Ficus carica as an Antidiabetic Agent: Evidence from a Meta-analysis of In Vivo Studies

Abstract

Recent evidence indicates that Ficus carica may exert glucose-lowering effects under diabetic conditions. However, reductions generally do not restore blood glucose to normal levels, raising questions about its reliability as an antidiabetic agent. This study aimed to systematically evaluate the glucose-lowering effects of F. carica in experimental diabetes models through meta-analysis, with additional assessments of dosage influence and comparison to glibenclamide. Relevant studies were retrieved from PubMed, Scopus, and Web of Science, including in vivo experiments on diabetic rats reporting blood glucose or insulin outcomes after F. carica intervention. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated using meta-analysis based on leaf extract, dosage, and comparator treatment. F. carica leaf extract significantly reduced blood glucose compared to diabetic controls (SMD = –5.92; 95% CI [–8.13, –3.72]; p = .00001). Subgroup analyses demonstrated consistent effects at doses below 500 mg/kg BW (SMD = –8.11; 95% CI [–12.83, –3.39]; p = .0008) and above 400 mg/kg BW (SMD = –4.95; 95% CI [–7.49, –2.40]; p < .0001). Leaf extract showed no superior effect compared to glibenclamide (SMD = 2.10; 95% CI [0.91, 3.29]; p = .0006). A significant effect on insulin levels was observed in leaf extract (SMD = –3.65; 95% CI [–7.12, –0.18]; p = .04), though inconsistent effects were noted across other plant parts. In conclusion, F. carica demonstrates antidiabetic potential by reducing blood glucose in diabetic rats, but effects remain within the prediabetic range and are not superior to glibenclamide. Further research is needed to achieve normoglycemic reduction and consistent insulin effects under diabetic conditions.

Keywords

Diabetes herbal medicine alternative medicine

Introduction

According to the International Diabetes Federation, the number of people with diabetes mellitus is projected to increase by 45% from 2024 to 2050.¹ Diabetes is commonly treated with insulin therapy and several oral antidiabetic drugs that reduce blood glucose levels. However, these treatments cannot always restore glucose to normal levels, and patients often require lifelong use. Therefore, new antidiabetic agents with better efficacy and fewer side effects are still needed. Plant-based compounds may offer a promising alternative for diabetes treatment.² The World Health Organization (WHO) also supports the use of herbal medicine as a complementary or alternative approach in diabetes management.³

Ficus carica has recently been investigated for its antidiabetic potential through various in vivo studies.^4,5 Findings indicate that F. carica can improve hyperglycaemia under diabetic conditions. However, several studies have shown that the reduction in blood glucose levels due to F. carica intervention still falls within the prediabetic to diabetic range.^6,7 These outcomes may raise uncertainty and ambiguity regarding the potential of F. carica as a reliable antidiabetic agent.

Therefore, it is essential to conduct an evaluation based on the available evidence through systematic review and meta-analysis. To date, although several studies have reported the antidiabetic potential of F. carica, no comprehensive meta-analysis has specifically synthesized evidence from in vivo studies. Previous reports have primarily been limited to narrative reviews or individual experimental findings without quantitative integration. Furthermore, this study focuses on in vivo (animal) studies because clinical evidence in humans remains limited and insufficient for quantitative synthesis. In vivo models play a crucial role in preclinical research, allowing controlled evaluation of pharmacological effects, mechanisms of action, and dose–response relationships under diabetic conditions, and providing essential translational evidence prior to clinical trials. This approach aims to provide robust validation of the antidiabetic potential of F. carica. This evaluation aims to determine whether F. carica requires further in-depth investigation or is ready to advance into clinical trials.

Materials and Methods

Review Methodology

This meta-analysis followed the PRISMA 2020 guidelines, which give a clear and standardized method for systematic review and meta-analysis studies. The guidelines were used to ensure clarity, transparency, and accuracy in the research process. The study protocol was also registered in the PROSPERO database on July 10, 2025, and approved on July 29, 2025, with the registration number CRD420251091406 (https://www.crd.york.ac.uk/PROSPERO/view/CRD420251091406).

Eligibility Criteria

The studies included in this review met several specific criteria. They had to use an experimental design with animal models such as Wistar rats, Sprague–Dawley rats, or Mus musculus. The treatment had to be given in extract form with a clearly defined dosage, and each study needed to include both an intervention and a control group. Studies were excluded if they were not written in English, were incomplete, or did not clearly report their results.

Information Sources

Relevant studies were searched from major journal databases, including Scopus, PubMed, and Web of Science (WoS). The literature search was carried out until August 14, 2025.

Search Strategy

Search keywords were defined using both MeSH and non-MeSH terms as follows: (“Fig” OR Ficus carica) AND (“Diabetes Mellitus” OR “Hyperglycaemia” OR “Glucose Intolerance”). No publication date limits were applied, and only studies published in English were included. The collected data were saved as “PubMed Set” and “RIS” files and then imported into Mendeley to prevent data loss.

Selection Process

The study selection process was assisted by Rayyan.ai (www.rayyan.ai), which helped detect duplicate studies, screen abstracts for relevance, and distinguish between research articles and review articles. To minimize bias, AI-assisted selection was followed by manual checking by two reviewers to ensure validity and compliance with the established inclusion and exclusion criteria.

Data Collection Process

Data were extracted independently by two reviewers using a standardized extraction form. Extracted information included: author, year of publication, animal model, induction method, extract type and dose, duration of treatment, comparator drug (if any), and primary outcomes (blood glucose and insulin levels). Discrepancies were resolved by consensus.

Data Items (Outcomes)

The main outcomes were fasting blood glucose (FBG) and insulin levels after F. carica administration. Other extracted variables included the type of extract, treatment duration, and comparator used (e.g., glibenclamide).

Study of Risk of Bias Assessment

Risk of bias for individual studies was assessed using SYRCLE’s Risk of Bias Tool for animal studies.⁸ The evaluation covered randomization, allocation concealment, blinding, completeness of data, and selective outcome reporting. Disagreements between assessors were discussed until consensus was achieved.

Effect Measures

For quantitative synthesis, the standardized mean difference (SMD) and 95% confidence intervals (CIs) were calculated for continuous outcomes (blood glucose and insulin levels). Negative SMD values indicated a glucose-lowering effect compared with controls.

Synthesis Methods

Meta-analysis was performed using a random-effects model (DerSimonian and Laird method) to account for potential heterogeneity. Statistical heterogeneity was evaluated using I² statistics and Cochran’s Q test. Considering the phytochemical variability among different parts of F. carica (e.g., leaves, fruit, bark, and seed oil), the meta-analysis was restricted to studies utilizing F. carica leaves, as this subgroup provided sufficient data for quantitative synthesis. Studies using other plant parts were not included in the pooled analysis due to limited data availability and were instead described qualitatively. All analyses were performed using RevMan version 5.4 (Cochrane Collaboration, London, UK). A p < .05 was considered statistically significant.

Reporting Bias Assessment

Publication bias was assessed visually using funnel plots. The overall certainty of evidence was evaluated by considering the risk of bias, consistency of results across studies, relevance of the animal models to clinical conditions, and reliability of reported data, following the code framework as “ +,” “?,” and “–”; then categorized as “Low,” “Unclear,” or “High.”

GRADE Assessment

The overall certainty of evidence across studies was assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) framework adapted for preclinical animal studies, as described by Hooijmans et al. (2018). Five domains were evaluated: (a) risk of bias, informed by the results of SYRCLE’s Risk of Bias tool; (b) inconsistency, evaluated using I² statistics and Cochran’s Q test; (c) indirectness, reflecting the translational gap between chemically induced animal diabetes models and human Type 2 diabetes mellitus; (d) imprecision, based on the width of 95% CIs and the number of included studies; and (e) publication bias, assessed visually through funnel plots. The certainty started at “high” and was downgraded by one level for serious concerns (−1) or two levels for very serious concerns (−2) in each domain. The final certainty was categorized as high, moderate, low, or very low.⁹

Results

Study Selection

The selection process for relevant studies is presented in Figure 1. The search across three databases identified 584 studies. Screening removed 61 duplicate studies. A further manual screening yielded 13 studies that were relevant and met the criteria for systematic review. However, only five of these studies provided sufficient data for statistical testing in the meta-analysis.

Study Characteristics and Results

The characteristics of each study that met the inclusion criteria are presented in Table 1. The potential of F. carica as an antidiabetic agent has been investigated in various countries. Most studies were conducted in India (three studies). Two studies were conducted in Turkey, while China, Indonesia, Morocco, Malaysia, Saudi Arabia, the United Arab Emirates, Iraq, and Pakistan each contributed one study.

Table 1.

Data Extraction Summary of Included Studies.

Studies	Country	Animal Sample	Ficus carica Part Extract, Doses and Duration of Intervention	Control	Outcome
Umarqayum Abu Bakar, et al. (2020)⁷	Malaysia	Sprague–Dawley rats Sex: Male Age: 8 weeks BW: Not specified Diabetic inducer: STZ 50 mg/kg BW	Leaf extract, 400 mg/kg BW 21 days, oral gavage	Diabetic rats diabetic rats + metformin	F. carica treatment lowered fasting blood glucose (FBG), improved sperm quality, and enhanced fertility-related protein expression significantly
El-Ghouizi et al. (2023)¹⁰	Morocco	Wistar rats Sex: Male Age: 8 weeks BW: 220–230 g Diabetic inducer: Alloxan 65 mg/kg BW	Leaf (200 mg/kg) Bud (200 mg/kg) Combo (100 + 100 mg/kg) 30 days, oral	Diabetic rats	F. carica treatment reduced FBG, malondialdehyde (MDA), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), creatinine, urea, uric acid, cholesterol, triglycerides, and increased catalase and Glutathione peroxidase (GPx).
Qodriah et al. (2023)¹¹	Indonesia	Strain: DDY (Mus musculus) Sex: Male Age: 2–3 months BW: Average weight of 20–30 g Diabetic inducer: STZ	Extract: F. carica L (leaves) Doses: 250, 500, 600 mg/kg BB, oral) Duration: 28 days	Diabetic mice diabetic mice + glibenclamide	F. carica demonstrated antidiabetic and anti-obesity effects by lowering blood glucose, reducing cholesterol, and decreasing body weight in rats.
Oktay et al. (2024)⁴	Turkey	Wistar albino rats Sex: Male Age: Adult BW: 250–260 g Diabetic inducer: STZ 50 mg/kg BW	F. carica seed oil (FCSO) Doses: 4 mL/kg/day Duration: 5 weeks	Diabetic rat	F. carica seed oil (FCSO) treatment alleviated hyperglycaemia, oxidative stress, inflammation, and neuropathy markers, restoring levels close to those of normal controls.
Roy et al. 2021)⁶	India	Strain: Albino Wistar rats Sex: Male and female Age: 8–12 weeks BW: 150–220 g Diabetic inducer: STZ 60 mg/kg BW	Extract: F. carica leaves in different solutions (petroleum ether, ethyloacetate, methanol and aqueous) Doses: 500 mg/kg BW Duration: 9 days	Diabetic rat	Ethyl acetate, methanolic, and aqueous extracts of F. carica leaves significantly reduced blood glucose and body weight in STZ-induced diabetic rats.
Zhang et al. (2019)¹²	China	Strain: Mice C57BL/6J Sex: male BW: 180–220 g Diabetic inducer: STZ 150 mg/kg BW	Extract: F. carica leaves Doses: 1 g/kg BW Duration: 6 weeks	Diabetic mice	FCL extract inhibited hepatic gluconeogenesis by downregulating Phosphoenolpyruvate carboxykinase (PEPCK), Glucose-6-Phosphatase (G6Pase), Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), Hepatocyte Nuclear Factor 4-alpha (HNF4α), Forkhead box O1 (FOXO1), and activating (AMP-activated protein kinase) AMPK, effects attenuated by AMPK inhibitor.
Irudayaraj et al. (2017)¹³	Saudi Arabia	Strain: Wistar Sex: Male BW:170–190 g Diabetic inducer: STZ 40 mg/kg BW	Leaves extract Doses: 250 mg/kg BW, 500 mg/kg BW Duration: 28 days	Diabetic rat diabetic rat + glibenclamide	An extract of F. carica leaves (250–500 mg/kg) significantly improved glucose tolerance, lipid profile, body weight, and hepatic glycogen in diabetic rats. It restored key carbohydrate-metabolizing enzymes, enhanced glucose utilization, and protected pancreatic β-cells, confirming its potent antihyperglycemic and cytoprotective effects.
Sharma (2022)¹⁴	India	Strain: Not specified Sex: Not specified Age: Not specified BW: Not specified Diabetic inducer: Alloxan	Fruit extract Doses: 400 mg/kg BW Duration: 21 days	Diabetic rat diabetic rat + metformin	F. carica extracts showed superior antioxidant, anti-inflammatory, antimicrobial, and antihyperglycemic effects, significantly reducing blood glucose in diabetic models.
Arafa et al. (2020)¹⁵	Uni Emirate Arab	Strain: Wistar Sex: Male Age: Not specified BW: 170–200 g Diabetic inducer: STZ 30 mg/kg BW	Fruit extract Doses: 250 mg/kg BW, 500 mg/kg BW Duration: 28 days	Diabetic rat diabetic rat + metformin	F. carica are effective in obesity-linked diabetes by regulating various glucose, lipid metabolic products, and oxidative stress factors.
Saleem et al. (2023)¹⁶	Pakistan	Strain: Wistar Sex: Not specified Age: Not specified BW: 180–200 g Diabetic inducer: Alloxan 150 mg/BW	Fruit extract Doses: 400 mg/kg BW Duration: 28 days	Diabetic rat	Administration of fig extract improved fasting blood glucose, serum glucose, and insulin levels, while reversing pancreatic cell damage. Notably, 10% dried fig effectively controlled hyperglycemia, likely due to fiber content, whereas fig extract showed stronger effects in modulating INS-1, INS-2, Pdx-1, amylin, and GLUT-2 gene expression.
Shwayekh et al. (2024)⁵	Iraq	Strain: Wistar Sex: Male Age: 10–12 weeks BW: 180–250 g Diabetic inducer: STZ 35 mg/kg BW	Peel extract Doses: 200 mg/kg BW Duration: 21 days	Diabetic rat	F. carica exhibits significant antioxidant activity, reducing oxidative stress in a Type 2 diabetes rat model. The extract also shows liver protection, with milder liver tissue changes in treated rats compared to untreated ones
Mert et al. (Turkey)¹⁷	Turkey	Strain: Wistar Sex: Female Age: 8–10 weeks BW: 250–300 g Diabetic inducer: STZ 45 mg/kg BW	Seed oil Doses: 6 mL/kg BW Duration: 12 days	Diabetic rat	Fig seed oil significantly reduced blood glucose, urea, creatinine, ALT, AST, AOPP, and MDA, while increasing GSH levels in diabetic rats. Histopathological, immunohistochemical, and immunofluorescent analyses confirmed pancreatic protection.
Ahmad et al. (2013)¹⁸	India	Strain: Wistar Sex: Not specified Age: Not specified BW: 150–250 g Diabetic inducer: STZ	Bark extract Doses: 500 mg/kg BW Duration 21 days	Diabetic rat	F. carica extract lowered blood glucose, triglycerides, and cholesterol while increasing insulin levels in diabetic rats, demonstrating strong antidiabetic and antihyperlipidemic protective effects.

Thirteen studies reported the type of experimental animals used. Nine studies used the Rattus norvegicus strain Wistar, one study used R. norvegicus strain Sprague–Dawley, and two studies used M. musculus, while one study did not specify the animal strain. To induce diabetes, 10 studies used streptozotocin (STZ), while three used alloxan. Eight studies reported the STZ dose (30–150 mg/kg BW), whereas one did not. Similarly, two studies reported the alloxan dose (65 and 150 mg/kg BW), while one did not. The dose and duration of F. carica intervention also varied. The reported doses ranged from 200 to 1 g/kg BW, with one study expressing the dose in mL/kg BW. The duration of intervention ranged from 9 days to 6 weeks.

All included studies measured serum blood glucose levels, and most also assessed additional biomarkers (Table 2). These included serum insulin, body weight, lipid profile, and oxidative stress markers in organs such as the kidney, liver, and pancreas. Some studies further evaluated inflammatory parameters and sperm count. Among all assessed biomarkers, only blood glucose and insulin levels, which are treated with leaf F. carica extract, met the criteria for quantitative analysis across all studies.

Table 2.

Laboratory Outcome of Biomarkers.

Studies	Parts and Dosages	Biomarker
Studies	Parts and Dosages	Diabetes + Ficus carica	Diabetes Control	Diabetes + Glibenclamide
Umarqayum Abu Bakar et al. (2020)	Leaf extract, 400 mg/kg BW	Blood glucose (mg/dL) 227.027 ± 26.591	Blood glucose (mg/dL) 427.027 ± 35.858
El-Ghouizi et al. (2023)	Leaf (200 mg/kg) Bud (200 mg/kg) Combo (100 + 100 mg/kg BW)	Blood glucose (mg/dL) Leaf: 190 ± 52 Bud: 127 ± 30 Leaf/Bud: 162 ± 40	Blood glucose (mg/dL) 419 ± 56
Qodriah et al. (2023)	Leaf extract Doses: 250, 500, 600 mg/kg BW	Body weight (gram) 250 mg/kg BW: 30.1 ± 0.90 500 mg/kg BW: 31.0 ± 0.80 600 mg/kg BW: 31.9 ± 0.91 Blood glucose (mg/dL) 250 mg/kg BW: 168.4 ± 2.41 500 mg/kg BW: 157.6 ± 1.67 600 mg/kg BW: 144.6 ± 3.65 Cholesterol (mg/dL) 250 mg/kg BW: 195.4 ± 1.43 500 mg/kg BW: 193.6 ± 1.67 600 mg/kg BW: 184.6 ± 1.15	Body weight (gram) 19.36 ± 1.11 Blood glucose (mg/dL) 299.4 ± 2.07 Cholesterol (mg/dL) 269.4 ± 1.07
Oktay et al. (2024)	Seed oil (FCSO) Doses: 4 mL/kg BW	Body weight (gram) 293.67 ± 37.61 Blood glucose (mg/dL) Graph Cytokines pro- inflammatory (pg/mL) TNF-α: Graph IL-6: Graph IL-1β: Graph Antioxidant activity MDA (ng/mL): Graph SOD (ng/mL): Graph CAT (mIU/mL): Graph	Body weight (gram) 200.77 ± 12.94 Blood glucose (mg/dL) Graph Cytokines pro- inflammatory (pg/mL) TNF-α: Graph IL-6: Graph IL-1β: Graph Antioxidant activity MDA (ng/mL): Graph SOD (ng/mL): Graph CAT (mIU/mL): Graph
Roy et al. (2021)	Leaf extract in different solutions (petroleum ether, ethyloacetate, methanol and aqueous) Doses: 500 mg/kg BW	Blood glucose (mg/L) PE: 320 ± 18,59 Ethyl Acetate: 220.7 ± 66,82 Methanol: 208.5 ± 37,77 Aqueous: 201.8 ± 54.3	Blood glucose (mg/dL) 339.8 ± 4.45	Blood glucose (mg/dL) 139.2 ± 6.178
Zhang et al. (2019)	Leaf extract Doses: 1 g/kg BW	Blood glucose (mg/dL) Graphic Insulin (mIU/L) Graphic	Blood glucose (mg/dL) Graphic Insulin (mIU/L) Graphic
Irudayaraj et al. (2017)	Leaf extract Doses: 250 mg/kg BW, 500 mg/kg BW	Blood glucose (mg/dL) 250 mg/kg BW: 137.27 ± 7.24 500 mg/kg BW: 129.14 ± 8.23 Insulin (µU/mL) 250 mg/kg BW: 20.77 ± 0.84 500 mg/kg BW: 15.84 ± 0.76	Blood glucose (mg/dL) 281.22 ± 13.52 Insulin (µU/mL) 25.31 ± 0.46	Blood glucose (mg/dL) 131.32 ± 9.13 Insulin (µU/mL) 16.13 ± 0.53
Sharma (2022)	Fruit extract Doses: 200 and 400 mg/kg BW	Blood glucose (mg/dL) 200 mg/kg BW: 200 400 mg/kg BW: 160	Blood glucose (mg/dL) 275
Arafa et al. (2020)	Fruit extract Doses: 250 mg/kg BW, 500 mg/kg BW	Body weight (gram) 250 mg/kg BW: Graphic 500 mg/kg BW: Graphic Blood glucose (mg/dL) 250 mg/kg BW: Graphic 500 mg/kg BW: Graphic Cholesterol (mg/dL) 250 mg/kg BW: Graphic 500 mg/kg BW: Graphic TG (mg/dL) 250 mg/kg BW: Graphic 500 mg/kg BW: Graphic HDL (mg/dL) 250 mg/kg BW: Graphic 500 mg/kg BW: Graphic LDL (mg/dL) 250 mg/kg BW: Graphic 500 mg/kg BW: Graphic VLDL (mg/dL) 250 mg/kg BW: Graphic 500 mg/kg BW: Graphic	Body weight (gram) 250 mg/kg BW: Graphic 500 mg/kg BW: Graphic Blood glucose (mg/dL) 250 mg/kg BW: Graphic 500 mg/kg BW: Graphic Cholesterol (mg/dL) 250 mg/kg BW: Graphic 500 mg/kg BW: Graphic TG (mg/dL) 250 mg/kg BW: Graphic 500 mg/kg BW: Graphic HDL (mg/dL) 250 mg/kg BW: Graphic 500 mg/kg BW: Graphic LDL (mg/dL) 250 mg/kg BW: Graphic 500 mg/kg BW: Graphic VLDL (mg/dL) 250 mg/kg BW: Graphic 500 mg/kg BW: Graphic
Saleem et al. (2023)	Fruit extract Doses: 400 mg/kg BW	Blood glucose (mg/dL) 261.23 ± 11.19 Blood insulin (µIU/mL) 24.33 ± 0.79	Blood glucose (mg/dL) 345.74 ± 12.77 Blood insulin (µIU/mL) 15.28 ± 0.79	Blood glucose (mg/dL) 284.74 ± 10.41 Blood insulin (µIU/mL) 22.69 ± 0.88
Shwayekh et al. (2024)	Peel extract Doses: 200 mg/kg BW	MDA (mmol/L) Graphic	MDA (mmol/L) Graphic
Mert et al. (Turkey)	Seed oil Doses: 6 mL/kg BW	Body weight (gram) 208.20 ± 22.160 Blood glucose (mg/dL) 484.80 ± 26.13 Urea (mg/dL) 79.08 ± 12.28 Creatinine (mg/dL) 0.40 ± 0.02 ALT (U/L) 540.8 ± 268.03 AST (U/L) 784.20 ± 218.17 GSH (mg/dL) 175.43 ± 25.12 MDA (nmol/mL) 1.8 ± 0.42	Body weight (gram) 205.40 ± 20.62 Blood glucose (mg/dL) 564.20 ± 37.21 Urea (mg/dL) 97.02 ± 9.44 Creatinine (mg/dL) 0.44 ± 0.06 ALT (U/L) 895.20 ± 236.13 AST (U/L) 1381.20 ± 618.48 GSH (mg/dL) 124.67 ± 16.65 MDA (nmol/mL) 2.46 ± 0.74
Ahmad et al. (2013)	Bark extract Doses: 500 mg/kg BW	Blood glucose (mg/dL) 174.76 + 3.98 Insulin (mU/L) 0.64 + 0.019 MDA (nmol/mg protein) 1.66 + 0.038	Blood glucose (mg/dL) 321.89 + 5.87 Insulin (mU/L) 0.43 + 0.023 MDA (nmol/mg protein) 1.19 + 0.030	Blood glucose (mg/dL) 108.64 + 2.12 Insulin (mU/L) 0.87 + 0.029 MDA (nmol/mg protein) 0.75 + 0.041

Risk of Bias in Studies

Risk of bias was assessed across 13 included preclinical animal studies using SYRCLE’s Risk of Bias Tool, with results summarized in Table 3. No study was classified as high risk. Nine studies (69.2%) demonstrated low risk of bias, while four studies (30.8%) Ahmad et al. (2013), Arafa et al. (2020), Saleem et al. (2023), and Sharma (2022) were classified as unclear risk, primarily attributable to insufficient reporting of sequence generation (Domain 1, unclear in 9/13 studies) and allocation concealment (Domain 3, unclear in 12/13 studies). In contrast, all studies demonstrated adequate blinding of outcome assessors (Domain 7), complete outcome data reporting (Domain 8), freedom from selective reporting (Domain 9), and absence of other identifiable bias sources (Domain 10). Four studies additionally identified gaps in caregiver blinding (Domain 5) and random outcome selection (Domain 6), which may theoretically introduce performance or detection bias; however, these concerns are partially mitigated by the consistent implementation of outcome assessor blinding across all studies. Taken together, the risk of bias profile of the included evidence base is considered satisfactory for meta-analytic synthesis, though findings should be interpreted with appropriate caution given the inherent reporting limitations of preclinical research.

Table 3.

Risk of Bias Assessment Using the SYRCLE’s Checklist Tool.

Studies	1	2	3	4	5	6	7	8	9	10	Conclusion
Ahmad et al. (2013)	?	+	?	+	+	?	+	+	+	+	Unclear
Arafa et al. (2020)	?	+	?	+	?	?	+	+	+	+	Unclear
El Ghouizi et al. (2023)	?	+	?	+	+	+	+	+	+	+	Low
Irudayaraj et al. (2017)	?	+	?	+	+	+	+	+	+	+	Low
Mert et al. (2024)	+	+	?	+	+	+	+	+	+	+	Low
Oktay et al. (2024)	+	+	?	+	+	+	+	+	+	+	Low
Qodriah et al. (2023)	?	+	+	+	+	+	+	+	+	+	Low
Roy et al. (2021)	?	+	?	+	+	+	+	+	+	+	Low
Saleem et al. (2023)	?	+	?	+	?	?	+	+	+	+	Unclear
Sharma (2022)	?	+	?	?	?	?	+	+	+	+	Unclear
Shwayekh et al. (2024)	+	+	?	+	+	+	+	+	+	+	Low
Umarqayum Abu Bakar et al. (2020)	?	+	?	+	+	+	+	+	+	+	Low
Zhang et al. (2019)	+	+	?	+	+	+	+	+	+	+	Low
Domain	1. Sequence generation 2. Baseline characteristic 3. Allocation concealment 4. Random housing 5. Blinding					6. Random outcome assessment 7. Blinding 8. Incomplete outcome data 9. Selective outcome reporting 10. Other sources of bias

Results of Syntheses

All parts of F. carica demonstrate potential anti-hyperglycemic properties. The data indicate that blood glucose levels in diabetic rats treated with F. carica extract were lower compared to the diabetic control group. However, this interpretation must be approached with caution. This is due to the fact that the parts of F. carica used to prepare the extracts remained heterogeneous across studies. Furthermore, a comprehensive statistical analysis could not be conducted, as the data reporting the specific parts of F. carica utilized as extracts were limited.

The induction of extracts derived from different parts of F. carica yielded varying results. Studies conducted by Ahmad et al. (2013), Saleem et al. (2023), and Irudayaraj et al. (2017) each utilized extracts from distinct parts of F. carica, namely the bark, fruit, and leaf, respectively. Diabetic rats treated with extracts derived from the bark and fruit exhibited higher blood insulin levels compared to the diabetic control group. In contrast, opposing results were observed in diabetic rats treated with the leaf extract. The blood insulin levels of rats treated with F. carica leaf extract were lower than those of the diabetic control group.

Beyond blood glucose and insulin levels, several other parameters were also affected by the administration of F. carica extract under diabetic conditions. The seed oil and bark extracts of F. carica exhibit antioxidant potential, as evidenced by their ability to reduce malondialdehyde (MDA) levels in diabetic conditions. Notably, the seed oil of F. carica shows promise in providing hepatoprotective effects against liver damage. This is supported by the observed reduction in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity under diabetic conditions. The fruit extract of F. carica also demonstrates potential in improving the lipid profile under diabetic conditions by reducing levels of cholesterol, triglycerides (TG), low- density lipoprotein (LDL), and very low-density lipoprotein (VLDL), while simultaneously increasing high-density lipoprotein (HDL) levels. Furthermore, F. carica fruit extract shows potential in enhancing renal filtration activity, as demonstrated by lower creatinine and urea levels compared to the diabetic control group.

Meta-analysis

Effect of Leaf F. carica Extract on Blood Glucose Level

Figure 2 illustrates the statistical analysis of the effects of leaf F. carica extract on blood glucose levels in diabetic rats. The results showed a significant effect size for leaf F. carica extract in reducing blood glucose levels (SMD = –5.92; 95% CI [–8.13, –3.72]; p = .00001). Subgroup analysis by dosage indicated that both doses below 500 mg/kg BW (SMD = –8.11; 95% CI [–12.83, –3.39]; p = .0008) and above 400 mg/kg BW (SMD = –4.95; 95% CI [–7.49, –2.40]; p = .0001) significantly lowered blood glucose compared with the control group. However, both dosage ranges reduced glucose only to the prediabetic level, without reaching the normal range (Figure 3A and 3B). It should be noted that the results of this meta-analysis demonstrate a high level of heterogeneity. This is attributed to numerous factors, including variations in dosage, extraction processes, and the solvents used during extraction. Differences in the chemical agents employed to induce diabetes across individual studies also contribute to this variability. Therefore, caution is warranted when interpreting the findings of this meta-analysis.

A subgroup analysis was also performed to compare the effects of leaf F. carica extract with glibenclamide on blood glucose levels (Figure 4A–4C). The results indicated that F. carica did not reduce blood glucose more effectively than glibenclamide (SMD = 2.10; 95% CI [0.91, 3.29]; p = .0006). At doses below 500 mg/kg BW (SMD = 2.82; 95% CI [–2.66, 8,30]; p = .31) and above 400 mg/kg BW (SMD = 2.10; 95% CI [0.77, 3.42]; p = .002), F. carica similarly showed no superior effect compared with glibenclamide.

Effect of Leaf F. carica Extract on Insulin Level

Figure 5 presents the statistical results of leaf F. carica extract on insulin levels in diabetic rats. The findings indicate that leaf F. carica extract had a significant effect on insulin levels under diabetic conditions (SMD = –3.65; 95% CI [–7.12, –0.18]; p = .04).

Certainty of Evidence (GRADE Assessment)

Beginning from a high certainty rating, the evidence was downgraded by a total of four levels: one level for serious risk of bias (−1), two levels for very serious inconsistency (−2), and one level for serious indirectness (−1). The overall certainty of evidence is therefore rated as Very Low (Table 4). This rating indicates that the true effect of F. carica on blood glucose levels in preclinical animal models remains highly uncertain, and that the observed effect sizes may differ substantially from the effects that would be anticipated in a human clinical population. These findings underscore the importance of cautious interpretation and highlight the need for rigorously designed clinical investigations, including standardized extract characterization, dose-escalation studies in humans, and long-term safety assessments before any therapeutic extrapolation from the preclinical evidence base can be warranted.

Table 4.

GRADE Assessment.

GRADE Domain	Rationale	Judgment	Downgrade	Certainty
Risk of bias	Sequence generation and allocation concealment were unclear in the majority of studies; four studies were classified as overall unclear risk	Serious	−1	High → moderate
Inconsistency	High I²; variability in extraction solvents, diabetic induction agents (STZ vs. alloxan), dosage (10–600 mg/kg), and treatment duration (9 days–6 weeks)	Very serious	−2	Moderate → very low
Indirectness	Chemically induced models (STZ/alloxan) do not fully recapitulate human T2DM; glucose reductions remained in the prediabetic range	Serious	−1	Already very low
Imprecision	Wide CIs in individual studies; no additional downgrade as evidence already rated very low	Not downgraded	0	Already very low
Publication bias	Mild funnel plot asymmetry observed; attributed to heterogeneity and small-study effects rather than selective reporting; formal testing not feasible (n < 10)	Not downgraded	0	Already very low
Overall certainty	Very low (high −1 −2 −1 = very low)

Discussion

F. carica as an Antidiabetic Agent

F. carica has been widely recognized as a plant with a rich phytochemical profile. Its major bioactive compounds include phenolic substances such as anthocyanins (cyanidin-3-O- rutinoside, cyanidin-3,5-O-diglucoside, and pelargonidin derivatives), with epicatechin reported as the most dominant phenolic compound in the fruit, while flavonoids such as myricetin, kaempferol, and quercetin are present in smaller amounts. The plant also contains tocopherols, particularly γ-tocopherol as the most abundant form, along with other seed-derived compounds including gamma-sitosterol and polyunsaturated fatty acids. Additionally, flavonoids, terpenoids, and tannins have been consistently identified across various parts of the plant, whereas saponins and alkaloids were generally absent or detected in negligible amounts.^19,20 These bioactive compounds are found throughout the entire plant, including the leaves, fruits, roots, and stem bark.¹⁹ Given this diverse phytochemical composition, a growing number of studies have investigated the potential of F. carica as a natural antidiabetic agent.^21,22

All parts of F. carica extract showed hypoglycemic effects under diabetic conditions. Leaf extract was the most commonly used and produced the greatest reduction in blood glucose levels, bringing values closest to the normal range. In contrast, seed oil, fruit, and bark extracts showed weaker blood glucose-lowering effects compared to the leaf extract. The leaf fraction is particularly rich in flavonoid compounds such as tannins and quercetin, while the fruit fraction contains higher amounts of epicatechin. Seed oil, on the other hand, is predominantly composed of terpenoid compounds, especially tocopherols.¹⁹ Each part of the F. carica extract showed a different effect on insulin levels. Leaf extract administration resulted in lower insulin levels compared to the diabetic control group. In contrast, bark and fruit extract administration produced higher insulin levels compared to the diabetic control group. These differences are likely explained by the distinct phytochemical composition of each plant part, which influences their respective antidiabetic mechanisms and potency.

The antidiabetic effects of F. carica are hypothesized to act through several mechanisms. Flavonoids in F. carica are suggested to improve tissue sensitivity to insulin, thereby enhancing glucose uptake. F. carica may also increase the expression of insulin receptor substrate 1 (IRS-1) in hepatic tissue, and this effect is likely to occur in adipose and muscle tissues as well.²³ Phenolic acids have also been reported to enhance IRS-1 expression in tissues.²⁴ Increased IRS-1 expression in hepatic, muscle, and adipose tissues can promote glucose uptake, resulting in decreased blood glucose levels.²⁵ In addition to improving tissue response to insulin, phenolic compounds, anthocyanins, and flavonoid derivatives such as epicatechin and quercetin have been reported to inhibit the activity of α-amylase and α-glucosidase enzymes and help control glucose absorption from the digestive system into the bloodstream.^22,25,26

In addition to improving insulin sensitivity, F. carica is also suggested to play a role in inhibiting hepatic gluconeogenesis. This effect is indicated by reduced ALT and AST levels following F. carica administration.²⁷ Both enzymes are important in providing substrates for gluconeogenesis. A decrease in ALT reduces the conversion of alanine to pyruvate, while a decrease in AST limits the formation of oxaloacetate from aspartate. Consequently, gluconeogenic activity decreases, leading to reduced endogenous glucose production by the liver and improved hyperglycemia in diabetes.²⁸ Chlorogenic acid and quercetin, flavonoid compounds confirmed to be present in F. carica,²³ may contribute to this effect. Yang and Kang (2018) demonstrated that quercetin reduced ALT and AST levels in STZ-induced diabetic rats,²⁹ while Shirkhani et al. (2022) confirmed that chlorogenic acid decreased ALT and AST levels in diabetic rats.³⁰

Beyond enhancement of peripheral tissue insulin sensitivity, inhibition of carbohydrate-digesting enzymes, and suppression of hepatic gluconeogenesis, F. carica also demonstrates potential in protecting pancreatic β-cells from damage. These findings suggest that the glucose-lowering effect of F. carica may be predominantly mediated through insulin-independent pathways, including inhibition of intestinal α-glucosidase, enhanced GLUT4 translocation in tissues, and suppression of hepatic gluconeogenesis. However, the possibility of a partial insulin-mediated contribution cannot be entirely excluded, as evidenced by the inconsistent directional effects observed across individual studies. Future studies with standardized protocols are warranted to further elucidate the precise mechanisms underlying the antidiabetic activity of F. carica.

Although all parts of F. carica extract demonstrate potential antidiabetic properties, the observed reduction in blood glucose levels remained within the prediabetic range. This may be attributed to the complexity of the metabolic environment in diabetes, which can influence the overall antidiabetic efficacy of F. carica. Furthermore, the diabetic animal model itself represents a critical confounding factor, as chemical induction by alloxan or STZ causes extensive damage to pancreatic tissue, thereby impairing insulin synthesis and peripheral tissue response.^31,32

The findings of this study indicate that F. carica extract is only effective in reducing blood glucose levels at the prediabetic stage. Nevertheless, F. carica demonstrates additional pharmacological potential that warrants consideration as an alternative herbal agent, including antioxidant, antihyperlipidemic, and anti-inflammatory properties. Hyperlipidemia also contributes to the worsening of diabetes. This condition interferes with the ability of tissues to respond to insulin signals, leading to the development of insulin resistance.³³ Reactive oxygen species (ROS) contribute significantly to the progression of diabetes. Excessive ROS levels can cause oxidative stress, leading to pancreatic β-cell damage and reducing their ability to secrete insulin. Moreover, ROS accumulation disrupts insulin signaling in target tissues through the activation of inflammatory pathways and abnormal phosphorylation of signaling proteins, thereby inducing insulin resistance. Thus, oxidative stress mediated by ROS directly contributes to impaired insulin secretion and insulin resistance, two key mechanisms in the progression of diabetes mellitus.³⁴ Furthermore, ROS can induce lipid peroxidation, producing byproducts such as MDA. Evidence shows that MDA can trigger inflammation and cell death, including in pancreatic cells and other tissues.³⁵

Polyphenolic compounds have been widely confirmed to possess antioxidant activity. Polyphenols act as antioxidants through three main mechanisms: Hydrogen Atom Transfer (HAT), by donating a hydrogen atom to stabilize free radicals; single electron transfer (SET), by transferring an electron to neutralize free radicals; and transition metal chelation (TMC), by binding to metal ions, especially Fe and Cu, thereby preventing the catalytic formation of ROS.³⁶ In addition, polyphenols can enhance antioxidant enzyme activity by indirectly strengthening the cellular defense system, particularly through the activation of the Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, which regulates the expression of endogenous antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT).³⁷ These findings are consistent with previous studies reporting that F. carica reduces MDA levels and increases the activity of antioxidant enzymes such as SOD and CAT, most likely due to its polyphenolic content.

High blood glucose levels (hyperglycemia) can trigger chronic inflammation through the activation of inflammatory pathways, including nuclear factor kappa B (NF-κB) and inflammasomes. This activation increases the production of pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), which contribute to organ damage, insulin resistance, and the development of diabetic complications. F. carica has been shown to exhibit anti-inflammatory activity. Oktay et al. (2024) reported that administration of F. carica seed oil reduced TNF-α, IL-6, and interleukin-1 beta (IL-1β) levels under diabetic conditions.⁴ The tocopherol content in F. carica plays an important role in its anti-inflammatory effects, as confirmed by previous studies.³⁸

Glibenclamide is an antidiabetic drug that enhances insulin granule exocytosis into the bloodstream. It induces the closure of ATP-dependent K⁺ channels, leading to intracellular K⁺ accumulation and subsequent membrane depolarization. As a result, ATP-dependent Ca²⁺ channels open, allowing Ca²⁺ influx, which triggers insulin secretion into the circulation. Insulin then acts as a signal for peripheral tissues to take up glucose from the blood.³⁹ In this study, insulin levels in diabetic rats treated with F. carica versus glibenclamide need further development. Blood glucose levels in diabetic rats treated with F. carica were not superior and appeared less effective than the glibenclamide-treated group. These findings indicate that both F. carica and glibenclamide may exert comparable effects on blood glucose regulation and insulin secretion.

Regarding long-term safety, the included studies did not systematically report adverse effects or toxicity profiles of F. carica extract, which represents a notable gap in the current evidence base.⁴⁰ In contrast, glibenclamide, which was used as the pharmacological comparator in the included studies, is a sulfonylurea agent associated with well- documented adverse effects. Prolonged use of glibenclamide has been shown to predispose patients to hypoglycemia and beta-cell exhaustion/failure.^41,42 It should be noted, however, that glibenclamide remains a widely utilized antidiabetic agent, particularly in low- and middle-income countries, owing to its proven glucose-lowering efficacy, affordability, and accessibility. Nevertheless, its adverse effect profile underscores the ongoing clinical need to identify alternative agents with a more favorable safety margin.⁴³

Based on the subgroup analysis, F. carica leaf extract demonstrated significant antihyperglycemic effects across all dose levels examined (below 500 mg/kg and above 400 mg/kg body weight), with consistent effects observed throughout this range. To assess the clinical translatability of these doses, human equivalent doses (HED) were estimated using the FDA body surface area allometric scaling method (Km: rat = 6, mouse = 3, human = 37), assuming a standard adult body weight of 60 kg.^44,45 The effective preclinical dose range of 400–500 mg/kg corresponded to HED values of approximately 1,944–4,866 mg/day substantially exceeding the 1,000–2,000 mg/day typically achievable through standardized capsule supplementation (two to four capsules at 500 mg each) and the estimated 300–2,000 mg/day deliverable through conventional F. carica leaf tea (three to four cups prepared from 2 to 5 g dried leaf, yielding 5%–10% extractable bioactive content). These findings indicate that while the antihyperglycemic effect of F. carica leaf extract is robust across the preclinical dose range, the clinically feasible human equivalent corresponds more closely to the lower tier of studied animal doses. Future dose-optimization studies in humans should therefore prioritize standardized extract formulations with verified bioavailability, rather than direct extrapolation from crude animal dose protocols.

Strengths and Limitations

This study is the first meta-analysis conducted to evaluate the potential of F. carica as an antidiabetic agent based on in vivo studies, particularly regarding its hypoglycemic effects. This represents a major strength of the present research. However, the study also has some limitations. First, the animal models used in the included studies were not uniform. Second, the plant parts used for extract preparation were heterogeneous. Third, out of 13 studies, only five studies (using leaf extract of F. carica) had sufficient data to be included in the meta-analysis. This was due to the limited availability of biomarker data regarding the antidiabetic effects of F. carica extracts derived from parts other than the leaf. Fourth, the risk of bias assessment revealed that methodological reporting quality was suboptimal in several included studies. Specifically, Domain 1 (sequence generation) and Domain 3 (allocation concealment) were frequently rated as unclear risk. These four limitations may influence the strength and consistency of this study’s findings.

The high heterogeneity observed in this meta-analysis warrants careful interpretation. Beyond methodological variability in extraction solvents and diabetic induction agents, a key confounding factor is the phytochemical heterogeneity between different parts of F. carica. As described qualitatively in this study, the leaf, fruit, bark, and seed oils each carry distinct bioactive profiles. This phytochemical variability between plant parts represents a major confounding factor that limits the generalizability of findings across studies and reinforces the decision in this meta-analysis to restrict quantitative pooling exclusively to leaf extract studies.

Prospective Study

F. carica has been shown to reduce blood glucose levels in diabetic conditions; however, the reduction only reached the prediabetic range. This highlights the need for further studies to achieve normalization of glucose levels. One potential direction is through extract modification. For example, Sa et al. (2023) reported that the addition of Au and Co metal nanoparticles to butterfly pea extract successfully lowered blood glucose levels to non-diabetic levels.⁴⁶ Furthermore, alternative extraction methods such as fermentation deserve further exploration. It has been reported that fermented F. carica fruit extract was able to reduce blood glucose levels to the normal range.⁴⁷

Conclusion

F. carica shows potential as a natural herbal agent in diabetes management. In addition, it demonstrates antioxidant, anti- lipidemic, and anti-inflammatory properties. However, further research is required to ensure its glucose-lowering effect reaches non-diabetic levels, rather than remaining only at the prediabetic stage.

Footnotes

Acknowledgements

Not applicable.

Authors’ Contribution

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. All the authors are eligible to be author as per the International Committee of Medical Journal Editors (ICMJE) requirements/guidelines.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval

This study does not involve experiments on animals or human subjects.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Informed Consent

Not applicable.

Use of Artificial Intelligence-assisted Tools

The authors used Rayyan.ai to help identify duplicate studies, title and abstract screening, and classification of article types during the study selection process. This approach aimed to improve time efficiency during the process of selecting eligible studies.

Abbreviations

References

IDF. Diabetes Atlas. 11th ed. 2025, pp. 1–399. International Diabetes Federation Location: Brussels, Belgium.

Chauhan

, Kaur

, Vyas

, . Comparison of antidiabetic and antioxidant activity of wild and cultivated variety of Rauwolfia serpentina. Asian J Pharm Clin Res, 2017; 10(12): 404–406.

World Health Organization. WHO global report on traditional and complementary medicine 2019. Geneva: World Health Organization, 2019, pp.1–228.

Oktay

. Neuroprotective effects of Ficus carica seed oil in diabetic neuropathy: A preclinical study in Wistar rats. J Clin Pract Res, 2024; 46(6): 584–592.

Shwayekh

HAJI

, AL-Mosawi

and Mahrath

. Potential antidiabetic activity of Ficus carica: The concept of antioxidant properties in a rat model. Hilla Univ Coll J Med Sci, 2024; 2(2): 66–71.

Roy

, Paul

, Chowdhury

, . Antihyperglycemic activity of Ficus carica leaves extracts on streptozotocin induced diabetic rats. Res J Pharm Technol, 2021; 14(8): 4151–4156.

Bakar

, Subramaniam

, Bashah

NAK

, . Sperm proteomics analysis of diabetic induced male rats as influenced by Ficus carica leaf extract. Processes, 2020; 8(4): 1–22.

Hooijmans

, Rovers

, de Vries

, . SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol, 2014; 14(43). https://doi.org/10.1186/1471-2288-14-43

Hooijmans

, de Vries

RBM

, Ritskes-Hoitinga

, . GRADE Working Group. Facilitating healthcare decisions by assessing the certainty in the evidence from preclinical animal studies. PLoS One. 2018; 13(1): e0187271. doi: 10.1371/journal.pone.0187271

10.

El Ghouizi

, Ousaaid

, Laaroussi

, . Ficus carica (Linn.) leaf and bud extracts and their combination attenuates type-1 diabetes and its complications via the inhibition of oxidative stress. Foods, 2023; 12(4): 1–16.

11.

Qodriah

, Kumala

, Syamsudin

, . Antimetabolic syndrome effect of 70% ethanol leaves extract Ficus carica Linn. in streptozotocin-induced and high-fat diet rats. J Ilmu Kefarmasian Indones, 2023; 21(1): 153.

12.

Zhang

, Chen

, Zeng

, . Involvement of AMPK activation in the inhibition of hepatic gluconeogenesis by Ficus carica leaf extract in diabetic mice and HepG2 cells. Biomed Pharmacother, 2019; 109(October 2018): 188–194.

13.

Irudayaraj

, Christudasa

, Antony

, . Protective effects of Ficus carica leaves on glucose and lipids levels, carbohydrate metabolism enzymes and β-cells in type 2 diabetic rats. Pharm Biol, 2017; 55(1): 1074–1081.

14.

Sharma

. Phytochemical profile and pharmacological properties of Ficus carica extracts. Int J Multidiscip Trends, 2022; 4(2): 242–245.

15.

Arafa

ESA

, Hassan

, Murtaza

, . Ficus carica and Sizigium cumini regulate glucose and lipid parameters in high-fat diet and streptozocin-induced rats. J Diabetes Res, 2020; 2020: 1–9.

16.

Saleem

, Sharif

, Butt

, . Assessment of antidiabetic and cyto-regenerative activity of Ficus carica through gene expression analysis in diabetic rat model. Proc Pakistan Acad Sci Part B, 2023; 60(3): 443–454.

17.

Mert

, Mert

, Cibuk

, . Antidiabetic effect of fig seed oil in rats with diabetes induced by streptozotocin. J Oleo Sci, 2024; 73(5): 717–727.

18.

Ahmad

, Ali

and Mir

. Anti-diabetic activity of Ficus carica L. stem barks and isolation of two new flavonol esters from the plant by using spectroscopical techniques. Asian J Biomed Pharm Sci, 2013; 3(18): 22–28.

19.

Khalid

, Shahid

and Ikram

Fig (Ficus carica) as a source of bioactive compounds: Nutritional, medicinal, and food industry perspectives. Int J Food Sci Technol, 2025; 60(2): 1–21.

20.

Reza

, Ghanbari-movahed

, Barton

, . A systematic review on potential anticancer activities of Ficus carica L. with focus on cellular and molecular mechanisms. Phytomedicine 2022; 105: 154333. DOI: 10.1016/j.phymed.2022.154333.

21.

Mopuri

and Islam

. Antidiabetic and anti-obesity activity of Ficus carica: In vitro experimental studies. Diabetes Metab, 2016; 42(4): 300.

22.

Hernández

. Phenolic compounds, antioxidant and antidiabetic activity of different cultivars of Ficus carica L. fruits. J Funct Foods, 2016; 25: 421–432.

23.

Dsouza

, Purushothama

, Pujari

, . Ameliorative effects of Ficus carica leaf extract on hepatic steatosis and pancreatic β-cell function in db/db diabetic mice. J Chem Health Risks, 2025; 15(3): 591–609.

24.

Kang

, Francis

, Hill

, . Dietary polyphenols and gene expression in molecular pathways associated with type 2 diabetes mellitus: A review. Int J Mol Sci, 2020; 21(1): 1–26.

25.

Kuppusamy

, Ayyadurai

and Radha

Exploring the mechanistic pathways of promising bioflavonoid quercetin in diabetes management. Nat Resour Hum Health, 2024; 4(4): 379–386.

26.

Humairah

, Darmawan

, Hassan

, . Green tea kombucha in diabetes management: Dependent doses analysis for anti-diabetic, antioxidant, and anti-inflammatory in STZ-induced rats. J Med Pharm Chem Res, 2026; 8(3): 530–544.

27.

Irudayaraj

, Stalin

, Sunil

, . Antioxidant, antilipidemic and antidiabetic effects of ficusin with their effects on GLUT4 translocation and PPARγ expression in type 2 diabetic rats. Chem Biol Interact, 2016; 256: 85–93.

28.

, Yang

, Yuan

, . Association between liver enzymes and type 2 diabetes: A real-world study. Front Endocrinol (Lausanne), 2024; 15(February): 1–10.

29.

Yang

and Kang

. Anti-diabetic effect of cotreatment with quercetin and resveratrol in streptozotocin-induced diabetic rats. Biomol Ther, 2018; 26(2): 130–138.

30.

Shirkhani

, Marandi

, Esfahani

MHN

, . Effects of exercise training and chlorogenic acid supplementation on hepatic lipid metabolism in prediabetes mice. Diabetes Metab J, 2023; 47(6): 771–783.

31.

Athmuri

and Shiekh

. Experimental diabetic animal models to study diabetes and diabetic complications. MethodsX, 2023; 11(November): 102474. DOI: 10.1016/j.mex.2023.102474.

32.

Lenzen

. The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia, 2008; 51(2): 216–226.

33.

Jahdkaran

and Sistanizad

From lipids to glucose: Investigating the role of dyslipidemia in the risk of insulin resistance. J Steroid Biochem Mol Biol, 2025; 250(January): 106744. DOI: 10.1016/j.jsbmb.2025.106744.

34.

Chen

, Xie

, Feng

, . Oxidative stress in diabetes mellitus and its complications: From pathophysiology to therapeutic strategies. Chin Med J (Engl), 2025; 138(1): 15–27.

35.

Shabalala

, Johnson

, Basson

, . Detrimental effects of lipid peroxidation in type 2 diabetes: Exploring the neutralizing influence of antioxidants. Antioxidants, 2022; 11(10): 1–17.

36.

Rudrapal

, Khairnar

, Khan

, . Dietary polyphenols and their role in oxidative stress-induced human diseases: Insights into protective effects, antioxidant potentials and mechanism(s) of action. Front Pharmacol, 2022; 13(February): 1–15.

37.

, Long

, Gong

, . Current state of knowledge on the antioxidant effects and mechanisms of action of polyphenolic compounds. Nat Prod Commun, 2021; 16(7): 1–13.

38.

Barros

, Ribeiro

APD

, Offenbacher

, . Anti-inflammatory effects of vitamin E in response to Candida albicans. Microorganisms, 2020; 8(6): 1–13.

39.

Rodríguez-Rivera

and Barrera-Oviedo

. Exploring the pathophysiology of ATP-dependent potassium channels in insulin resistance. Int J Mol Sci, 2024; 25(7): 1–14.

40.

Fazel

, Abu

, Mohamad

MHN

, . Physicochemistry, nutritional, and therapeutic potential of Ficus carica: A promising nutraceutical. Drug Des Devel Ther, 2024; 18(March): 1947–1968.

41.

Rambiritch

, Maharaj

and Naidoo

Glibenclamide in patients with poorly controlled type 2 diabetes: A 12-week, prospective study. Clin Pharmacol Adv Appl, 2014; 6: 63–69.

42.

Patel

, Yan

and Remedi

. Loss of beta-cell identity and function as a mechanism of secondary failure of sulfonylurea therapy in diabetes. MedComm, 2026; 7(2); 1–15.

43.

Cai

, Li

, Guo

, . Multifaceted safety concerns of glibenclamide in managing type 2 diabetes: Evidence from real-world adverse event analysis. Eur J Pharmacol, 2025; 1005: 178113.

44.

Jacob

, Nair

and Morsy

. Dose conversion between animals and humans: A practical solution. Indian J Pharm Educ Res, 2022; 56(3): 600–607.

45.

Omale

, Amagon

, Johnson

, . A systematic analysis of anti-diabetic medicinal plants from cells to clinical trials. Peer J, 2023; 11: 1–41.

46.

, Tejaswani

, Pradhan

, . Antidiabetic and antioxidant effect of magnetic and noble metal nanoparticles of Clitoria ternatea. J Drug Deliv Sci Technol, 2023; 84(April): 104521. DOI: 10.1016/j.jddst.2023.104521.

47.

Choi

, Choi

, Jang

, . Anti-obesity and antidiabetic effects of fig (Ficus carica L.) fermented extract using Lactobacillus plantarum BT-LP-01. Appl Sci, 2024; 14(6412): 1–19.