovascular disease (CVD) complications are a major cause of mortality in both type 1 and type 2 diabetes patients (Patsoukaki et al., 2025). Approximately 30–40% of diabetes patients develop cardiovascular-related complications (Marassi & Fadini, 2023). Persistent hyperglycemia disrupts the balance between oxidative stress and endogenous antioxidant defense, promoting the overproduction of reactive oxygen species (ROS), which exacerbates oxidative injury and triggers the release of inflammatory mediators, consequently damaging cardiac structure and impairing function (Hashiesh et al., 2023).

The existing well-known conventional antidiabetic drugs exhibit suboptimal effectiveness, and adverse toxicity effects have driven growing interest in novel and alternative therapies (Ansari et al., 2024). Scientists have increasingly focused on medicinal plants as potential sources of safe alternative treatments (Yedjou et al., 2023). Recently, secondary metabolites from medicinal plants rich in antioxidants have been documented to effectively mitigate oxidative injury and ameliorate cellular function in DM patients (Sukhikh et al., 2023). Among these plants, Anacardium occidentale (A. occidentale) has been recognized for its ethnomedicinal properties. All parts of the tree, including the leaves, bark, and nuts, are extensively used in traditional medicine to combat various diseases. One study documented cardiovascular therapeutic effects of A. occidentale in non-diabetic patients (Brito et al., 2025). The nuts are rich in vitamins, dietary fiber, unsaturated fatty acids, and diverse bioactive compounds. They have been studied for their role in reducing inflammation, limiting oxidative damage, and preventing the progression of chronic metabolic diseases (Dias et al., 2024). Furthermore, molecular docking research identified propionic acid (PA) from the nuts as an efficient bioactive compound with antidiabetic drug-likeness properties (Ajao et al., 2023). However, there remains limited scientific experimental evidence on the in vivo effects of PA in mitigating organ damage in DM. The present research investigated the cardiopharmacological protective efficacy of PA in a T2DM rat model.

Methodology Experimental Animal

Twenty-five mature Wistar Albino rats weighing between 200–300 g was obtained from the animal breeding house of the Physiology Department, Ladoke Akintola University of Technology (LAUTECH), Ogbomoso, Oyo State, Nigeria. The animals were housed in clean polypropylene cages and acclimatized for 2 weeks, with free access to standard pelletized feed and water ad libitum. They were maintained under hygienic environmental conditions with 40–50% humidity, a temperature range of 25– 27 °C, and a 12:12 h light/dark cycle. All experimental procedures were conducted in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals.

High-Fat Diet and Diabetes Induction

The animals were initially divided into two groups. Five rats fed a normal diet served as the control group, and twenty rats fed a high-fat diet (carbohydrate: 30%, fat: 65%, protein: 5%) served as the group designated for diabetes induction. Each group was maintained on its respective diet for eight weeks. After this period, both the control and high-fat diet (HFD) groups were subjected to a 12-hour overnight fast. Animals in the HFD group were then intraperitoneally injected with a repeated dose of freshly prepared streptozotocin (STZ) (30 mg/kg b.wt) to induce diabetes. These animals received a 20% glucose solution to prevent STZ-induced hypoglycemic death. Diabetes induction was confirmed 72 hours after STZ injection using blood obtained from the tail vein and analyzed with a glucometer. Animals with fasting blood glucose (FBG) levels higher than 200 mg/dL were identified as diabetic and were selected as the DM group for the study.

Experimental Animal Grouping/Treatment

The rats were randomly assigned into five groups, with 5 rats per group. Animals in the control category were divided into two groups, while the DM animals were divided into three groups and treated with propionic acid (PA) or metformin (Met). The treatment lasted for 4 weeks and was organized as follows:

Group 1: Normal control (NC) Group 2: NC + PA (60 mg/kg b.wt) Group 3: DM (untreated)

Group 4: DM + PA (60 mg/kg b.wt)

Group 5: DM + Met (200 mg/kg b.wt)

During the treatment period, food intake and water intake were measured daily, and changes in body weight were recorded weekly.

Oral Glucose Tolerance Test (OGTT)

OGTT was performed on the animals during the treatment phase on days 1, 7, 14, 21, and 28. The animals were fasted overnight (12 h) and were then orally administered a 20% glucose solution. Blood glucose levels were measured at 0 min (before glucose ingestion) and at 30, 60, 90, and 120 min after glucose solution ingestion.

Electrocardiogram Recording

Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured noninvasively using a tail-cuff sphygmomanometer. Electrocardiogram (ECG) recordings were obtained through non- invasive three-lead electrodes placed in a lead II configuration, sampled at 1 kHz. The R–R interval, P– R interval, P wave, QRS complex, Q–T interval, and heart rate were analyzed. QTc was calculated from the QT interval using the formula: QTc = QT / (RR/f)¹ᐟ².

Biochemical Analysis

After the treatment, the animals were fasted overnight (12 h) and humanely sacrificed under anesthesia using ketamine (40 mg/kg b.wt) and xylazine (20 mg/kg b.wt). The abdominal–thoracic cavity was dissected to access the heart. Blood samples were collected from the apex beat of the heart, and the hearts were excised immediately after blood collection. The hearts were rinsed in normal saline to remove blood stains and homogenized in a cold phosphate-buffered solution. The blood samples were centrifuged at 3500 rpm for 15 min, and the heart tissue homogenates were centrifuged at 5000 rpm for 15 min at −4 °C using a cold Eppendorf centrifuge (5810R, Germany). After centrifugation, the retrieved serum and supernatant plasma were used for the estimation of biochemical parameters.

Fasting blood glucose was measured using the glucose oxidase/peroxidase method by placing a drop of pricked tail venous blood onto a glucometer (Acu-Chek). Serum insulin and glycated hemoglobin (HbA1c) levels were determined by the ELISA method using a specific rat ELISA kit. Serum levels of creatine kinase–myoglobin (CK-MB), troponin I (cTn-I), and brain natriuretic peptide (BNP), as well as cardiac levels of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), and reduced glutathione (GSH), were quantified using the enzyme-linked immunosorbent assay (ELISA) method with assay kits specific to each parameter, following the manufacturers’ protocols. In addition, cardiac lactate dehydrogenase, caspase-3, and B-cell lymphoma-2 were measured spectrophotometrically using commercial kits according to the manufacturers’ guidelines.

The cardiac lipid profile—triglycerides (TG), total cholesterol (TC), and high-density lipoprotein cholesterol (HDL-cholesterol)—was determined using an enzymatic colorimetric method with commercially available assay kits. Low-density lipoprotein cholesterol (LDL-cholesterol) was calculated using the formula of Friedewald et al.:

LDL-cholesterol = TC − (HDL-C + TG/5) (Friedewald et al., 1972).

Statistical Analysis

Data were expressed as the mean ± SEM and analyzed using one-way analysis of variance (ANOVA) with GraphPad Prism (version 10.3 software), followed by a Bonferroni post hoc test for comparison of significant differences. Statistical significance was set at p < 0.05.

Ethical Consideration

The research obtained ethical clearance from the Faculty of Basic Medical Science Ethical Approval Committee of Ladoke Akintola University of Technology, Nigeria with reference number: ERCFBMSLAUTECH: 049/06/2024 in 2024.

Results

PA Effect on body and heart weight in HFD/STZ-Induced Diabetic Rats

HFD/STZ-induced diabetic rats exhibited significant (p<0.05) lower body and heart weight in comparison with controls. Diabetic rats administered with PA showed an improvement in body and heart weight compared to diabetic controls (Table 1)

PA Effect on Food and Water Intake in HFD/STZ-Induced Diabetic Rats

Food and water intake increased (p<0.05) significantly in diabetic rats compared with the control rats. PA reduced the intake of food and water in diabetic treated rats compared with the untreated (Table 1).

PA Effect on Serum OGTT, Insulin, FBG, and HbA1c in HFD/STZ-Induced Diabetic Rats

There was a significant (p<0.05) increase in serum OGTT, insulin, FBG and HbA1c in diabetic rats compared with normal controls. PA administration improves the OGTT and reduces the levels of insulin, FBG and HbA1c in diabetic rats compared to untreated diabetic rats (Figure 1: A-D).

PA Effect on Cardiac Biomarkers in HFD/STZ-Induced Diabetic Rats

Serum CK-MB, TnP-I, LDH and BNP were significantly (p<0.05) higher in diabetic rats in comparison with control rats. PA administration to the diabetic rats lowered the cardiac biomarker levels compared with non-treated diabetic rats (Figure 2: A-D).

PA Effect on HR, BP and ECG parameters in HFD/STZ-Induced Diabetic Rats

HR, systolic and diastolic BP, PR-interval, QRS-interval, QT-interval and QTc-interval increased (p<0.05) significantly, and P-wave reduced (p<0.05) significantly in diabetic rats in comparison with the control. Administration of PA reduced the HR, BP, and ECG intervals and raised the P-wave compared with untreated diabetic rats (Table 2).

PA Effect on Cardiac Lipid Profile in HFD/STZ-Induced Diabetic Rats

There was a significant (p<0.05) decrease in HDL-cholesterol. Triglycerides, TC, and LDL-cholesterol increased (p<0.05) significantly in diabetic rats compared to controls. PA administration to the diabetic rats increased cardiac HDL-cholesterol levels, and reduced the levels of triglycerides, TC and LDL- cholesterol compared with non-treated diabetic rats (Figure 2: E-H).

PA Effect on Cardiac Oxidative Stress in HFD/STZ-Induced Diabetic Rats

Cardiac malondialdehyde increased (p<0.05) significantly, and cardiac SOD, CAT and GSH were significantly (p<0.05) reduced in diabetic rats in comparison with controls. Malondialdehyde levels reduced and antioxidant levels increased in diabetic rats treated with PA compared with untreated (Figure 3: A-D).

PA Effect on Cardiac Inflammatory Cytokines in HFD/STZ-Induced Diabetic Rats

TNF-alpha, IL-1beta and IL-6 increased (p<0.05) significantly in the cardiac of diabetic rats compared with controls. PA administration reduced the inflammatory cytokines in the diabetic rat hearts compared with the non-treated (Figure 3: E-G).

PA Effect on Cardiac Apoptotic and Anti-apoptotic Markers HFD/STZ-Induced Diabetic Rats

Caspase-3 increased (p<0.05) significantly and B-cell lymphoma-2 decreased in the hearts of diabetic rats compared with controls. PA administration reduced the caspase-3 and elevated the B-cell lymphoma-2 in the diabetic rat hearts compared with the non-treated (Figure 3: H & I).

Figure 1: PA Effect on Serum (A) Oral Glucose Tolerance Test, (B) Insulin, (C) Fasting Blood Glucose, (D) HbA1c in HFD/Streptozotocin-Induced Diabetic Rats. Data Values Expressed as Standard Error of Mean (n=5). Hsignificant at p<0.05 vs Control; Xsignificant at p<0.05 vs Diabetic

Table 1: PA Effect on Body Weight, Heart Weight, Food Intake and Water Intake HFD/STZ- Induced Diabetic Rats

Data values expressed as standard error of mean (n=5). Hsignificant at p<0.05 vs control; Xsignificant at p<0.05 vs diabetic.

Data values expressed as standard error of mean (n=5). Hsignificant at p<0.05 vs Control; Xsignificant at p<0.05 vs diabetic.

Figure 2: PA Effect on Heart (A) CK-MB, (B) cTn-I, (C) LDH, (D) BNP, (E) HDL-Cholesterol, (F) TG, (G) TC, (H) LDL-Cholesterol in HFD/Streptozotocin-Induced Diabetic Rats

Table 2: PA Effect on Heart Rate, Blood Pressure, and Electrocardiograph Parameters in HFD/STZ-Induced Diabetic Rats

Data values expressed as standard error of mean (n=5). Hsignificant at p<0.05 vs control; Xsignificant at p<0.05 vs diabetic.

Data values expressed as standard error of mean (n=5). Hsignificant at p<0.05 vs control; Xsignificant at p<0.05 vs diabetic

Figure 3: PA Effect on Heart (A) MDA, (B) SOD, (C) CAT, (D) GSH, (E) TNF-α, (F) IL-1β, (G) IL-6,

(H) Caspase-3, (I) Bcl-2 in HFD/Streptozotocin-Induced Diabetic Rats

Discussion

The prevalence of type-2 diabetes mellitus (T2DM) persistently increases and accounts for over 90% of DM incidence (Migdalis, 2024). T2DM patients are three times likely to develop cardiovascular diseases (Shah et al., 2025) and CVDs emerged as the major causes of mortality (about 70%) in T2DM. Over the past decades, the use of medicinal plants’ natural active compounds has been considered as less toxic and an alternative treatment option for DM and its related complications (Scarpa et al., 2024). The current experiment investigates the cardiovascular protective effect of propionic acid, an active phytochemical of A. occidentale nuts in diabetic rats.

Diabetes symptoms include polyphagia, polydyspia, polyuria, and uncontrollable loss of body weight (Tegegne et al., 2024). Insulin deficiency alters glucose use for energy, causing breakdown of fat and structural proteins in muscle, resulting in a remarkable loss of weight (Almalki, et al., 2024). Similar increase in water intake, food intake and reduced body and heart weight was noticed in the diabetic rat model of the present finding, supporting the other literature (Barka et al., 2024). Oral treatment of diabetic rats with PA alleviates these symptoms and improves body weight, as well as heart weight. The effect of PA could be linked to enhancing insulin sensitivity for glucose uptake, thereby preventing the breakdown of protein and fat in muscle for restoring body weight.

Diabetic patients are clinically diagnosed with sustained hyperglycemia and insulin resistance (Hurtado- Carneiro et al., 2024). In T2DM, spontaneous release of insulin by pancreatic beta-cells is a compensatory mechanism to regulate sustained hyperglycemia and insensitivity of the targeted organs to insulin effects leads to hyperglycemia-hyperinsulinemia (Attanasio et al., 2024). Corroborating the findings of Racine et al. (2025), diabetic rats obviously exhibited the hallmark of T2DM in our study, as evidenced by elevated levels of blood glucose and insulin in serum. Active bioactive compounds in medicinal plants have been studied with ability to enhance insulin sensitivity and inhibit hepatic glycogenolysis (Horvath et al., 2025). Supporting this report, the PA administration lowered the blood glucose and returned the insulin level to a desirable level. Scientifically, these results indicate that PA possesses the potential to inhibit glucose absorption in the intestinal tract, modulate insulin sensitivity at peripheral organs and tissues for glucose uptake, and regulate glucose-dependent insulin release.

Evidence from a previous study established that poorly managed chronic hyperglycemia affects cardiac electrophysiological patterns (El-Nasr et al., 2025). Elongation in QT interval and abnormal repolarization patterns, are signs of risk of developing arrhythmias and sudden cardiac arrest in diabetes (Welten et al., 2023). In consistent with El-Nasr et al. findings of El-Nasr et al. (2025), changes in ECG parameters, such as prolonged QTc-interval, QT-interval and reduced P-wave amplitudes, were noticed in the ECG record of the diabetic rats of this study. Conversely, PA administration exhibited a noteworthy cardioprotective efficacy in diabetic rats by reducing heart rate, QTc intervals, QT and improving the P-wave, highlighting PA potential as a treatment agent to alleviate diabetes-induced heart dysfunction, which aligns with the result of Sarker et al. (2024), on Astaxanthin enhanced heart rate variability and alleviated myocardial injury in diabetic rats, primarily through its ability to suppress oxidative stress and inflammation, key factors driving the development of cardiac disease in diabetes.

Chronic hyperglycemia in diabetes adversely damaged the cardiac structure, tissue integrity, and function independently of other cardiovascular risk factors, ultimately contributing to diabetic cardiomyopathy and heart failure (Akhtar et al., 2023). Lactate dehydrogenase (LDH), a key enzyme involved in cellular energy metabolism, is released into circulation following tissue injury and therefore serves as a biomarker of cardiac damage (Zhang et al., 2024). Similarly, creatine kinase (CK), a guanidino-kinase that catalyzes the reversible conversion of creatine to phosphocreatine, is predominantly expressed in skeletal muscle and myocardium. Among its isoenzymes, creatine kinase- MB (CK-MB) is widely used as a sensitive and specific indicator in evaluating the extent of myocardial damage (Li et al., 2023). Due to cardiac muscle damage and ventricular dysfunction, serum LDH and CK-MB have been reported to increase in diabetic patients (Netala et al., 2025). Over many decades, serum cardiac troponin-I (cTn-I) has been regarded as the typical biomarker for the diagnosis of acute myocardial necrosis. Also, brain natriuretic peptide (BNP) plays a significant role in cardiac homeostasis and has been noticed to be disrupted in clinical conditions (Liao et al., 2025). In our findings, these biomarkers were elevated in the serum, suggesting cardiac damage in the diabetic rats, which accords with the previous reports of Welten et al. (2023). However, treatment with PA lessens these cardiac injury biomarkers and could be due to its antioxidant properties that attenuate oxidative damage, which supports the cardioprotective effect of this compound.

Dyslipidaemia is a key risk factor for cardiovascular disease progression in DM. The oxidizing of fatty acids by the liver produces fuel and mobilization of LDL-cholesterol to peripheral tissues (Barka et al., 2024). Elevated cholesterol is the most common lipid anomaly in DM and is driven by increased cholesterol formation, impaired cholesterol absorption, and enhanced lipolysis. Insulin deficiency further accelerates the influx of fatty acids into the liver for excessive cholesterol synthesis (Rao et al., 2025). Inactivation of the enzyme lipoprotein lipase to hydrolyze triglyceride due to insulin deficiency causes high triglyceride (Suzuki et al., 2016), and a deficiency in cholesterol clearance from the peripheral tissue contributes to high triglyceride and diminished high-density lipoprotein-cholesterol (Diaz et al., 2025). Hypertriglyceridemia, elevated total cholesterol and LDL-cholesterol, coupled with reduced HDL-cholesterol, was observed in the hearts of diabetic rats in our study. The lipid abnormalities observed in the cardiac tissue may be attributed to impaired insulin sensitivity for regulation of lipid metabolism, which is in line with a finding report of Barka et al. (2024). Nevertheless, the administration of PA reduced the cardiac triglyceride, total cholesterol, LDL-cholesterol and improved the HDL- cholesterol. The cardiac lipid-lowering potency of PA may be due to the restoration of insulin secretion, which regulates lipoprotein hydrolysis and its influx into peripheral tissues, supporting previous research reports on the anti-hyperlipidemic effects of Quercetin (Ozorowski et al., 2025).

Myocardial damage in diabetes is influenced by hyperglycemia-induced oxidative stress and inflammation (Caturano, et al., 2025). Long-term hyperglycemia affects oxidant balance, causing the production of high reactive oxygen species (ROS), and the endogenous antioxidant incapacity to eliminate free radicals majorly contributes to cellular damage (Caturano et al., 2023). A report showed cardiac oxidative stress marker malondialdehyde (MDA) elevation in diabetic rats (Li et al., 2023). Corroborating this report, our study also observed a decrease in antioxidant activity of SOD, CAT and GSH, along with elevated malondialdehyde in the heart of diabetic rats. PA showed a remarkable anti- oxidative effect by attenuating the marker of oxidative damage and up-regulating the cardiac antioxidant activity in diabetic rat hearts, which indicates PA cardiac therapeutic effect in diabetes and could be linked to its insulin secretion restoration for glycemic regulation. These results are in harmony with a study that reveals certain flavonoids prevent cardiac oxidative stress by activating nuclear factor erythroid 2-related factor 2 (NRF2), thereby enhancing antioxidant enzymes (Emeka et al., 2024).

Hyperglycemia-induced oxidative stress is known to stimulate diverse inflammatory responses through the activation of nuclear factor kappa-B (NF-κB) cells, which facilitates the release of inflammatory cytokines such as TNF-α, interleukin-1β, and interleukin-6 in the diabetic heart. These inflammatory cytokines contribute to the progression of cardiac cell damage (Masenga et al., 2023). The present findings also detect an upsurge in the circulation of pro-inflammatory cytokines, especially TNF-α, as well as IL-1β and IL-6 in the hearts of diabetic rats, which aligns with findings of Zhang and Dhalla (2024). PA supplement potently reduced these pro-inflammatory cytokines in the diabetic rat hearts. In agreement with research findings that revealed the capability of phytochemicals in reducing cardiac inflammation (Deng et al., 2024). PA could exert these anti-inflammatory properties through its anti- oxidative potency by scavenging free radical generation in the heart, further supporting the cardio- protective effects of this bioactive compound in diabetic conditions.

The unregulated oxidative stress and inflammatory cytokines activate cardiac apoptosis in diabetes (Li et al., 2023). The expression of caspase-3, a pro-apoptotic marker, has been reported to increase in diabetic hearts with a reduction in anti-apoptotic marker, B-cell lymphoma-2 expression (Wang et al., 2020). Similarly, up-regulation of caspase-3 and down-regulation of B-cell lymphoma-2 were observed in the hearts of diabetic rats. Chronic hyperglycemia has been documented to reduce activation of the AKT signalling network by excessive ROS, thereby promoting the activity of the forkhead box 3 (FOXO3) gene that favours apoptosis. Polyphenol compounds such as resveratrol have been recently reported to reduce FOXO3 to prevent cardiovascular damage by eliminating oxidants (Li et al., 2023). In support of the report, PA administration lowered the pro-apoptotic marker and increased the anti-apoptotic marker level, which might result from its anti-oxidative efficacy in enhancing the activation of AKT signalling pathway to down-regulate the FOXO3 gene activity.

Conclusion

Treatment with propionic acid successfully prevents cardiac damage in diabetic rats. The supplementation of propionic acid alleviates the cardiac oxidative stress, inflammation and apoptosis. Propionic acid could be utilized as a new promising therapy for cardiac disease in diabetes. Clinical trial investigations to authenticate these efficacies in humans would provide a safer and alternative therapy approach to lessen diabetes-related cardiovascular mortality.

Conflict of Interest

The author(s) declare that there is no conflict of interest regarding the publication of this article.

Acknowledgement

The researcher would like to express sincere gratitude to the research team members for their valuable contributions to this research. Their support in data collection, reviewing the manuscript, and providing feedback has been greatly appreciated.

References

Ajao, F.O., Iyedupe, M.O., Oneosinina, A.R., Olaolu, K.N., & Isaac, A.T. (2023). Molecular docking and admet properties of Anacardium occidentale methanolic nut extract against inflammatory, oxidative and apoptotic markers of diabetes. Journal of Medical Sciences, 93(3), e885. https://doi.org/10.20883/medical.e885

Akhtar, M. S., Alavudeen, S. S., Raza, A., Imam, M. T., Almalki, Z. S., Tabassum, F., & Iqbal, M. J. (2023). Current understanding of structural and molecular changes in diabetic cardiomyopathy. Life Sciences, 332, 122087. https://doi.org/10.1016/j.lfs.2023.122087

Almalki, N. A., Al-Abbasi, F. A., Moglad, E., Afzal, M., Al-Qahtani, S. D., Alzarea, S. I., ... & Kazmi, I. (2024). Protective activity of hirsutidin in high-fat intake and streptozotocin-induced diabetic rats: In silico and in vivo study. Heliyon, 10(19). https://doi.org/10.1016/j.heliyon.2024.e38625

Ansari, P., Khan, J. T., Chowdhury, S., Reberio, A. D., Kumar, S., Seidel, V., ... & Flatt, P. R. (2024). Plant-based diets and phytochemicals in the management of diabetes mellitus and prevention of its complications: A review. Nutrients, 16(21), 3709. https://doi.org/10.3390/nu16213709

Attanasio, U., Mercurio, V., & Fazio, S. (2024). Insulin Resistance with Associated Hyperinsulinemia as a Cause of the Development and Worsening of Heart Failure. Biomedicines, 12(12), 2890. https://doi.org/10.3390/biomedicines12122890

Barka, C.E., Bensenane, B., Merzouk, H., Mebarki, A., Haddam, H.Y., Berroukeche, F., & Mokhatri- Soulimane, N. (2024). Antidiabetic Effects of Coffee Silverskin Extract in Streptozotocin-Induced Diabetic Wistar Rats. Waste Biomass Valorization, 15, 5219–5234. https://doi.org/10.1007/s12649- 024-02504-5.

Brito, L. B., Leal, B. O., Silva, J. R. D., Barbosa, K. M. P., Silva, V. T. D., Costa, A. S., ... & Araújo, M. F. M. D. (2025). Efecto del consumo de galletas a base de harina de anacardo (Anacardium occidentale l.) en niños con sobrepeso: un ensayo clínico piloto aleatorizado. Nutrición Hospitalaria, 42(1), 19-25. https://doi.org/10.20960/nh.05241

Caturano, A., D’Angelo, M., Mormone, A., Russo, V., Mollica, M. P., Salvatore, T., ... & Sasso, F. C. (2023). Oxidative stress in type 2 diabetes: impacts from pathogenesis to lifestyle modifications. Current Issues in Molecular Biology, 45(8), 6651-6666. https://doi.org/10.3390/cimb45080420

Caturano, A., Rocco, M., Tagliaferri, G., Piacevole, A., Nilo, D., Di Lorenzo, G., ... & Sasso, F. C. (2025). Oxidative stress and cardiovascular complications in type 2 diabetes: from pathophysiology to lifestyle modifications. Antioxidants, 14(1), 72. https://doi.org/10.3390/antiox14010072

Deng, T., Xu, J., Wang, Q., Wang, X., Jiao, Y., Cao, X., ... & Xiao, C. (2024). Immunomodulatory effects of curcumin on macrophage polarization in rheumatoid arthritis. Frontiers in Pharmacology, 15, 1369337. https://doi.org/10.3389/fphar.2024.1369337

Dias, T. D. S., Almondes, K. G. D. S., Firmino, M. A., Oliveira, L. F. N. D., Freire, W. B. D. S., Barbosa Jr, F., ... & Maia, C. S. (2024). Effect of Cashew Nut Consumption on Biomarkers of Copper and Zinc Status in Adolescents with Obesity: A Randomized Controlled Trial. Nutrients, 17(1), 163. https://doi.org/10.3390/nu17010163

Diaz, L., & Bielczyk-Maczynska, E. (2025). High-density lipoprotein cholesterol: how studying the ‘good cholesterol’could improve cardiovascular health. Open biology, 15(2), 240372. https://doi.org/10.1098/rsob.240372

El-Nasr, N. M. A., Hussien, Y. A., El-Baset, M. A., Shabana, M. E., & Saleh, D. O. (2025). Astaxanthin mitigates diabetic cardiomyopathy and nephropathyin HF/HFr/STZ diabetic rats via modulating NOX4, fractalkine, Nrf2, and AP-1 pathways. Scientific Reports, 15(1), 20199. https://doi.org/10.1038/s41598- 025-06263-8

Emeka, P. M., Badger-Emeka, L. I., Thirugnanasambantham, K., & Alatawi, A. S. (2024). Rutin- Activated Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Attenuates Corneal and Heart Damage in Mice. Pharmaceuticals, 17(11), 1523. https://doi.org/10.3390/ph17111523

Friedewald, W. T., Levy, R. I., & Fredrickson, D. S. (1972). Estimation of the concentration of low- density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clinical chemistry, 18(6), 499-502. https://doi.org/10.1093/clinchem/18.6.499

Hashiesh, H. M., Sheikh, A., Meeran, M. F. N., Saraswathiamma, D., Jha, N. K., Sadek, B., ... & Ojha, S. (2023). β-Caryophyllene, a dietary phytocannabinoid, alleviates diabetic cardiomyopathy in mice by inhibiting oxidative stress and inflammation activating cannabinoid type-2 receptors. ACS Pharmacology & Translational Science, 6(8), 1129-1142. https://doi.org/10.1021/acsptsci.3c00027

Horvath, C., Houriet, J., Kellenberger, A., Moser, C., Balazova, L., Balaz, M., ... & Wolfrum, C. (2025). Genkwanin glycosides are major active compounds in Phaleria nisidai extract mediating improved glucose homeostasis by stimulating glucose uptake into adipose tissues. Nature Communications, 16(1), 7648. https://doi.org/10.1038/s41467-025-62689-8

Hurtado-Carneiro, V., LeBaut-Ayuso, Y., Velázquez, E., Flores-Lamas, C., Fernández-de la Rosa, R., García-García, L., ... & Pozo, M. Á. (2024). Effects of chronic treatment with metformin on brain glucose hypometabolism and central insulin actions in transgenic mice with tauopathy. Heliyon, 10(15). https://doi.org/10.1016/j.heliyon.2024.e35752

Li, J., Feng, Z., Lu, B., Fang, X., Huang, D., & Wang, B. (2023). Resveratrol alleviates high glucose- induced oxidative stress and apoptosis in rat cardiac microvascular endothelial cell through AMPK/Sirt1 activation. Biochemistry and Biophysics Reports, 34, 101444. https://doi.org/10.1016/j.bbrep.2023.101444

Li, Y., Chen, Y., Shao, B., Liu, J., Hu, R., Zhao, F., ... & Wang, Y. (2023). Evaluation of creatine kinase (CK)-MB to total CK ratio as a diagnostic biomarker for primary tumors and metastasis screening. Practical Laboratory Medicine, 37, e00336. https://doi.org/10.1016/j.plabm.2023.e00336

Liao, X., Wang, Q., Yang, X., Yao, Y., Zhu, D., Feng, J., & Wang, K. (2025). Bisacurone ameliorates myocardial ischemia/reperfusion injury in rats: regulation of inflammatory and apoptosis pathways via CHOP/GRP78 proteins. BMC Pharmacology and Toxicology, 26(1), 115. https://doi.org/10.1186/s40360-025-00949-5

Marassi, M., & Fadini, G. P. (2023). The cardio-renal-metabolic connection: a review of the evidence. Cardiovascular Diabetology, 22(1), 195. https://doi.org/10.1186/s12933-023-01937-x

Masenga, S. K., Kabwe, L. S., Chakulya, M., & Kirabo, A. (2023). Mechanisms of Oxidative Stress in Metabolic Syndrome. International Journal of Molecular Sciences, 24(9), 7898. https://doi.org/10.3390/ijms24097898

Migdalis, I. N. (2024). Chronic Complications of Diabetes: Prevalence, Prevention, and Management. Journal of Clinical Medicine, 13(23), 7001. https://doi.org/10.3390/jcm13237001

Netala, V. R., Hou, T., Wang, Y., Zhang, Z., & Teertam, S. K. (2025). Cardiovascular Biomarkers: Tools for Precision Diagnosis and Prognosis. International journal of molecular sciences, 26(7), 3218. https://doi.org/10.3390/ijms26073218

Ong, K. L., Stafford, L. K., McLaughlin, S. A., Boyko, E. J., Vollset, S. E., Smith, A. E., ... & Brauer, M. (2023). Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021. The Lancet, 402(10397), 203-234. https://www.thelancet.com/action/showPdf?pii=S0140-6736%2823%2901301-6

Ozorowski, M., Wiciński, M., Kuźmiński, O., Wojciechowski, P., Siedlecki, Z., Śniegocki, M., & Włodarczyk, E. (2025). The Effects of Quercetin on Vascular Endothelium, Inflammation, Cardiovascular Disease and Lipid Metabolism—A Review. Nutrients, 17(9), 1579. https://doi.org/10.3390/nu17091579

Patsoukaki, V., Lind, L., Lampa, E., Radhi, S., Eeg-Olofsson, K., Eliasson, B., & Eriksson, J. W. (2025). Risk differences and underlying factors of cardiovascular events and mortality in patients with type 2 diabetes versus type 1 diabetes: a longitudinal cohort study of Swedish nationwide register data. The Lancet Diabetes & Endocrinology, 13(10), 848-862. https://doi.org/10.1016/S2213-8587(25)00165-2

Racine, K. C., Iglesias-Carres, L., Herring, J. A., Wieland, K. L., Ellsworth, P. N., Tessem, J. S., Ferruzzi, M. G., Kay, C. D., & Neilson, A. P. (2024). The high-fat diet and low-dose streptozotocin type-2 diabetes model induces hyperinsulinemia and insulin resistance in male but not female C57BL/6J mice. Nutrition research, 131, 135–146. https://doi.org/10.1016/j.nutres.2024.09.008

Rao, B. M., Vedavijaya, T., Ramani, Y. R., Sayana, S. B., & Vedavijaya, T. (2025). Protective Role of Methanol Leaf Extract of Catharanthus Roseus in Lipid Profile Modulation in Diabetic Wistar Rats. Cureus, 17(1). https://doi.org/10.7759/cureus.77420.

Sarker, M., Chowdhury, N., Bristy, A. T., Emran, T., Karim, R., Ahmed, R., ... & Reza, H. M. (2024). Astaxanthin protects fludrocortisone acetate-induced cardiac injury by attenuating oxidative stress, fibrosis, and inflammation through TGF-β/Smad signaling pathway. Biomedicine & Pharmacotherapy, 181, 117703. https://doi.org/10.1016/j.biopha.2024.117703

Scarpa, E. S., Antonelli, A., Balercia, G., Sabatelli, S., Maggi, F., Caprioli, G., ... & Micucci, M. (2024). Antioxidant, anti-inflammatory, anti-diabetic, and pro-osteogenic activities of polyphenols for the treatment of two different chronic diseases: type 2 diabetes mellitus and osteoporosis. Biomolecules, 14(7), 836. https://doi.org/10.3390/biom14070836

Shah, M. U., Roebuck, A., Srinivasan, B., Ward, J. K., Squires, P. E., Hills, C. E., & Lee, K. (2025). Diagnosis and management of type 2 diabetes mellitus in patients with ischaemic heart disease and acute coronary syndromes-a review of evidence and recommendations. Frontiers in Endocrinology, 15, 1499681. https://doi.org/10.3389/fendo.2024.1499681

Singh, A., Shadangi, S., Gupta, P. K., & Rana, S. (2025). Type 2 diabetes mellitus: A comprehensive review of pathophysiology, comorbidities, and emerging therapies. Comprehensive Physiology, 15(1), e70003. https://doi.org/10.1002/cph4.70003

Sini, M., Dongmo, F., Mvongo, C., Fokam Tagne, M. A., Jidibe, P., Foyet Fondjo, A., ... & Kamgang, R. (2025). Antihyperglycemic and Antioxidative Stress Effects of Erythrophleum africanum (Fabaceae)

Trunk Bark Powder Fractions on High‐Calorie Diet‐Induced Type 2 Diabetes in Rats. Food Science & Nutrition, 13(5), e70290. https://doi.org/10.1002/fsn3.70290

Sukhikh, S., Babich, O., Prosekov, A., Kalashnikova, O., Noskova, S., Bakhtiyarova, A., ... & Ivanova, S. (2023). Antidiabetic properties of plant secondary metabolites. Metabolites, 13(4), 513. https://doi.org/10.3390/metabo13040513

Suzuki, T., Sawada, S., Ishigaki, Y., Tsukita, S., Kodama, S., Sugisawa, T., ... & Katagiri, H. (2016). Lipoprotein lipase deficiency (R243H) in a type 2 diabetes patient with multiple arterial aneurysms. Internal Medicine, 55(9), 1131-1136. https://doi.org/10.2169/internalmedicine.55.5239

Tegegne, B. A., Adugna, A., Yenet, A., Yihunie Belay, W., Yibeltal, Y., Dagne, A., ... & Zeleke, T. K. (2024). A critical review on diabetes mellitus type 1 and type 2 management approaches: from lifestyle modification to current and novel targets and therapeutic agents. Frontiers in Endocrinology, 15, 1440456. https://doi.org/10.3389/fendo.2024.1440456

Wang, L., Bai, Y., Cao, Z., Guo, Z., Lian, Y., Liu, P., ... & Chen, Q. (2024). Histone deacetylases and inhibitors in diabetes mellitus and its complications. Biomedicine & Pharmacotherapy, 177, 117010. https://doi.org/10.1016/j.biopha.2024.117010

Wang, Y., Sun, H., Zhang, J., Xia, Z., & Chen, W. (2020). Streptozotocin-induced diabetic cardiomyopathy in rats: ameliorative effect of PIPERINE via Bcl2, Bax/Bcl2, and caspase-3 pathways. Bioscience, Biotechnology, and Biochemistry, 84(12), 2533-2544. https://doi.org/10.1080/09168451.2020.1815170

Welten, S. J., Elders, P. J., Remmelzwaal, S., Doekhie, R., Kee, K. W., Nijpels, G., & van der Heijden, A. A. (2023). Prolongation of the heart rate-corrected QT interval is associated with cardiovascular diseases: systematic review and meta-analysis. Archives of Cardiovascular Diseases, 116(2), 69-78. https://doi.org/10.1016/j.acvd.2022.11.007

Yedjou, C. G., Grigsby, J., Mbemi, A., Nelson, D., Mildort, B., Latinwo, L., & Tchounwou, P. B. (2023). The Management of Diabetes Mellitus Using Medicinal Plants and Vitamins. International Journal of Molecular Sciences, 24(10), 9085.https://doi.org/10.3390/ijms24109085

Zhang, H., & Dhalla, N. S. (2024). The role of pro-inflammatory cytokines in the pathogenesis of cardiovascular disease. International Journal of Molecular Sciences, 25(2), 1082. https://doi.org/10.3390/ijms25021082

Zhang, H., Kang, K., Chen, S., Su, Q., Zhang, W., Zeng, L., Lin, X., Peng, F., Lin, J., & Chai, D. (2024). High serum lactate dehydrogenase as a predictor of cardiac insufficiency at follow-up in elderly patients with acute myocardial infarction. Archives of gerontology and geriatrics, 117, 105253. https://doi.org/10.1016/j.archger.2023.105253