Volume 37 Issue 4

Introduction

Diabetes mellitus (DM) is a chronic condition resulting from either inadequate insulin production by the pancreas or inefficient utilisation of insulin. The International Diabetes Federation (IDF) estimates that in 2024, there were 589 million adults worldwide living with diabetes, representing 11.1% of the global population. Projections suggest that the number of people with diabetes will rise to 643 million by 2030 and to 783 million by 2045.¹ Most patients with DM can be categorised into two primary etiopathogenetic groups.² Type 1 DM (T1DM) results from insufficient insulin synthesis.³ Type 2 DM (T2DM) is characterised by compromised insulin sensitivity and impaired lipid, carbohydrate, and protein metabolism.⁴ T1DM accounts for 5–10% of all cases, while T2DM is estimated to comprise 90-95% of global diabetes diagnoses, although this percentage varies by country.^2,5

In developing nations, such as Indonesia, the prevalence of both T1DM and T2DM has rapidly increased.^6,7 Over the past decade, the incidence of T1DM has surged sevenfold.⁷ In Indonesia, the prevalence of T2DM was estimated at 7% in 2016, impacting around 18 million people.⁸

Failing to manage diabetes mellitus can result in severe complications, including neuropathy, nephropathy (damage to the renal system), and retinopathy (damage to the eyes). Additionally, it can cause cardiovascular disease, stroke, and peripheral vascular disease.⁹ Individuals with DM are especially vulnerable to depression, particularly those who lack adequate social support.¹⁰ The widespread impact of DM on physical and mental health underscores the need for effective management.¹¹ T2DM can be managed through various approaches, including adopting a healthy lifestyle and utilising medications to decrease blood glucose levels.³

Pharmacological treatments for blood glucose management in T2DM include metformin, dipeptidyl peptidase IV inhibitors (DPP-4 inhibitors), GLP-1, dual glucagon-like peptide-1/gastric inhibitory polypeptide receptor agonists (GLP-1/GIP receptor agonists), sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors), sulfonylureas, and thiazolidinediones.¹² Nevertheless, the use of pharmacological medications is often constrained by various adverse reactions. For instance, metformin has been linked to vitamin B12 deficiency, which may result in anemia and neuropathy. While DPP-4 inhibitors may trigger nasopharyngitis, upper respiratory tract infections, and headaches.¹³ Exploring herbal remedies as alternatives could offer a viable approach for managing blood glucose and mitigating side effects associated with existing pharmaceuticals.

Herbal remedies consist of plant-derived medicinal substances that may be used to treat various ailments. Aloe vera, a well-known traditional remedy across different cultures, contains a variety of bioactive compounds such as alkaloids, anthraquinones, and saponins. These components exhibit therapeutic properties such as anti-inflammatory, antioxidant, antibacterial, and antidiabetic effects.^14,15 These properties are explored in this review, underscoring on the molecular mechanisms of action.

Several studies indicate that Aloe vera is a promising alternative for improving glycemic control in individuals with prediabetes and T2DM. Aloe vera supplementation provides significant benefits regarding free fatty acids (FFA), hepatic transaminase levels, fasting total cholesterol (TC), triglycerides (TG), phospholipids, and reductions in fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), and blood glucose (FBG).^16–18 Moreover, the active compounds present in Aloe vera have been shown to notably elevate plasma insulin levels and inhibit the production of methylglyoxal and arginine, thereby suppressing the glycation process.^18,19 Despite this evidence, few reviews have focused on the molecular mechanisms by which Aloe vera alleviates diabetes. This scoping review aims to provide a comprehensive understanding of the molecular mechanisms through which Aloe vera influences diabetes, contributing to the advancement of knowledge in the field and potentially informing the development of novel therapeutic approaches for managing diabetes mellitus.

Methods

Study design

This scoping review was based on the Preferred Reporting Items for Scoping Review protocol (PRISMA-ScR). This scoping review aimed to scope of the evidence of the molecular mechanisms of Aloe vera’s effect on type-1 or type-2 DM models. This question included information about the population (rats or humans with Type-1 or Type-2 DM), the concept (usage of Aloe vera in DM), and the context (the molecular mechanism of Aloe vera in DM).

This review was conducted in accordance with the PRISMA-ScR statement, which is an updated guideline for reporting scoping reviews. The method of summarising this review is conducted on the scoping review.

Eligibility criteria

To represent the current evidence regarding Aloe vera extract, we included original research papers. All included studies met several criteria, including all experiments related to type-1 or type-2 DM using Aloe vera extract, and were conducted on mice or cells. Studies were excluded if the paper was not written in English, or if the full text could not be found. Case reports and duplicate studies were also excluded from the analysis.

Search strategy

The PubMed Central, Science Direct, and Scopus databases were searched for articles published from January 2013 to January 2023. A flowchart of the study results is shown in Figure 1.1. Keywords were: “Diabetes Mellitus,” “Aloe vera,” “aloctin I,” and “experimental.” The PubMed search was supplemented with MeSH headings.

Study selection

Four authors (IL, GC, JD, and CJ) independently reviewed the abstracts, followed by a full-text assessment of studies that met the inclusion criteria. Discrepancies were resolved through discussion. The inclusion criteria were based on the population, concept, and context, specifically focusing on, in vitro and in vivo studies in animals (rats, mice) or clinical trials including humans with diabetes mellitus. The use of Aloe vera extract as the concept, and the context of this scoping review spans from January 2013 to January 2023 (Table 2).

 

Table 1. Search strategy

 

Table 2. Population, concept, and context of this scoping review

 

Data extraction

Four authors (IL, GC, JD, and CJ) gathered data from all full-text articles that were approved for the final analysis. The collected information included the author’s surname, study year, study location, research design, population demographics, intervention details, Aloe vera administration specifics, induction methods, outcomes, and the molecular mechanisms involved.

Risk of bias Assessment

The risk of bias analysis for this scoping review was performed using two distinct instruments that were specific to the study-type. For in vivo studies, the SYRCLE’s risk of bias tool was employed to assess the methodological quality and risk of bias. This tool systematically evaluates several domains, including selection, performance, detection, attrition, and reporting bias, to determine the rigor of animal research. For in vitro studies, the EEQAT (Expanded Experimental Quality Assessment Tool) was used. This tool provides a structured framework for evaluating the quality of laboratory-based experiments by scrutinising aspects such as cell culture methods, reagent validation, and data reporting to mitigate the risk of technical or methodological bias.

Result

A total of 3,210 articles were initially obtained from the PubMed Central, Science Direct, and Scopus database, of which 201 articles were duplicates. Title and abstract screening of 3,009 articles excluded 2,990. Reasons for exclusion of 1,827 articles was due to in the wrong population, 468 presented a different concept to diabetes models, 252 used a different study design, 430 were published outside the time period, and 12 were excluded as they were not published in English language. Ultimately, 19 full-text articles were evaluated for eligibility. From these 13 were excluded due to a lack of methodological description of the molecular mechanisms that were presented. This resulted in the inclusion of six studies in the qualitative synthesis (Figure 1).

 

Figure 1. Result of data extraction

 

Data were extracted from the six included articles and presented according to the author, country, study design (in vivo or in vitro), reference, population characteristics, and intervention (extract preparation).

Experimental methods

The most common method for inducing diabetes models in animal studies was with injection of streptozotocin (STZ) which is toxic to insulin-producing beta cells in the pancreas and consistently produces fasting blood glucose (FBG levels of  300-540 mg/dL).^24,26,32,34 Other methods included alloxan injection, which resulted in FBG of approximately 380 mg/dL in female mice,²³ and high fat diet (HFD) in male mice, which resulted in an FBG of 181.8 mg/dL.²⁵

Study characteristics are presented in Table 3.

 

Table 3. Summary of included studies

 

Risk of bias

For the included in vivo Studies, three studies used a random component for sequence generation, though the specific method was not detailed. Three studies did not randomly allocate animals, but they followed consistent guidelines. Four studies lacked blinding for outcome assessors. Notably, in all studies, the investigators were not blinded during intervention, the allocation was not concealed, and animals were not randomly selected for outcome assessment. No protocols were available for any of these studies. Additionally, two studies had authors with a financial interest in a pharmaceutical company. The quality assessment of in vivo studies is presented in Table 4.

 

Table 4. Risk of bias analysis of in vivo using SYRCLE’s risk of bias tool

 

For in vitro Studies, all three had a clearly defined research question and used a new method. They all mentioned clear objectives, with one study focused on therapeutic efficacy, and two on evaluating chemical properties and composition. All studies used biological tissues with anonymity maintained, though one study did not specify whether the tissues were sterilised beforehand. All materials were biocompatible and approved by national bodies, but one study failed to mention proper waste disposal. The studies did not justify their sample size, mention randomisation methods, or implement blinding. While the results were not based on repeated readings, the analysis used appropriate statistical tests. All studies concluded that their objectives were met and that the research could be replicated in in vivo or clinical settings. The qualty assessment of in vitro studies is presented in Table 5.

 

Table 5. EEQAT risk of bias tools

 

Mechanisms of Aloe vera in diabetes models

Impaired insulin secretion

Aloe vera impacts insulin secretion was shown in diabetic animal models. A dose of 300 mg/kg BW increased insulin secretion in diabetic rats from 116.5 pmol/L to 146.1 pmol/L over three weeks, and associated with an increase in the number of pancreatic islet cells.²² A separate study by Yimam et al. (2014) showed that administering UP780, an Aloe vera polysaccharide, at 2000 mg/kg to alloxan-induced T1DM model rats increased insulin levels by 60.1% after four weeks of treatment.²³ Govindarajan et al. (2021) also demonstrated that an Aloe vera derived carbohydrate fraction (AVCF), at concentrations of 20 and 60 μg/mL increased insulin levels by 40.2% and 58.5%, respectively, in streptozotocin (STZ)-treated cells²⁴. However, a study by Yimam et al. (2013) showed a reduction in plasma insulin levels by 28.5% with UP780 (200 mg/kg) in mice consuming a high-fat diet (HFD).²⁵ Another study outlined a proposed mechanism of a peptide/polypeptide fraction (PPF) from Aloe vera  enhancing plasma insulin levels by inhibiting the DPP-IV enzyme.²⁶

Decrease in glucose absorption

Aloe vera was shown to decrease the rate of glucose absorption in the gastrointestinal tract. AVCF, which contains arabinose, rhamnose, and mannose, may inhibit the α-amylase and α-glucosidase enzymes, leading to decreased postprandial glucose levels in the range of 60.44 ± 1.02 μg and 82.85 ± 1.05 μg, respectively.²⁷ This was supported by another study demonstrating that Aloe vera methanol extract, at a concentration of 5 mg/mL. reduced α-glucosidase and α-amylase activity by 66% and 87%, respectively. However, at lower concentrations of 0.60 and 0.30 mg/mL, the methanol Aloe extract showed no inhibitory activity against these enzymes.¹⁹

Increased glucose uptake in cells

Aloe vera may enhance cellular glucose uptake. The use of AVCF in yeast cells was shown to enhance glucose uptake by facilitating the binding of various disaccharides to glucose molecules, activating glycolysis in skeletal muscle cells, and enhancing glucose storage in the liver.²⁴ In addition to AVCF, aloin, a bioactive compound in Aloe vera, enhanced glucose uptake by modulating the insulin receptor substrate-1 (IRS1)/phosphoinositide-3-kinase (PI3K) pathway.^28–30 Haghani et al. further supported this, showing that aloin enhances glucose tolerance by modulating the IRS1 and PI3K pathways.³¹

Antioxidant properties

Aloe vera possesses antioxidant properties. Tabatabei et al. (2017) observed that oral administration of Aloe vera gel at 100 mg/kg/day significantly reduced elevated malondialdehyde (MDA) levels in STZ-induced rats. The treated group showed significantly higher levels of superoxide dismutase (SOD) (p = 0.009) and catalase (CAT) (p = 0.001) activity compared to the STZ group.³² Govindarajan et al. (2021) investigated the effect of AVCF on diabetic rats, showed similar results, with a significant increase in SOD levels in the liver (69.3%) and pancreas (50.8%), and CAT levels in the liver (50.1%) and pancreas (54.9%). Additionally, MDA levels in the kidneys of diabetic rats declined by 60.1% after AVCF treatment.²⁴

Enhancing insulin sensitivity

Several compounds in Aloe vera have been shown to enhance insulin sensitivity. UP780, for example, suppresses genes involved in lipid synthesis while increasing genes for fatty acid-binding proteins, leading to a reduction in free fatty acids.²⁵ This is supported by Misawa et al., who showed that Aloe vera phytosterols decreased free fatty acid levels.³³ Zhong et al. also found that aloin reduced insulin resistance by inhibiting c-Jun NH2-terminal kinase (JNK) protein expression.³⁴ Feng et al. (2023) demonstrated significant JNK inhibition at varying doses of aloin (10, 20, and 40 mg/kg).²⁸

Anti-inflammatory properties

Aloe vera was shown to exhibit anti-inflammatory properties. In STZ-treated pancreatic beta cells, AVCF at concentrations of 20 and 60 μg/mL reduced tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) levels, and increased bromo deoxy uridine (BrdU) levels.^24,35 A PPF caused a reduction in IL-6 and TNF-α levels, 54.9% and 61.6%; and 56.8% and 59.5% respectively, equivalent to the effects of sitagliptin.²⁶ These mechanisms are summarised in Figure 2.

 

Figure 2

 

Bioavailability of Aloe vera

Studies on the bioavailability of Aloe vera extracts show that it may enhance the absorption of other compounds. In vitro studies using Caco-2 cells demonstrated that both Aloe vera gel and extracts of the whole-leaf decreased transepithelial electrical resistance (TEER), indicating the opening of tight junctions.^36,37 Both extracts also increased the apparent permeability coefficient (Papp) for FITC-dextran (FD-4) across the Caco-2 cells, though not for larger molecules³⁷.

A randomised, double-blind, crossover trial in humans found that Aloe vera gel increased the bioavailability of vitamin C by 3.04-fold and vitamin E by 3.69-fold, while whole-leaf extract increased the AUC of vitamin E by 1.98-fold^38,39.

Comparison of Aloe vera Dosage and Outcome

The studies showed that different Aloe vera compounds and dosages had varied effects on FBG. Yimam et al. (2013) found that oral administration of UP780 at 200 mg/kg to HFD mice significantly lowered FBG.²⁵ A later study by Yimam et al. (2014) showed a 10-fold higher dose of UP780 (2000 mg/kg) in alloxan-induced diabetic mice also significantly reduced FBG, outperforming glyburide.²³ PPF at 0.45 mg/kgbw in STZ-induced rats decreased FBG from 387.6 mg/dL to 135.1 mg/dL in three weeks.²⁶ An AVCF at 54 mg/kgbw in STZ-induced rats significantly reduced FBG by 74.8%, while a 27 mg/kg dose showed no significant effect.²⁴ Aloe vera gel at 100 mg/kg/day in STZ-induced rats lowered blood glucose from 536.7 mg/dL to 255.4 mg/dL over eight weeks.³² Finally, aloin at 90 mg/kg in a T2DM mouse model resulted in an FBG of 199.9 mg/dL after two weeks, a level comparable to that of metformin.³⁴

Discussion

The findings from this review indicate that Aloe vera may modulate the pathophysiology of diabetes mellitus through multifaceted mechanisms. These include the regeneration of pancreatic beta cells, glucose absorption and metabolism, insulin secretion and sensitivity, and antioxidant and anti-inflammatory protection. However, results of some studies were conflicting and bioavailability may be dose related.

The conflicting results of Aloe vera’s effects on insulin concentrations varied due to the type of diabetes being investigated. In T1DM, the aim of therapy is to restore and/or supplement insulin production, whereas in T2DM (often augmented by HFD), the goal is to improve insulin sensitivity, and lower plasma insulin levels. Aloe vera reduced postprandial hyperglycemia by acting as a non-competitive inhibitor of key digestive enzymes α-amylase and α-glucosidase,²⁷ and delaying carbohydrate breakdown, glucose absorption and reducing post-prandial insulin concentrations. These findings, revealed in HFD mice models, suggested that glucose absorption from the gastrointestinal tract is a pathway for lowering glycemic concentration after meals. The dose-dependent nature of this effect, highlighted by lower doses of the methanol extract with no observed inhibitory effects, underscores the importance of sufficient concentrations for affecting insulin sensitivity.

In addition to regulating glucose absorption, Aloe vera may enhance cellular glucose uptake via two mechanisms; the AVCF facilitation of glucose transport and through Aloin enhancing core insulin signaling pathways. While the study on yeast cells provides insight into the potential of an AVCF to enhance glucose transport, it is important to note the difference in cellular mechanisms between yeast and human cells. A significant finding relevant to human use, is the role of aloin in activating the IRS1/PI3K pathway.^28–30 This pathway is key in insulin signaling, and may lead to increased glucose uptake in muscle and liver cells. Aloin may mimic or amplify the effects of insulin, thereby increasing cellular glucose utilisation and contributing to lowered glycemic levels. The mechanism of action for PPF, which inhibits the DPP-IV enzyme to elevate GLP-1 levels, mirrors the effects of conventional anti-diabetic drugs like sitagliptin^26,43, highlighting a powerful pathway for managing diabetes.

The research also suggests that Aloe vera compounds, particularly UP780 and aloin, may directly address insulin resistance, a central feature of T2DM pathogenesis.^25,34 UP780’s ability to regulate lipid synthesis and reduce free fatty acids is a crucial contributor, as excess free fatty acids are a primary cause of insulin resistance in adipose and muscle tissue.^25,33 Furthermore, aloin’s action on the JNK-IRS1/PI3K pathway provides a detailed molecular explanation for its anti-diabetic effects. By inhibiting the JNK protein expression, leading to the inactivation of the insulin receptor, aloin maintains cellular responsiveness to insulin, thereby addressing the underlying pathology of insulin resistance and helping to control blood sugar levels.^28,41

The antioxidant and anti-inflammatory effects of Aloe vera are also important and consistent with findings that flavonoids with a similar chromone structure can protect beta cells from oxidative damage.⁴⁰ Complications in diabetes are often associated with excessive reactive oxygen species (ROS) and oxidative stress,⁴² with damage to pancreatic beta cells.  By increasing antioxidant enzymes such as SOD and CAT, and reducing MDA levels, Aloe vera may support neutralisation of ROS and cellular protection.^24,32 Additionally, its anti-inflammatory effects may mitigate beta-cell destruction. ^24,35 Both AVCF and PPF from Aloe vera were shown to reduce pro-inflammatory cytokines, including TNF-α and IL-6.

The bioavailability of Aloe vera extracts is an important consideration. Results from both in vitro and human studies demonstrate that Aloe vera may enhance the absorption of digestive compounds by increasing the permeability of the intestinal wall, likely by modulating tight junctions.^36,37 This suggests that Aloe vera could improve the bioavailability of its own bioactive compounds as well as co-administered drugs. However, the studies also highlight the effect of molecular weight, or size on absorption, and that various preparation methods and resultant viscosity may influence overall absorption.³⁷

The human trial data, which showed enhanced vitamin C and E absorption with the gel compared to the whole-leaf extract, suggests that the specific type of extract and its preparation are contributory factors that should be considered in both research and practical applications.^38,39

These mechanisms collectively suggest that Aloe vera has a multifaceted approach to enhancing insulin sensitivity, making it a promising natural agent for blood glucose management in  T2DM.

Finally, the variability in induction models of diabetes used in the animal models across the studies (STZ, alloxan, and HFD),^{23–26,32,34} may present results from different forms of diabetes, which limits direct comparisons and emphasises the need for standardised protocols. The dose-dependent effects of Aloe vera compounds²⁴ underscore the importance of accurate dosage. The apparent inconsistency in the UP780 studies^23,25 can be attributed to the different diabetic models, emphasising that the underlying pathology of the disease dictates the effectiveness of the treatment. These findings collectively suggest that effective treatment requires a careful consideration of the specific Aloe vera compound, its optimal dosage, and the type of diabetes it is intended to treat.

Limitations and strengths

This review’s primary strength lies in its transparent, systematic approach and adherence to the PRISMA-ScR protocol. The search was comprehensive across three major databases, screening for inclusion criteria was independently conducted by four authors. The use of specific tools, SYRCLE for in vivo and EEQAT for in vitro studies, allowed for a structured risk of bias assessment, adding a layer of critical appraisal. The resulting synthesis provides a comprehensive overview of the multifaceted molecular mechanisms by which Aloe vera may modulate diabetes.

However, the review is constrained by limitations inherent in the body of evidence. The most critical being that findings are derived exclusively from preclinical (in vitro and in vivo (animal)) models, and the applicability of these mechanisms to patients with diabetes remains speculative. The small number of studies (six) that met the final inclusion criteria restricts indicates the need for replication of the findings. Moreover, the included research exhibited substantial heterogeneity in the types, dosages and constituents of Aloe vera , the methods for inducing diabetes (STZ, alloxan, HFD), and the derived outcomes, made comparisons difficult. Finally, the review’s own bias assessment revealed significant methodological weaknesses in the primary studies, such as a lack of blinding and randomisation, which inherently limits the quality of this review’s conclusions.

Guide for future research

The extent and applicability of Aloe vera in the treatment of T1DM and T2DM in humans is yet to be explored. Further research is needed, particularly clinical trials in human patients. Aloe vera is a traditional medicine frequently used in traditional medicine systems around the globe, areas where diabetes prevalence is predicted to grow. Further studies may reveal an effective adjunct or treatment for people with diabetes, with ready accessibility low costs and high acceptability ultimately benefitting patients with diabetes.

Conclusion

In this study, Aloe vera and its constituents demonstrated numerous beneficial mechanisms in T1DM and T2DM pre-clinical models, including decreased blood glucose levels, antioxidant activity, enhanced insulin sensitivity, and anti-inflammatory effects. Further research of regarding the use of Aloe vera in humans clinical trials is warranted to determine the clinical efficacy of treatment in T1DM and T2DM.

Conflict of interest

The researchers have no conflict of interests to declare.

Funding

We’d like to thank Universitas Sebelas Maret (UNS) Surakarta, Indonesia, which provide support for Open Access publishing of this manuscript (PKGR UNS Grant 371/UN27.22/PT.01.03/2025).

Author(s)

Ratih Dewi Yudhani MD, MSc, PhD  ORCID 0000-0001-6781-8251^1
1Department of Pharmacology, Universitas Sebelas Maret, Surakarta, Indonesia

Ivan Lucianto ORCID 0009-0002-2435-6274^2
2Faculty of Medicine, Universitas Sebelas Maret, Surakarta, Indonesia

Grace Calvinia  ORCID 0009-0006-7104-0220²

Jonathan Daniel Sulastyo  ORCID 0009-0007-4627-7485²

Celine Judith  ORCID 0009-0009-9494-2085²

Benedictus Benedictus MD  ORCID 0000-0003-1485-9193^3
3Disease Control Research Group, Faculty of Medicine, Universitas Sebelas Maret, Surakarta, Indonesia

Kenneth Tan MD  ORCID 0000-0002-5328-185X³

Ratih Puspita Febrinasari* MD, MSc, PhD  ORCID 0000-0001-9767-3284¹

Email ratihpuspita@staff.uns.ac.id

References

1. IDF (2023). Facts & figures. Int. Diabetes Fed. https://idf.org/about-diabetes/facts-figures/.
2. American Diabetes Association (2011). Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 34, S62–S69. https://doi.org/10.2337/dc11-S062.
3. WHO (2023). Diabetes. https://www.who.int/news-room/ fact-sheets/detail/diabetes.
4. Motahari-Tabari, N., Ahmad Shirvani, M., Shirzad-e-Ahoodashty, M., Yousefi-Abdolmaleki, E., and Teimourzadeh, M. (2014). The Effect of 8 Weeks Aerobic Exercise on Insulin Resistance in Type 2 Diabetes: A Randomized Clinical Trial. Glob. J. Health Sci. 7, p115. https://doi.org/10.5539/gjhs.v7n1p115.
5. Green, A., Hede, S.M., Patterson, C.C., Wild, S.H., Imperatore, G., Roglic, G., and Beran, D. (2021). Type 1 diabetes in 2017: global estimates of incident and prevalent cases in children and adults. Diabetologia 64, 2741–2750. https://doi.org/10.1007/s00125-021-05571-8.
6. Misra, A., Gopalan, H., Jayawardena, R., Hills, A.P., Soares, M., Reza-Albarrán, A.A., and Ramaiya, K.L. (2019). Diabetes in developing countries. J. Diabetes 11, 522–539. https://doi.org/10.1111/1753-0407.12913.
7. Pulungan, A.B., Fadiana, G., and Annisa, D. (2021). Type 1 diabetes mellitus in children: experience in Indonesia. Clin. Pediatr. Endocrinol. 30, 11–18. https://doi.org/10.1297/cpe.30.11.
8. Asril, N.M., Tabuchi, K., Tsunematsu, M., Kobayashi, T., and Kakehashi, M. (2020). Predicting Healthy Lifestyle Behaviours Among Patients With Type 2 Diabetes in Rural Bali, Indonesia. Clin. Med. Insights Endocrinol. Diabetes 13, 117955142091585. https://doi.org/10.1177/1179551420915856.
9. Deshpande, A.D., Harris-Hayes, M., and Schootman, M. (2008). Epidemiology of Diabetes and Diabetes-Related Complications. Phys. Ther. 88, 1254–1264. https://doi.org/10.2522/ptj.20080020.
10. Azmiardi, A., Murti, B., Febrinasari, R.P., and Tamtomo, D.G. (2022). Low Social Support and Risk for Depression in People With Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis. J. Prev. Med. Pub. Health 55, 37–48. https://doi.org/10.3961/jpmph.21.490.
11. Azmiardi, A., Murti, B., Febrinasari, R.P., and Tamtomo, D.G. (2021). The effect of peer support in diabetes self-management education on glycemic control in patients with type 2 diabetes: a systematic review and meta-analysis. Epidemiol. Health 43, e2021090. https://doi.org/10.4178/epih.e2021090.
12. ADA (2023). Oral and Injectable Diabetes Medications | ADA. https://diabetes.org/healthy-living/medication-treatments/oral-other-injectable-diabetes-medications.
13. Fogelman, Y., Kitai, E., Blumberg, G., Golan-Cohen, A., Rapoport, M., and Carmeli, E. (2017). Vitamin B12 screening in metformin-treated diabetics in primary care: were elderly patients less likely to be tested? Aging Clin. Exp. Res. 29, 135–139. https://doi.org/10.1007/s40520-016-0546-1.
14. Lanka, S. (2018). A REVIEW ON ALOE VERA-THE WONDER MEDICINAL PLANT. J. Drug Deliv. Ther. 8, 94–99. https://doi.org/10.22270/jddt.v8i5-s.1962.
15. Haghani, F., Arabnezhad, M.-R., Mohammadi, S., and Ghaffarian-Bahraman, A. (2022). Aloe vera and Streptozotocin-Induced Diabetes Mellitus. Rev. Bras. Farmacogn. 32, 174–187. https://doi.org/10.1007/s43450-022-00231-3.
16. Suksomboon, N., Poolsup, N., and Punthanitisarn, S. (2016). Effect of Aloe vera on glycaemic control in prediabetes and type 2 diabetes: a systematic review and meta-analysis. J. Clin. Pharm. Ther. 41, 180–188. https://doi.org/10.1111/jcpt.12382.
17. Zhang, Y., Liu, W., Liu, D., Zhao, T., and Tian, H. (2016). Efficacy of Aloe Vera Supplementation on Prediabetes and Early Non-Treated Diabetic Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients 8, 388. https://doi.org/10.3390/nu8070388.
18. Malik, J.A., Iqbal, S., Biswas, J., Riaz, U., and Datta, S. (2021). Antidiabetic Property of Aloe vera (Aloe barbadensis) and Bitter Melon (Momordica charantia). In Medicinal and Aromatic Plants, T. Aftab and K. R. Hakeem, eds. (Springer International Publishing), pp. 257–269. https://doi.org/10.1007/978-3-030-58975-2_10.
19. Muñiz-Ramirez, A., Perez, R.M., Garcia, E., and Garcia, F.E. (2020). Antidiabetic Activity of Aloe vera Leaves. Evid. Based Complement. Alternat. Med. 2020, 1–9. https://doi.org/10.1155/2020/6371201.
20. Hooijmans, C.R., Rovers, M.M., De Vries, R.B., Leenaars, M., Ritskes-Hoitinga, M., and Langendam, M.W. (2014). SYRCLE’s risk of bias tool for animal studies. BMC Med. Res. Methodol. 14, 43. https://doi.org/10.1186/1471-2288-14-43.
21. Iyer, R.R., and Sethuraman, R. (2022). Evidence, Ethics, and Quality Appraisal Tool for In Vitro Studies: A Concept Note Based on Scoping Review of Current Tools Relevant to Dental In Vitro Research. J. Datta Meghe Inst. Med. Sci. Univ. 17, 984–989. https://doi.org/10.4103/jdmimsu.jdmimsu_379_22.
22. Noor, A., Gunasekaran, S., and Vijayalakshmi, M. (2017). Improvement of insulin secretion and pancreatic β-cell function in streptozotocin-induced diabetic rats treated with Aloe vera extract. Pharmacogn. Res. 9, 99. https://doi.org/10.4103/pr.pr_75_17.
23. Yimam, M., Zhao, J., Corneliusen, B., Pantier, M., Brownell, L., and Jia, Q. (2014). Blood glucose lowering activity of aloe based composition, UP780, in alloxan induced insulin dependent mouse diabetes model. Diabetol. Metab. Syndr. 6, 61. https://doi.org/10.1186/1758-5996-6-61.
24. Govindarajan, S., Babu, S.N., Vijayalakshmi, M.A., Manohar, P., and Noor, A. (2021). Aloe vera carbohydrates regulate glucose metabolism through improved glycogen synthesis and downregulation of hepatic gluconeogenesis in diabetic rats. J. Ethnopharmacol. 281, 114556. https://doi.org/10.1016/j.jep.2021.114556.
25. Yimam, M., Zhao, J., Corneliusen, B., Pantier, M., Brownell, L.A., and Jia, Q. (2013). UP780, a Chromone-Enriched Aloe Composition Improves Insulin Sensitivity. Metab. Syndr. Relat. Disord. 11, 267–275. https://doi.org/10.1089/met.2012.0135.
26. Babu, S.N., Govindarajan, S., Vijayalakshmi, M.A., and Noor, A. (2021). Role of zonulin and GLP-1/DPP-IV in alleviation of diabetes mellitus by peptide/polypeptide fraction of Aloe vera in streptozotocin- induced diabetic wistar rats. J. Ethnopharmacol. 272, 113949. https://doi.org/10.1016/j.jep.2021.113949.
27. Hullatti, K., and Telagari, M. (2015). In-vitro α-amylase and α-glucosidase inhibitory activity of Adiantum caudatum Linn. and Celosia argentea Linn. extracts and fractions. Indian J. Pharmacol. 47, 425. https://doi.org/10.4103/0253-7613.161270.
28. Feng, Y., Qiao, H., Liu, H., Wang, J., and Tang, H. (2023). Exploration of the mechanism of aloin ameliorates of combined allergic rhinitis and asthma syndrome based on network pharmacology and experimental validation. Front. Pharmacol. 14, 1218030. https://doi.org/10.3389/fphar.2023.1218030.
29. Maffei, A., Lembo, G., and Carnevale, D. (2018). PI3Kinases in Diabetes Mellitus and Its Related Complications. Int. J. Mol. Sci. 19, 4098. https://doi.org/10.3390/ijms19124098.
30. Sánchez, M., González-Burgos, E., Iglesias, I., and Gómez-Serranillos, M.P. (2020). Pharmacological Update Properties of Aloe Vera and its Major Active Constituents. Molecules 25, 1324. https://doi.org/10.3390/molecules25061324.
31. Haghani, F., Arabnezhad, M.-R., Mohammadi, S., and Ghaffarian-Bahraman, A. (2022). Aloe vera and Streptozotocin-Induced Diabetes Mellitus. Rev. Bras. Farmacogn. 32, 174–187. https://doi.org/10.1007/s43450-022-00231-3.
32. Tabatabaei, S.R.F., Ghaderi, S., Bahrami-Tapehebur, M., Farbood, Y., and Rashno, M. (2017). Aloe vera gel improves behavioral deficits and oxidative status in streptozotocin-induced diabetic rats. Biomed. Pharmacother. 96, 279–290. https://doi.org/10.1016/j.biopha.2017.09.146.
33. Misawa, E., Tanaka, M., Nomaguchi, K., Yamada, M., Toida, T., Takase, M., Iwatsuki, K., and Kawada, T. (2008). Administration of phytosterols isolated from Aloe vera gel reduce visceral fat mass and improve hyperglycemia in Zucker diabetic fatty (ZDF) rats. Obes. Res. Clin. Pract. 2, 239–245. https://doi.org/10.1016/j.orcp.2008.06.002.
34. Zhong, R., Chen, L., Liu, Y., Xie, S., Li, S., Liu, B., and Zhao, C. (2022). Anti-diabetic effect of aloin via JNK-IRS1/PI3K pathways and regulation of gut microbiota. Food Sci. Hum. Wellness 11, 189–198. https://doi.org/10.1016/j.fshw.2021.07.019.
35. Bargsten, G. (2004). Cytological and immunocytochemical characterization of the insulin secreting insulinoma cell line RINm5F. Arch. Histol. Cytol. 67, 79–94. https://doi.org/10.1679/aohc.67.79.
36. Kus, M., Ibragimow, I., and Piotrowska-Kempisty, H. (2023). Caco-2 Cell Line Standardization with Pharmaceutical Requirements and In Vitro Model Suitability for Permeability Assays. Pharmaceutics 15, 2523. https://doi.org/10.3390/pharmaceutics15112523.
37. Haasbroek, A., Willers, C., Glyn, M., Du Plessis, L., and Hamman, J. (2019). Intestinal Drug Absorption Enhancement by Aloe vera Gel and Whole Leaf Extract: In Vitro Investigations into the Mechanisms of Action. Pharmaceutics 11, 36. https://doi.org/10.3390/pharmaceutics11010036.
38. Laux, A., Gouws, C., and Hamman, J.H. (2019). Aloe vera gel and whole leaf extract: functional and versatile excipients for drug delivery? Expert Opin. Drug Deliv. 16, 1283–1285. https://doi.org/10.1080/17425247.2019.1675633.
39. Vinson, J.A., Al Kharrat, H., and Andreoli, L. (2005). Effect of Aloe vera preparations on the human bioavailability of vitamins C and E. Phytomedicine 12, 760–765. https://doi.org/10.1016/j.phymed.2003.12.013.
40. Deora, N., and Venkatraman, K. (2022). Aloe vera in diabetic dyslipidemia: Improving blood glucose and lipoprotein levels in pre-clinical and clinical studies. J. Ayurveda Integr. Med. 13, 100675. https://doi.org/10.1016/j.jaim.2022.100675.
41. Yung, J.H.M., and Giacca, A. (2020). Role of c-Jun N-terminal Kinase (JNK) in Obesity and Type 2 Diabetes. Cells 9, 706. https://doi.org/10.3390/cells9030706.
42. Bhatti, J.S., Sehrawat, A., Mishra, J., Sidhu, I.S., Navik, U., Khullar, N., Kumar, S., Bhatti, G.K., and Reddy, P.H. (2022). Oxidative stress in the pathophysiology of type 2 diabetes and related complications: Current therapeutics strategies and future perspectives. Free Radic. Biol. Med. 184, 114–134. https://doi.org/10.1016/j.freeradbiomed.2022.03.019.
43. Zhang, Y., Chen, Y., Cheng, J., Guo, Z., Lu, Y., and Tian, B. (2015). DPP IV inhibitor suppresses STZ-induced islets injury dependent on activation of the IGFR/Akt/mTOR signaling pathways by GLP-1 in monkeys. Biochem. Biophys. Res. Commun. 456, 139–144. https://doi.org/10.1016/j.bbrc.2014.11.048.

 

Supplementary information

Table I. Risk of Bias Analysis of In Vivo Using SYRCLE’s Risk of Bias Tool

The risk of bias analysis of in vivo in this review was done by using SYRCLE’s risk of bias tool¹. Based on the risk of bias analysis of the studies included in this scoping review (Table I), there were three studies that used random component in the sequence generation process for randomisation. In the studies, the authors stated the animals were selected randomly. However, the authors did not specify how the randomisation was done. There were three studies which the investigator did not randomly place the animal within the room. However, all the animals were controlled the same criteria according to the guidelines. There were four studies which outcome assessor were not blinded.  In all of the studies, the allocation of intervention and control group animal were not concealed, the investigators were not blinded when doing intervention during the experiment, the animals were not selected randomly during outcome assessment. There were no protocol available for all of the studies. There were two studies that have a competing interest. In the two studies, several of it’s author is a researcher of a manufacture pharmacological drugs with a financial interest.

 

Table V. EEQAT risk of bias tools

 

The risk of bias analysis of in vitro of this review was done using EEQAT risk of bias tools². Based on the risk of bias analysis of the studies included in this scoping review (Table II), all three studies uses clearly defined research question and new method under investigation. There were no previously done similar in vitro study and all of them can be translated into an in vivo study.

The objectives of all the studies mentioned and clear, of which one of them are related to ascertaining the efficacy of the therapeutic agent. There are two studies that are related to the evaluation of chemical properties and one of them are also related to assessment of chemical composition.

All three studies used biological tissues and anonymity are maintained. One of the studies didn’t clearly state whether there the tissues were subjected to the standard protocol for sterilisation or disinfection before handling or not. All of the materials used were biocompatible and approved by National regulatory bodies. One of the studies didn’t clearly state whether the materials used were disposed according to the biomedical waste disposal guidelines of the country or not. All the methods used are acceptable to subjects in case and the studies were approved by Institutional Ethics Committee.

The studies didn’t clearly mention whether the sample size was justified or not. All of the studies were based on inclusion criteria, but none of them mentioned about the method of randomisation. The blinding were also not done in all of the studies. All of the result were not based on repeated readings, but the analysis were based on appropriate statistical test. All three studies also mentioned that the objectives of the study were met and the study can be replicated as in vivo/clinical research.

References

1. Hooijmans, C.R., Rovers, M.M., De Vries, R.B., Leenaars, M., Ritskes-Hoitinga, M., and Langendam, M.W. (2014). SYRCLE’s risk of bias tool for animal studies. BMC Med. Res. Methodol. 14, 43. https://doi.org/10.1186/1471-2288-14-43.
2. Iyer, R.R., and Sethuraman, R. (2022). Evidence, Ethics, and Quality Appraisal Tool for In Vitro Studies: A Concept Note Based on Scoping Review of Current Tools Relevant to Dental In Vitro Research. J. Datta Meghe Inst. Med. Sci. Univ. 17, 984–989. https://doi.org/10.4103/jdmimsu.jdmimsu_379_22.