Int J Pharm Pharm Sci, Vol 16, Issue 11, 12-16Review Article

UNDERSTANDING THE BENEFITS OF STEVIA REBAUDIANA BERTONI FOR DIABETES: A COMPREHENSIVE REVIEW

B. DHARANI*, SUBA A., STEPHY SEBASTIAN

Department of Physiology, A. C. S. Medical College and Hospital, Dr. M. G. R. Educational and Research Institute, Chennai, India
*Corresponding author: B. Dharani; *Email: doctordharanibhaskaran@gmail.com

Received: 17 Aug 2024, Revised and Accepted: 30 Sep 2024

ABSTRACT

Diabetes Mellitus (DM) is a complicated metabolic condition defined by long-term elevated blood glucose levels. This chronic hyperglycemia induces metabolic dysfunctions that cause structural and functional disruptions in the vasculature, leading to macrovascular and microvascular complications. Stevia rebaudiana Bertoni, commonly known as Stevia, is a perennial shrub that contains various bioactive constituents responsible for its sweetness and several other activities. Many studies on Stevia have shown that it possesses various beneficial effects on health, including being zero-calorie, anti-obesity, anti-diabetic, anti-hypertensive, antioxidant, antimicrobial and anti-tumor. Several studies have found that neither gastric juice nor digestive enzymes decompose stevioside. The presence of bioactive phenolic and flavonoid compounds supports Stevia's medicinal properties and its potential use in both the food/nutraceutical and pharmaceutical industries. A significant antioxidant capacity of Stevia has been identified recently. It can also help limit essential nutrient supply to tumor cells. Research on Stevia's effects on the human body has largely found no negative side effects. The growing body of evidence underscores Stevia's potential role in managing various health conditions, particularly for diabetic patients, due to its minimal impact on blood sugar levels. However, to fully harness its benefits and meet the increasing global demand, further scientific research is essential to optimize its cultivation, enhance its chemical constituents and ensure its safety. Overall, Stevia stands out as a promising natural sweetener with significant health benefits for diabetic patients. In this review article, we explore different aspects of Stevia and its beneficial effects on diabetic patients.

Keywords: Stevia rebaudiana bertoni, Stevia, Natural sweetener, Zero-calorie sweetener, Stevioside, Rebaudioside a, Diabetes

© 2024 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/)
DOI: https://dx.doi.org/10.22159/ijpps.2024v16i11.52382 Journal homepage: https://innovareacademics.in/journals/index.php/ijpps

INTRODUCTION

Diabetes Mellitus (DM) is an endocrine disease diagnosed by high levels of blood glucose. DM is known as one of the fastest-growing and most common diseases worldwide [1]. It was projected to affect around 693 million adults by 2045 [2]. The leading cause of mortality and morbidity in diabetes is its vascular complications. These include both macrovascular and microvascular complications [3]. It poses a significant financial burden in both developing and developed countries [4].

Hyperglycemia in diabetes results from a defect in insulin secretion or insulin action, which causes chronic carbohydrate, protein and fat metabolic dysfunctions [5, 6]. These metabolic dysfunctions disrupt normal functioning and affect the kidneys, heart, eyes and nerves. In Type 1 Diabetes Mellitus (T1DM), insulin production is reduced because the beta cells are destroyed [7]. The destruction of β-cells occurs due to autoimmune reactions [8]. Type 2 Diabetes Mellitus (T2DM) is strongly linked to environmental factors like poor diet, obesity and reduced physical activity. Research has indicated that physical activity can lower HbA1C levels [9]. Symptoms associated with high blood sugar include frequent urination, increased hunger, excessive thirst, extreme fatigue, blurred vision and weight changes [10].

The disease's covert nature often results in many patients not being diagnosed until complications develop [11]. The complications are Diabetic retinopathy, Diabetic nephropathy, Atherosclerotic Cardio Vascular Disease (ASCVD), Diabetic autonomic neuropathy and Diabetic gastroparesis. In elderly patients with diabetic neuropathy, factors such as dyslipidemia, Coronary Artery Disease (CAD), Hypertension (HTN) and high Body Mass Index (BMI) contribute to its progression. Additionally, the duration of diabetes and comorbidities like HTN and dyslipidemia further exacerbate the condition. Metabolic syndrome associated with T2DM often manifests as liver disease [12-14].

Stevia rebaudiana bertoni, is a perennial shrub that belongs to the family Compositae (Asteraceae) [15]. It is commonly known as Stevia. It contains various bioactive constituents that are responsible for sweetness and several activities [16]. Stevia is frequently referred to as “the sweet herb of Paraguay” since it was indigenous to Paraguay and Brazil [17]. Several centuries ago, the natives of Paraguay used the leaves of this plant to sweeten their bitter drinks. In 1888, this plant was discovered by Dr. Moises Santiago Bertoni. It was scientifically named Stevia Rebaudiana after Dr. Rebaudi, a Paraguayan chemist [18].

It has been cultivated in various regions of the world like North America, Asia and Europe [19]. It is a subtropical semi-humid plant that can be grown easily even in the kitchen garden [20]. As the demand for natural sweeteners has increased, Stevia has been cultivated on a large scale in India. Currently, China is said to be the world’s largest producer of Stevia, which is cultivated in 13400 acres of land and around 40 thousand tonnes of stevia leaves are produced per day [21]. China is said to be the leading exporter of stevioside.

There are different species of Stevia, which contain several sweetening compounds among which S. rebaudiana is the sweetest of all. Stevia consists of a group of natural sweeteners called Diterpene glycosides. It has eight steviol glycosides (ent-kaurene glycosides) which are rebaudioside A-E, dulcoside A, stevioside and steviolbioside which are naturally occurring in its leaves [22, 23]. The extracts of Stevia contain potential sweetening compounds namely rebaudioside and stevioside. These glycosides are 200-300 times sweeter than conventional sucrose.

In the early 1970s, the first commercial products of Stevia were launched in the country Japan [24]. Progressively Stevia is used as a substitute for sugar in many countries [25]. The World Health Organization (WHO) and the Joint Food and Agriculture Organization (FAO) agreed on an acceptable daily intake (ADI) of steviol glycosides as 2 mg/kg. This, after a few years, was modified by FAO and WHO and increased the ADI to 4 mg/kg [26, 27]. Subsequently, Stevia products were approved in major markets such as the US, Europe and Oceania. It was estimated that 500 million US dollars of global market for Stevia [28].

The treatment of diabetes requires comprehensive management including a balanced diet, physical activity, proper knowledge of a balanced diet, good quality sleep and proper anti-diabetic medications. Stevia is a valuable addition to the diet of individuals with diabetes due to its natural sweetness without affecting blood glucose levels. Many studies on stevia have shown that it possesses various beneficial effects on health such as anti-obesity, anti-diabetic, anti-hypertensive, anti-oxidant, anti-microbial and anti-tumor [29].

In this review article, we try to explore different aspects of Stevia and its beneficial effects on diabetic patients.

DISCUSSION

Pharmacokinetics of stevia

Several studies have found that neither gastric juice nor digestive enzymes decompose stevioside [30-32]. Fig. 1 illustrates that oral stevioside, due to its high molecular weight, does not get absorbed at the level of the upper small intestine. But it gets degraded by bacterial intestinal flora of the Bacteroides genus in the lower gastrointestinal tracts of mice, rats, pigs and humans. This transforms it into free steviol, which is an aglycone of steviol glycosides [33-35].

Fig. 1: Metabolism and excretion of stevia

Bioactive compounds in stevia

Stevia, is a rich source of many phytochemicals. Stevia leaves are known to contain a diverse mix of sweet diterpene glycosides, such as stevioside, steviolbioside, rebaudioside (A, B, C, D, and E) and dulcoside A. Another study identified several phytochemicals in Stevia, including austroinullin, β-carotene, dulcoside, steviol, stevioside, rebaudi oxides, riboflavin and thiamine [36]. Additionally, the extract from Stevia leaf residue-obtained from byproducts during the production of steviol glycosides—has been found to contain several significant phenolic compounds. The presence of these bioactive phenolic and flavonoid compounds supports Stevia's medicinal properties and its potential use in both the food/nutraceutical and pharmaceutical industries.

Beneficial effects of stevia in diabetes

Zero calorie ingredient

S. rebaudiana, is known by its other names such as sugar leaf, sweet and candy leaf. It is being used as a natural sugar substitute and sweetener [37]. It has been used as a sweetener in chocolates, beverages, canned vegetables, chewing gums, ice cream, tabletop sweeteners, ketchup and yogurts. Stevia is rich in metabolites such as thiamine, β-carotene, riboflavin, austroinulin, diverse terpenes and flavonoids [38]. Stevioside and rebaudioside are the two major sweetening compounds present in Stevia. Even though it has a sweet taste, it has a zero-calorie property. This could be beneficial for diabetic and obese patients. In contrast to this, sucrose, which is extracted from sugarcane and beetroot can increase the calories and can cause dental caries and stomach infections [39].

Anti-oxidant property

Oxidative stress is a condition in which there is an unbalanced redox status that leads to increased production and accumulation of Reactive Oxygen Species (ROS) and decreased ability of antioxidant systems in cells or tissues [40]. High blood sugar is associated with oxidation and leads to increased formation of free radicals [41]. The vascular endothelial cells in diabetic patients are more commonly damaged due to oxidative stress that destroys endothelial junctions, leading to increased intravascular permeability. This ultimately leads to the development of microvascular and macrovascular complications [42].

A significant anti-oxidant capacity of Stevia was found in a study conducted using an aqueous leaf extract of S. rebaudiana [43]. Proanthocyanidins and flavonoids in Stevia were found to inhibit the production of Nitric oxide in macrophages when stimulated by Lipo-Polysaccharides (LPS)/Interferon-γ (INFγ). The natural diterpenoids like austroinulin and 6-O-acetyl austroinulin in Stevia inhibit the formation of Nitric Oxide Synthase (iNOS), Prostaglandin E2 (PGE2) and pro-inflammatory cytokines such as TNF-α, IL-6, IL-1β, and mast protease-1 cells. This is due to inhibition of MAPK phosphorylation and NF-κB activation [44, 45].

Anti-hyperglycemic effect

Diabetes is a metabolic disorder which is characterized by high blood glucose levels in the body [46]. Diabetes is said to be the most common non-communicable disease worldwide. Diabetes occurs due to impaired insulin secretion, insulin resistance or defective insulin action. Its increasing prevalence is attributed to sedentary lifestyle, urbanization and obesity.

Steviosides were shown to have comparable anti-hyperglycaemic effects in human subjects. In a 2004 study by Gregersen et al., participants with T2DM were involved in a paired-crossover study. On two separate occasions, they consumed a standard test meal of 412 kcal (1,725 kJ) along with either 1g of stevioside or 1g of maize (control). Serum glucose, insulin, glucagon, Glucagon-Like Peptide 1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP) levels were measured at 30-minute intervals, starting 30 min before the test meal and continuing until 240 min afterward. The study found that 240 min after consuming stevioside, mean postprandial blood glucose levels were significantly lower by 18% compared to controls. Additionally, there was a notable 40% increase in the insulinogenic index, reflecting improved beta cell function with stevioside [47]. Steviosides enhance insulin secretion, leading to reduced long-term serum glucose levels. Beta cells in the islet of the pancreas synthesize and secrete insulin directly into the portal vein which will be delivered to the liver. The liver is known as the major site of insulin clearance [48]. A 2017 study by Philippaert et al. explored the specific molecular mechanisms through which Stevia extracts enhance insulin secretion. The researchers focused on the effect of stevioside on the transient receptor potential cation channel subfamily melastatin 5 (TRPM5), a monovalent Ca²⁺ activated cation channel present in type II taste receptor cells and pancreatic beta cells. They found that steviosides increase the frequency of glucose-stimulated action potentials and shift the voltage-dependent activation of TRPM5 to more negative membrane potentials, changing from a V1/2 of+145 mV to+42.8 mV. This shift leads to a more negative resting membrane potential, resulting in cell depolarization and enhanced signal potentiation with less electrical input. Overall, these results suggest that stevioside directly affects TRPM5 channels, extends their activation duration and enhances insulin secretion [49].

Anti-obesity property

Obesity is recognized as a state of chronic, low-grade inflammation in adipose tissue, leading to a pro-inflammatory environment in T2DM. Inflammatory cytokines play a significant role in the pathogenesis of T2DM [50]. In a 2012 study, Wang et al. investigated the effect of stevioside on inflammatory markers in mice. Over four months, mice were given either a normal or high-fat diet. In the fourth month, they received either 10 mg/kg/day of stevioside or a control vector. The researchers measured mRNA levels of inflammatory cytokines TNF-α, IL-6, IL-10, IL-1β, MIP-1α, KC, CD11b, and CD14 in adipose tissue using quantitative reverse transcriptase PCR. Results showed that mice on the high-fat diet had significantly higher levels of these inflammatory markers after three months, indicating a pro-inflammatory state typical of obesity. However, the addition of stevioside to the high-fat diet in the fourth month led to a significant reduction in all inflammatory markers compared to the control vector and decreased macrophage infiltration in the adipose tissue of mice fed a high-fat diet [51].

Several studies have explored the impact of Stevia consumption on satiety and weight loss. In a 2010 study, Anton et al. investigated the impact of Stevia consumption on satiety in both lean (BMI = 19.5–24.9 kg/m²) and obese (BMI = 30–39.9 kg/m²) human subjects. Participants attended three separate study days. The researchers found that daily calorie intake was significantly lower in the Stevia (2257 kcal/day) and Aspartame (2248 kcal/day) groups compared to the sucrose group (2557 kcal/day), likely due to the zero-calorie nature of the sweeteners. Since food intake was only assessed over a single study day, the long-term effects of Stevia on appetite and weight loss cannot be concluded. A more extended, blinded and interventional study would be needed to better understand Stevia's impact on these factors [52].

Anti-hyperlipidemic property

Research has demonstrated that stevioside can significantly lower total cholesterol, triglyceride, LDL and VLDL levels while increasing HDL levels. The reduction in total cholesterol is attributed to the increased excretion of bile acids, achieved by preventing their reabsorption in the small intestine through the disruption of micelle formation. This increased bile acid excretion activates 7α-hydroxylase, which enhances the conversion of liver cholesterol to bile acids, thereby reducing cholesterol levels [53, 54].

Stevioside reduces triglyceride levels by stimulating the activity of the lipase enzyme produced by the liver, which leads to lipid breakdown and increased excretion of triglycerides through faeces [55]. The hypolipidemic effect of Stevia is also due to the activation of PPAR receptors. PPAR, a regulating factor in lipogenesis, enhances the expression of Lipoprotein Lipase (LPL) and the C-II apo gene, boosts liver absorption and free fatty acid esterification, and increases the oxidation of mitochondrial free fatty acids. Additionally, Stevia decreases the activity of acetyl-coenzyme A carboxylase and fatty acid synthase [56].

Anti-hypertension property

Cardiovascular disease is a common complication of DM and recent research indicates that Stevia and its metabolites may support cardiovascular health by reducing HTN. Several clinical trials have investigated the antihypertensive effects of Stevia compounds. In a study by Chan et al., 106 healthy adults with mild to moderate HTN (baseline diastolic blood pressures between 95 and 110 mmHg) participated in a multi-center, double-blind, placebo-controlled trial. The participants were instructed to take 250 mg of stevioside or a placebo three times a day and were monitored monthly for a year. Within just three months, the stevioside group showed a significant reduction in mean systolic blood pressure from 166.5 mmHg to 152.6 mmHg and mean diastolic blood pressure from 102.1 mmHg to 90.3 mmHg [57]. A 2008 study by Barriocanal et al. supported these findings, showing no significant differences in blood pressure between the groups taking 250 mg of Stevia three times daily and those receiving a placebo over a 3-month period. The study included participants with T1DM/T2DM/no diabetes, all of whom had normal or low-normal blood pressure [58]. Stevioside shows promising therapeutic effects in individuals with HTN and does not carry the risk of causing hypotension, highlighting its potential clinical value for treating cardiovascular patients.

Anti-cancer property

It was also found that occupational stress contributes to the development of T2DM, potentially due to negative psychological factors [59, 60]. In recent years, there has been a significant increase in cancer cases seen in diabetic patients, particularly in tumor types linked to lifestyle risk factors and occupational stress. Stevia can significantly contribute to cancer prevention by reducing blood glucose levels, thereby mitigating risk factors such as obesity, inflammation and oxidative stress. Additionally, it can help limit an essential nutrient supply for tumor cells [61]. Since only a few studies have examined the effectiveness, future research should thoroughly investigate this crucial parameter before we can confidently label Stevia products as "cancer preventive and therapeutic" agents.

Safety profile

Stevia is often compared to table sugar, but it cannot replace it completely. This is because steviol glycosides do not have all the desirable properties of sucrose. For example, Stevia does not influence on color of the product and does not form a proper texture [62].

However, its extensive traditional use by Paraguayans for over 1500 years serves as a long-standing testament to its safety [63]. Steviosides have been consumed in substantial quantities in Japan for over 20 y without any reported adverse effects. The safety of Stevia can also be attributed to the fact that steviol glycosides are minimally absorbed in both humans and rats in the stomach and upper intestine [64]. The acceptable daily intake of Stevia dry extract, as established by the Scientific Committee on Food of the European Food Safety Authority (EFSA) and the Food and Drug Administration (FDA), is 4 mg/kg of body weight [65]. Research on Stevia's effects on the human body has largely found no negative side effects [66-68]. The authors concluded that hamsters fed stevioside at a dose as high as 2.5 g/kg body weight per day exhibited no abnormalities in growth or reproductive performance [69]. Usami et al. investigated the teratogenic effects of stevioside by giving pregnant rats doses of 0, 250, 500 and 1000 mg/kg/d. The study found that stevioside did not cause any teratogenic effects and no adverse impacts were observed in either the pregnant rats or their foetuses [70]. A thorough weight-of-evidence assessment of the full genotoxicity profile for steviol glycosides has demonstrated that the consumption of stevioside and rebaudioside A does not pose a risk of genetic mutations in humans [71].

CONCLUSION

In conclusion, the comprehensive review of Stevia highlights its multifaceted benefits and applications. The growing body of evidence underscores its potential role in managing various health conditions, particularly for diabetic patients, due to its natural sweetness and minimal impact on blood sugar levels. The rich phytochemical profile of Stevia contributes to its therapeutic properties, making it a valuable ingredient in both the pharmaceutical and food industries. However, to fully harness its benefits and meet the increasing global demand, further scientific research is essential to optimize its cultivation, enhance its chemical constituents and ensure its safety. Overall, Stevia stands out as a promising natural sweetener with significant health benefits for diabetic patients.

ACKNOWLEDGEMENT

In preparing this review article, I would like to extend my deepest gratitude to all those who have supported and contributed to its development. My heartfelt thanks go to my colleagues and mentors, whose insightful feedback and constructive critiques were invaluable in shaping the direction of this work. I am also grateful to the researchers whose pioneering studies provided the foundation for this review; their dedication and innovative approaches have significantly enriched this field.

FUNDING

No financial support, grants, or other assistance was provided.

AUTHORS CONTRIBUTIONS

All authors played a role in the study's conception and design. B. Dharani, Suba. A and Stephy Sebastian conducted the data collection and analysis. The initial draft of the manuscript was prepared by B. Dharani and Suba. A, while Stephy Sebastian assisted with article collection. Each author reviewed earlier drafts, provided feedback and approved the final version.

CONFLICTS OF INTERESTS

The authors declare that they have no conflicts of interest.

REFERENCES

  1. Cole JB, Florez JC. Genetics of diabetes mellitus and diabetes complications. Nat Rev Nephrol. 2020 May 12;16(7):377-90. doi: 10.1038/s41581-020-0278-5.

  2. Cho NH, Shaw JE, Karuranga S, Huang Y, DE Rocha Fernandes JD, Ohlrogge AW. IDF diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018 Apr;138:271-81. doi: 10.1016/j.diabres.2018.02.023, PMID 29496507.

  3. Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H. Mortality and causes of death in the WHO multinational study of vascular disease in diabetes. Diabetologia. 2001 Sep;44 Suppl 2:S14-21. doi: 10.1007/pl00002934, PMID 11587045.

  4. DA Rocha Fernandes J, Ogurtsova K, Linnenkamp U, Guariguata L, Seuring T, Zhang P. IDF Diabetes atlas estimates of 2014 global health expenditures on diabetes. Diabetes Res Clin Pract. 2016 Jul;117:48-54. doi: 10.1016/j.diabres.2016.04.016, PMID 27329022.

  5. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014;37 Suppl 1:S81-90. doi: 10.2337/dc14-S081.

  6. Introduction: standards of medical care in diabetes 2018. Diabetes Care. 2018;41 Suppl 1:S1-2. doi: 10.2337/dc18-Sint01.

  7. Jha DK, Koneri R, Samaddar S. Antidiabetic activity of phytosaponin in STZ-induced type I diabetes in rats. Res J Pharm Technol. 2019;12(8):3919. doi: 10.5958/0974-360X.2019.00675.9.

  8. Sarkar S, Sadhu S, Roy R, Tarafdar S, Mukherjee N, Sil M. Contemporary drifts in diabetes management. Int J App Pharm. 2023 Mar 7;15(2):1-9. doi: 10.22159/ijap.2023v15i2.46792.

  9. Suja Pandian R, Ramalingam M. Consequences of physical activity on the markers of glycemic status among type 2 diabetic subjects. Res J Pharm Technol. 2012 Nov;5(11):1413-6.

  10. Shinde AD, Bhise SB. Optimization of pharmacokinetics by loading bioenhancer in optimized nasal mucoadhesive microspheres of insulin. Res J Pharm Technol. 2010 Apr;3(2):613-8.

  11. Das AK, Ghosh D, Ghosh J. Assessment of patients knowledge attitude and practice regarding diabetes mellitus in a Tertiary Care Hospital in Eastern India. Asian J Pharm Clin Res. 2023 Jan 1;16(1):29-34. doi: 10.22159/ajpcr.2023.v16i1.46328.

  12. Jaya MK, Swastini DA, Nopitasari BL, Editors. Putu rika veryanti. A case-control study on risk factors affecting peripheral neuropathic complications in elderly with type 2 diabetes mellitus. Res J Pharm Technol. 2021;14(8):4040-6.

  13. Geetha P, Shanmugasundaram P. A prospective observational study on assessment of risk factor associated with diabetic retinopathy in patients diagnosed with type 2 diabetes mellitus in south indian population. Res J Pharm Technol. 2019;12(2):595. doi: 10.5958/0974-360X.2019.00106.9.

  14. Hassan N, Shahwan M, Alkhoujah S, Jairoun A. Association between serum liver enzymes and metabolic syndrome among type 2 diabetes mellitus patients. Res J Pharm Technol. 2021;14(2):1050-4. doi: 10.5958/0974-360X.2021.00188.8.

  15. Ahmad J, Khan I, Blundell R, Azzopardi J, Mahomoodally MF. Stevia rebaudiana bertoni: an updated review of its health benefits industrial applications and safety. Trends Food Sci Technol. 2020 Jun 1;100:177-89. doi: 10.1016/j.tifs.2020.04.030.

  16. Patel S, Navale A. The natural sweetener stevia: an updated review on its phytochemistry health benefits and anti-diabetic study. Curr Diabetes Rev. 2024 Feb 1;20(2):26-36. doi: 10.2174/1573399819666230501210803.

  17. Kamble K, Stevia KK. Stevia: alternative natural sugar for dairy industry. Just Agric. 2024 Feb;4(6):262-5.

  18. Gupta E, Purwar S, Sundaram S, Rai GK. Nutritional and therapeutic values of Stevia rebaudiana: a review. J Med Plants Res. 2013 Nov;7(46):3343-53.

  19. Masoumi SJ, Ranjbar S, Keshavarz V. The effectiveness of stevia in diabetes mellitus: a review. Int J Nutr Sci. 2020 Jun 1;5(2):45-9.

  20. Goyal SK, Samsher N, Goyal RK. Stevia (Stevia rebaudiana) a bio-sweetener: a review. Int J Food Sci Nutr. 2010 Feb 1;61(1):1-10. doi: 10.3109/09637480903193049.

  21. Ali A, Kant K, Gupta S, Kaur N, Jindal P, Naeem M. Enhancing nutritional and antidiabetic properties of Stevia rebaudiana bert. a sweet leaf plant through various scientific approaches. Antidiabetic Med Plants. 2024 Jan 1:229-53.

  22. Tavarini S, Angelini LG. Stevia rebaudiana bertoni as a source of bioactive compounds: the effect of harvest time experimental site and crop age on steviol glycoside content and antioxidant properties. J Sci Food Agric. 2013 Jul;93(9):2121-9. doi: 10.1002/jsfa.6016, PMID 23303701.

  23. Brahmachari G, Mandal LC, Roy R, Mondal S, Brahmachari AK. Stevioside and related compounds molecules of pharmaceutical promise: a critical overview. Arch Pharmazie. 2011 Jan;344(1):5-19. doi: 10.1002/ardp.201000181.

  24. Talevi A. Beneficial effects of Stevia rebaudiana bertoni and steviol-related compounds on health. In: Sweeteners. 2018;263-84. doi: 10.1007/978-3-319-27027-2_24.

  25. Momtazi Borojeni AA, Esmaeili SA, Abdollahi E, Sahebkar A. A review on the pharmacology and toxicology of steviol glycosides extracted from Stevia rebaudiana. Curr Pharm Des. 2017 Mar 1;23(11):1616-22. doi: 10.2174/1381612822666161021142835.

  26. Joint FAO/WHO Expert Committee on Food Additives. Evaluation of certain food additives. World Health Organ Tech Rep Ser. 2006;934:1-145.

  27. Jamuna P. Evaluation of certain food additives. Sixty-ninth report of the Joint FAO/WHO Expert Committee on Food Additives (JECFA). World Health Organ Tech Rep S. 2009;952:208. J Food Sci Technol. 2010;47(4):465–7. doi: 10.1007/s13197-010-0079-0.

  28. Statista. Stevia industry statistics and facts. Available from: https://www.statista.com/topics/2304/steviaindustry.

  29. Ahmad J, Khan I, Blundell R, Azzopardi J, Mahomoodally MF. Stevia rebaudiana bertoni: an updated review of its health benefits industrial applications and safety. Trends Food Sci Technol. 2020;100:177-89. doi: 10.1016/j.tifs.2020.04.030.

  30. Koyama E, Kitazawa K, Ohori Y, Izawa O, Kakegawa K, Fujino A. In vitro metabolism of the glycosidic sweeteners stevia mixture and enzymatically modified stevia in human intestinal microflora. Food Chem Toxicol. 2003;41(3):359-74. doi: 10.1016/s0278-6915(02)00235-1, PMID 12504168.

  31. Hutapea AM, Toskulkao C, Buddhasukh D, Wilairat P, Glinsukon T. Digestion of stevioside a natural sweetener by various digestive enzymes. J Clin Biochem Nutr. 1997;23(3):177-86. doi: 10.3164/jcbn.23.177.

  32. Koyama E, Sakai N, Ohori Y, Kitazawa K, Izawa O, Kakegawa K. Absorption and metabolism of glycosidic sweeteners of stevia mixture and their aglycone steviol in rats and humans. Food Chem Toxicol. 2003;41(6):875-83. doi: 10.1016/S0278-6915(03)00039-5.

  33. Geuns JM. Stevioside. Phytochemistry. 2003 Nov 1;64(5):913-21. doi: 10.1016/S0031-9422(03)00426-6.

  34. Gardana C, Simonetti P, Canzi E, Zanchi R, Pietta P. Metabolism of stevioside and rebaudioside a from Stevia rebaudiana extracts by human microflora. J Agric Food Chem. 2003;51(22):6618-22. doi: 10.1021/jf0303619.

  35. Geuns JM, Augustijns P, Mols R, Buyse JG, Driessen B. Metabolism of stevioside in pigs and intestinal absorption characteristics of stevioside rebaudioside a and steviol. Food Chem Toxicol. 2003;41(11):1599-607. doi: 10.1016/S0278-6915(03)00191-1.

  36. Lemus Mondaca R, Ah-Hen K, Vega Galvez A, Honores C, Moraga NO. Stevia rebaudiana leaves: effect of drying process temperature on bioactive components antioxidant capacity and natural sweeteners. Plant Foods Hum Nutr. 2016;71(1):49-56. doi: 10.1007/s11130-015-0524-3, PMID 26650384.

  37. Mohan SK, Veeraraghavan VP, Balakrishna JP, Rengasamy G, Rajeshkumar S. Antidiabetic activity of methanolic extract of Artabotrys suaveolens leaves in 3T3-L1 cell line. J Pure Appl Microbiol. 2020;14(1):573-80. doi: 10.22207/JPAM.14.1.59.

  38. Konoshima T, Takasaki M. Cancer chemopreventive effects of natural sweeteners and related compounds. Pure Appl Chem. 2002;74(7):1309-16. doi: 10.1351/pac200274071309.

  39. Debnath M. Clonal propagation and antimicrobial activity of an endemic medicinal plant Stevia rebaudiana. J Med Plants Res. 2008;2(2):45-51.

  40. Pizzino G, Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V. Oxidative stress: harms and benefits for human health. Oxid Med Cell Longev. 2017;2017(1):8416763. doi: 10.1155/2017/8416763, PMID 28819546.

  41. Das S, Vasisht S, Das S, Shrivastava N. Correlation between total antioxidant status and lipid peroxidation in hypercholesterolemia. Curr Sci. 2000;78(4):486-7.

  42. Scioli MG, Storti G, D Amico F, Rodriguez Guzman R, Centofanti F, Doldo E. Oxidative stress and new pathogenetic mechanisms in endothelial dysfunction: potential diagnostic biomarkers and therapeutic targets. J Clin Med. 2020;9(6):1995. doi: 10.3390/jcm9061995, PMID 32630452.

  43. Ali A, Shahu R, Balyan P, Kumari S, Ghodmare R, Jobby R. Antioxidation and antiglycation properties of a natural sweetener: Stevia rebaudiana. Sugar Tech. 2022;24(2):563-75. doi: 10.1007/s12355-021-01023-0.

  44. Cho BO, Ryu HW, SO Y, Cho JK, Woo HS, Jin CH. Anti-inflammatory effect of austroinulin and 6-O-acetyl austroinulin from Stevia rebaudiana in lipopoly saccharide stimulated RAW264.7 macrophages. Food Chem Toxicol. 2013;62:638-44. doi: 10.1016/j.fct.2013.09.011.

  45. Kim SY, JO MJ, Hwangbo M, Back YD, Jeong TY, Cho IJ. Anti-inflammatory effect of Stevia rebaudiana as a results of NF-κB and MAPK inhibition. The Journal of Korean Oriental Medical Ophthalmology and Otolaryngology and Dermatology. 2013;26(3):54-64. doi: 10.6114/jkood.2013.26.3.054.

  46. CS, Rajeshkumar S, Lakshmi T, Roy A. Antidiabetic activity of Piper longum and Stevia herbal formulation. J Complement Med Res. 2022;13(2):29. doi: 10.5455/jcmr.2022.13.03.06.

  47. Gregersen S, Jeppesen PB, Holst JJ, Hermansen K. Antihyperglycemic effects of stevioside in type 2 diabetic subjects. Metabolism. 2004;53(1):73-6. doi: 10.1016/j.metabol.2003.07.013.

  48. Klein S, Gastaldelli A, Yki-Jarvinen H, Scherer PE. Why does obesity cause diabetes? Cell Metab. 2022;34(1):11-20. doi: 10.1016/j.cmet.2021.12.012, PMID 34986330.

  49. Philippaert K, Pironet A, Mesuere M, Sones W, Vermeiren L, Kerselaers S. Steviol glycosides enhance pancreatic beta-cell function and taste sensation by potentiation of TRPM5 channel activity. Nat Commun. 2017;8(1):1-16. doi: 10.1038/ncomms14733.

  50. Philippaert K, Pironet A, Mesuere M, Sones W, Vermeiren L, Kerselaers S. Steviol glycosides enhance pancreatic beta-cell function and taste sensation by potentiation of TRPM5 channel activity. Nat Commun. 2017;8(1):1-16. doi: 10.1038/ncomms14733.

  51. Wang Z, Xue L, Guo C, Han B, Pan C, Zhao S. Stevioside ameliorates high fat diet induced insulin resistance and adipose tissue inflammation by downregulating the NF-κB pathway. Biochem Biophys Res Commun. 2012;417(4):1280-5. doi: 10.1016/j.bbrc.2011.12.130.

  52. Anton SD, Martin CK, Han H, Coulon S, Cefalu WT, Geiselman P. Effects of stevia aspartame and sucrose on food intake satiety and postprandial glucose and insulin levels. Appetite. 2010;55(1):37-43. doi: 10.1016/j.appet.2010.03.009.

  53. Sarowar H, Badrul AM, Muhammad A, Islam M, Monirul R. Antihyperglycemic and anti-hyperlipidemic effects of different fractions of Stevia rebaudiana leaves in alloxan induced diabetic rats. Int J Pharm Sci Res. 2011;2(7):1722-9.

  54. Brijesh K, Kamath M. Experimental evaluation of anti-hyperglycemic and hypolipidemic effects of stevia rebaudiana Anacardium occidentale on wistar rats. Int J Basic Clin Pharmacol. 2016;5(6):2463-7.

  55. Uswa A, Shabir AR, Sajid AM, Zarina M, Makhdoom S. Antihyperlipidemic efficacy of aqueous extract of Stevia rebaudiana Bertoni in albino rats. Lipids Health Dis. 2018 Jul 27;17(1):175. doi: 10.1186/s12944-018-0810-9.

  56. Assaei R, Mokarram P, Dastghaib S, Darbandi S, Darbandi M, Zal F. Hypoglycemic effect of aquatic extract of stevia in pancreas of diabetic rats: PPAR gamma dependent regulation or antioxidant potential. Avicenna J Med Biotechnol. 2016;8(2):65-74. PMID 27141265.

  57. Chan P, Tomlinson B, Chen YJ, Liu JC, Hsieh MH, Cheng JT. A double blind placebo controlled study of the effectiveness and tolerability of oral stevioside in human hypertension. Br J Clin Pharmacol. 2000;50(3):215-20. doi: 10.1046/j.1365-2125.2000.00260.x, PMID 10971305.

  58. Barriocanal LA, Palacios M, Benitez G, Benitez S, Jimenez JT, Jimenez N. Apparent lack of pharmacological effect of steviol glycosides used as sweeteners in humans a pilot study of repeated exposures in some normotensive and hypotensive individuals and in type 1 and type 2 diabetics. Regul Toxicol Pharmacol. 2008;51(1):37-41. doi: 10.1016/j.yrtph.2008.02.006, PMID 18397817.

  59. Prabavathy JV, Sangeetha R. An association between work stress and serum cortisol with the development of type 2 diabetes mellitus among industrial workers. Res J Pharm Technol. 2020;13(1):27-32. doi: 10.5958/0974-360X.2020.00005.0.

  60. Prabavathy JV, Sangeetha R. Stress induced type 2 diabetes mellitus among industrial workers a review. Res J Pharm Technol. 2019;12(1):396-402. doi: 10.5958/0974-360X.2019.00072.6.

  61. Iatridis N, Kougioumtzi A, Vlataki K, Papadaki S, Magklara A. Anti-cancer properties of stevia rebaudiana; more than a sweetener. Molecules. 2022;27(4):1362. doi: 10.3390/molecules27041362.

  62. Kurek JM, Krejpcio Z. The functional and health promoting properties of Stevia rebaudiana bertoni and its glycosides with special focus on the antidiabetic potential a review. J Funct Foods. 2019;61:103465. doi: 10.1016/j.jff.2019.103465.

  63. Singh SD, Rao GP. Stevia: the herbal sugar of 21st century. Sugar Tech. 2005;7(1):17-24. doi: 10.1007/BF02942413.

  64. Mathur S, Bulchandan N, Parihar S, Shekhawat GS. Critical review on steviol glycosides: pharmacological toxicological and therapeutic aspects of high potency zero caloric sweetener. Int J Pharmacol. 2017;13(7):916-28. doi: 10.3923/ijp.2017.916.928.

  65. Lohner S, Toews I, Meerpohl JJ. Health outcomes of non nutritive sweeteners: analysis of the research landscape. Nutr J. 2017;16(1):55. doi: 10.1186/s12937-017-0278-x.

  66. Kujur RS, Singh V, Ram M, Yadava HN, Singh KK, Kumari S. Antidiabetic activity and phytochemical screening of crude extract of Stevia rebaudiana in alloxan induced diabetic rats. Pharmacognosy Res. 2010;2(4):258-63. doi: 10.4103/0974-8490.69128, PMID 21808578.

  67. Nikiforov AI, Rihner MO, Eapen AK, Thomas JA. Metabolism and toxicity studies supporting the safety of rebaudioside D. Int J Toxicol. 2013;32(4):261-73. doi: 10.1177/1091581813492828, PMID 23766392.

  68. Ucar A, Yılmaz S, Yılmaz S, Kılıc MS. A research on the genotoxicity of stevia in human lymphocytes. Drug Chem Toxicol. 2018;41(2):221-4. doi: 10.1080/01480545.2017.1349135, PMID 28738695.

  69. Yodyingyuad V, Bunyawong S. Effect of stevioside on growth and reproduction. Hum Reprod. 1991;6(1):158-65. doi: 10.1093/oxfordjournals.humrep.a137251, PMID 1874950.

  70. Usami M, Sakemi K, Kawashima K, Tsuda M, Ohno Y. Teratogenicity study of stevioside in rats. Eisei Shikenjo Hokoku. 1995;(113):31-5. PMID 8717225.

  71. Carakostas MC, Curry LL, Boileau AC, Brusick DJ. Overview: the history technical function and safety of rebaudioside a naturally occurring steviol glycoside for use in food and beverages. Food Chem Toxicol. 2008;46(7):S1-S10. doi: 10.1016/j.fct.2008.05.003.