Skip to main content

The anti-diabetic activities of natural sweetener plant Stevia: an updated review

Abstract

Diabetes mellitus is one of the key metabolic diseases cause due to defects in the secretion of insulin, insulin resistance in peripheral tissues, or both. Plants remained an important source of nutrition as well as medicine. Stevia rebaudiana Bertoni is one of the important high qualities non-caloric sugar substitute sweetener plants against diabetes disease. The compounds like steviol, rebaudioside A, stevioside, etc. can lower the sugar level many fold. In addition, it decreases oxidative stress, hence reduces the risk of diabetes. Its leaves have been used for the control and treatment of diabetes and many other metabolic diseases. In animal model experiments it reduces blood sugar level and promotes liver and kidney functions. In this review, we highlighted the most recent literature on the safe use of Stevia for the treatment of diabetes, its use as a functional food, and its mode of therapeutic action in different animal model experiments. However, keeping Stevia as a model plant; detailed investigations are needed for the identification of new metabolites and its use against diabetes and related diseases.

Introduction

Stevia (Stevia rebaudiana Bertoni) is a branched bushy shrub and belongs to the family Asteraceae. It is considered native to the northeastern regions of Paraguay [27, 28]. It is also found in Brazil and Argentina. In addition, its cultivation is directly spread all over the world including Canada and some Asian and European regions [28]. It is known as “calorie free bio-sweetener of high quality” [34]. It shows resistance to high temperatures and used in many food products including beverages, jams, sauces, confections, and other dental products. The 50 g Stevia leaf can replace 1 kg of sugar and the stevioside does not indicate any brown appearance in cooking [32].

Diabetes mellitus is the most common metabolic disease characterized by an increase in glucose levels due to defects in the secretion of insulin, insulin resistance in peripheral tissues, or both [3]. According to World Health Organization (WHO), worldwide it will be the seventh leading cause of death by 2030 [30]. Proper diet, exercise, and medicine can overcome this lethal disease [29]. The pharmacological drugs and combinations have several side effects and are too costly. Therefore, use of traditional medicinal plants is a best option to treat diseases [23, 37, 43]. Stevia is one of the miracle medicinal plants against many diseases. Limited review articles are available on the applications of Stevia in medical field. No single comprehensive review is available that explain its role against diabetes diseases in different animal model of diseases and other human cell lines, and to discuss it functional food values for a healthy life. The present review highlighted the new up to date literature related to the anti-diabetic properties of Stevia plants and also emphasized its role against diabetes in the different animal models. The detailed functional food products of Stevia for the diabetic patients were also discussed.

Bioactive compounds of Stevia

More than 1200 medicinal plants mimic anti-diabetic activities have been identified so far. These phyto-therapies are considered safe and cost effective methods as compared to synthetic treatment options [41]. Stevia is full of many important phytochemicals/compounds that have properties to reduce blood cholesterol and sugar levels, as well as blood pressure. In addition, it can to enhance taste and flavor; and also have reported antibacterial properties [32]. The leaves contain eight important diterpene glycosides i.e. rebaudiosides A-E, dulcoside A, stevioside and steviolbioside [1]. Among 230 species of Stevia, the two species namely rebaudiana and phlebophylla produce important steviol glycosides [11]. The stevioside and rebaudioside A are the two important sweetening thermostable compounds used as a source of cooked foods [28]. Stevioside, is found in the leaves of S. rebaudiana Bertoni and is 300 times sweeter than sucrose [21]. The rebaudioside A is considering 250 to 400 times sweeter than sucrose and used for food/sweetener purposes [20]. The leaves are also full of carbohydrates [21].

Use of Stevia as functional food against diabetes

The functional food is useful to provide nutrient requirements to the body and helps against other degenerative diseases related to today’s changing lifestyles [25]. The modified coconut jelly was prepared by replacing 50% sugar with Stevia. This jelly decreases the postprandial Blood Glucose Level (BGL) without any release of insulin. Hence are recommended as a safe food product for the diabetic patient [15]. Ruiz-Ruiz et al. [36] designed an efficient functional wheat bread by replacing the sugars with the aqueous extract of S. rebaudiana Bertoni. The 50% sugars replaced with aqueous extract showed maximum anti-oxidant activities and lower level of sugar by inhibition of alpha amylase (IC50 = 198.40 μg/mL) and glucosidase (596.77 μg/mL). While the IC50 value (335.94 mg/mL) was noted with radical scavenging activity. They also found lower microbial growth during the shelf-life of soft Stevia extract. All the quality characteristics were more acceptable at 50% substitution through the sensory test. All the biological properties of retained after bread making process and they recommend it as optimum nutrient and quality of bread for human nutrition. Mayasari et al. [31] also reported that consumption of Rosella-Stevia Tea can decrease fasting BGL with no changes in 2-h postprandial BGL in pre-diabetic women. The application of Stevia as functional food is given in Table 1.

Table 1 The uses of Stevia as functional food for the treatment of diabetes disease

Anti-diabetic activities of Stevia

Various extracts of Stevia have been used for many years by South Americans a therapy for diabetes [16, 39]. Regular use of Stevia glycosides decreases sugar, cholesterol, and radionuclides level in the blood [7]. It possesses high anti-hyperglycemic activity [14, 24, 40], and serves as a substituent for saccharose in diabetes patients [14, 24, 35]. In vivo experiments show that S. rebaudiana increases glucose tolerance in diabetic rats by maintaining the blood glucose level [16]. In diabetic patients, it also leads hypoglycemia via lowering both the glycogenolysis and gluconeogenesis processes, and by absorbing the glucose in the duodenum part. In diabetic patients, Stevia and its glycosides have been found associated with antioxidant and anti-hyperglycemic activities in several body parts like the pancreas, liver, and kidney [5, 22, 38]. It has beneficial activities in pancreatic tissue by increasing the insulin level and enhances anti-diabetic properties in PPARγ-dependent manner, and through its anti-oxidant activities [5]. Moreover, the stevioside of Stevia has been reported to lower the inflammation by lowering the level of pro-inflammatory cytokines [44]. According to Jeppesen et al. [24] the stevioside increases the insulin level by affecting the β-cells of the pancreas and lowers the blood sugar levels. Ahmad and Ahmad [2] noted that extracts of Stevia lower random BGL, decreased fasting blood glucose level and glycosylated (HbA1c) hemoglobin (5.32%) amount in streptozotocin-induced diabetic albino rats. In addition, they recorded an improved level of insulin and liver glycogen in diabetic samples after eight weeks of treatments.

According to Chen et al. [13], stevioside not only increases insulin levels but also lowers the gluconeogenesis process by decreasing the expression of phosphoenolpyruvate carboxykinase gene in rats ‘liver; hence maintain optimum blood glucose levels. The stevioside and steviol are the two bioactive compounds that decrease inflammation by activation and increasing the expression IκBα gene (NF-κB localization inhibitor) [10]. Similar findings were also recorded by Bayat et al. [8] by using Stevia aquatic extracts against the interleukin-6 (IL-6) amounts in serum by using Streptozotocin-Nicotinamide based induced diabetic rats. They found that Stevia and metformin could lower fasting blood sugars and IL-6 amounts in the diabetic group and thus could help in lowering insulin resistance in diabetic patients. Fengyang et al. [19] reported that in RAW2647 cells, the stevioside inhibits the NF-κB and IκB amounts by lowering the important inflammatory factors i.e. IL-1β, IL-6, and TNF-α. Boonkaewwan et al. [10] found no cytotoxicity on human colon carcinoma cell line (Caco‐2). But, stevioside and steviol lower LPS‐induced pro‐inflammatory cytokine productions by affecting cytokine gene expression via IκBα/NF‐κB signaling pathway.

The steviol glycosides have been reported to increase uptake of glucose in neonatal rat fibroblast by activation of PI3K/Akt pathway; hence induces translocation of Glut4 to plasma membrane. It also acts as a strong antioxidant compound by lowering the concentration of glutathione and by increasing the expression of two important antioxidant enzymes i.e. superoxide dismutase and catalase (Fig. 1) [33]. The similar insulinomimetic activity of two bioactive compounds (steviol and stevioside) of Stevia was recorded by Bhasker et al. [9] in diabetes induced L6 and 3T3L1 cells. In STZ-diabetic rat model of experiment, Shivanna et al. [38] also found anti-diabetic activities with stevia leaves. In addition they also reported that it protect both liver and kidney by lowering the oxidative stress. The S. rebaudiana extracts could lower BGL in diabetic rats at time dependent manner [26]. It also protects rats from intreptozotocin-induced diabetes by lowering oxidative stress [38]. Das et al. [17] envisaged the anti-diabetic properties of the leaves based crystals of S. rebaudiana inalloxan induced type-1 diabetic mice. Their findings showed that crystal concentration (500 mg/kg) significantly improved the body weight loss and lower the BGL in the diabetic animal. The detailed applications of Stevia glycosides against diabetes disease are given in Table 2. However some previous studies showed some negative effect of Stevia glycosides in animal model experiments. For example, According to Dyrskog et al. [18] the oral use of rebaudioside A (0.025 g/kg BW/day) for eight weeks does not improve glycemic control in the Goto-Kakizaki rat. According to Toskulkao et al. [42] the steviol decrease the intestinal glucose absorption up to 43% at 1 mM concentration and also altered the morphology of the intestinal absorptive cells in hamster. Similarly, according to Aranda-Gonzalez et al. [4], the acute intraperitoneal or chronic oral administration of 20 mg/kg of minor steviol glycosides of S. rebaudiana had no antihyperglycemic effect in normoglycemic or induced-diabetic Wistar rats.

Fig. 1
figure1

Role of stevia glycosides as insulin-mimetic and antioxidant activities in neonatal rat fibroblast; S961; the insulin receptor antagonist; blocks the insulin and glycosides induced signals. Signals from the steviol glycoside lead to translocation of Glut4 from intracellular pool to plasma membrane, thus allowing glucose which mimics the insulin activity. The expression and activity of both the antioxidant enzymes SOD and CAT is also enhanced due to the activation of the same pathway (dashed arrows). Furthermore, GSH levels are also increased with steviol glycosides

Table 2 The Potential bioactive metabolites of Stevia and their mode of actions against diabetic disease

Conclusion

Stevia is full of many important phytochemicals (Steviol, Steviosides, rebaudiosides, etc.) that have properties to reduce blood sugar levels. It possesses high anti-hyperglycemic activity and serves as a substituent for saccharose in diabetes patients. It has beneficial activities in pancreatic tissue by increasing the insulin level and enhances anti-diabetic properties. It also helps in maintaining normal blood sugar level by lowering inflammation and oxidative response. It is a major source of high potency sweetener for the growing natural food market. The efficient functional Stevia breeds, tea, jelly, etc. can provide optimum nutrients to the body but also help in controlling of diabetes. Further research is needed to determine if its regular consumption brings sustained benefits for human.

References

  1. 1.

    Abou-Arab AE, Azza Abou-Arab A, Ferial Abu-Salem M (2010) Physico-chemical assessment of natural sweeteners steviosides produced from Stevia rebaudiana Bertoni plant. Afr J Food Sci 4:269–281

    Google Scholar 

  2. 2.

    Ahmad U, Ahmad RS (2018) Anti diabetic property of aqueous extract of Stevia rebaudiana Bertoni leaves in Streptozotocin-induced diabetes in albino rats. BMC Compl Alt Med 18(1):179

    MathSciNet  Article  Google Scholar 

  3. 3.

    American Diabetes Association (2014) Diagnosis and classification of diabetes mellitus. Diabetes Care 37(Suppl 1):S81-90

    Article  Google Scholar 

  4. 4.

    Aranda-Gonzalez I, Moguel-Ordonez Y, Chel-Guerrero L, Segura-Campos M, Betancur-Ancona D (2016) Evaluation of the antihyperglycemic effect of minor steviol glycosides in normoglycemic and induced-diabetic wistar rats. J Med Food 19(9):844–852

    Article  Google Scholar 

  5. 5.

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

    Google Scholar 

  6. 6.

    Assi AA, Abd El-hamid DH, Abdel-Rahman MS, Ashry EE, Bayoumi SA, Ahmed AM (2020) The potential efficacy of Stevia extract, Glimepiride and their combination in treating diabetic rats: a novel strategy in therapy of Type 2 diabetes mellitus. Egyptian J Basic Clin Pharmacol 10. doi:https://doi.org/10.32527/2020/101455

  7. 7.

    Atteh J, Onagbesan O, Tona K, Decuypere E, Geuns J, Buyse J (2008) Evaluation of supplementary Stevia (Stevia rebaudiana Bertoni) leaves and stevioside in broiler diets: Effects on feed intake, nutrient metabolism, blood parameters and growth performance. J Animal Physiol Animal Nut 92:640–649

    Article  Google Scholar 

  8. 8.

    Bayat E, Dastgheib S, Egdar S, Mokarram P (2017) Effect of the aquatic extract of Stevia on the serum level of interleukin-6 in streptozotocin-nicotinamide induced diabetic rats. Shiraz E-Med J 18(2):e45015

    Article  Google Scholar 

  9. 9.

    Bhasker S, Madhav H, Chinnamma M (2015) Molecular evidence of insulinomimetic property exhibited by steviol and stevioside in diabetes induced L6 and 3T3L1 cells. Phytomed 22(11):1037–1044

    Article  Google Scholar 

  10. 10.

    Boonkaewwan C, Burodom A (2013) Anti-inflammatory and immunomodulatory activities of stevioside and steviol on colonic epithelial cells. J Sci Food Agric 93(15):3820–3825

    Article  Google Scholar 

  11. 11.

    Brandle JE, Telmer PG (2007) Steviol glycoside biosynthesis. Photochem 68:1855–1863

    Article  Google Scholar 

  12. 12.

    Cadena RS, Gomes Cruz A, Rolim Netto R, Freitas Castro W, Fonseca Faria JA, Andrè Bolini HM (2013) Sensory profile and physicochemical characteristics of mango nectar sweetened with high intensity sweeteners throughout storage time. Food Res Int 54:1670–1679

    Article  Google Scholar 

  13. 13.

    Chen TH, Chen SC, Chan P, Chu YL, Yang HY, Cheng JT (2005) Mechanism of the hypoglycemic effect of stevioside, a glycoside of Stevia rebaudiana. Planta Med 71(2):108–113

    Article  Google Scholar 

  14. 14.

    Chen J, Jeppesen P, Abudula R, Dyrskog S, Colombo M, Hermansen K (2006) Stevioside does not cause increased basal insulin secretion or b-cell desensitization as does the sulphonylurea, glibenclamide: studies in vitro. Life Sci 78:1748–1753

    Article  Google Scholar 

  15. 15.

    Chupeerach C, Yothakulsiri C, Chamchan R, Suttisansanee U, Sranacharoenpong K, Tungtrongchitr A, On-Nom N (2018) The effect of coconut jelly with natural sweeteners Stevia (Stevia rebaudiana Bertoni) replacement on blood glucose, insulin, and C-peptide responses. Recent Pat Food Nutr Agric. https://doi.org/10.2174/2212798410666180717163852

    Article  Google Scholar 

  16. 16.

    Curi R, Alvarez M, Bazotte RB, Botion LM, Godoy JL, Bracht A (1986) Effect of Stevia rebaudiana on glucose tolerance in normal adult humans. Braz J Med Biol Res 19(6):771–774

    Google Scholar 

  17. 17.

    Das SR, Istiak ASME, Hazra P, Habiba U, Bhuiyan MKH, Rafiq K (2017) Effects of crystal derived from Stevia rebaudiana leaves on Alloxan induced type-1 diabetic mice. British J Pharma Res 17(2):1–11

    Article  Google Scholar 

  18. 18.

    Dyrskog SE, Jeppesen PB, Chen J, Christensen LP, Hermansen K (2005) The diterpene glycoside, rebaudioside A, does not improve glycemic control or affect blood pressure after eight weeks treatment in the Goto-Kakizaki rat. Rev Diabet Stud 2(2):84

    Article  Google Scholar 

  19. 19.

    Fengyang L, Yunhe F, Bo L, Zhicheng L, Depeng L, Dejie L (2012) Stevioside suppressed inflammatory cytokine secretion by downregulation of NF-kappaB and MAPK signaling pathways in LPS-stimulated RAW264.7 cells. Inflammation 35(5):1669–1675

    Article  Google Scholar 

  20. 20.

    Flavia VS, Rosangela B, Marcos GC, Andrade N, Nadia RC, Fernandes M (2007) Purification process of stevioside using zeolites and membranes. Int J Chem Reactor Eng 5(1):1–6

    Google Scholar 

  21. 21.

    Gasmalla MAA, Yang R, Hua X (2014) Stevia rebaudianaBertoni: An alternative sugar replacer and its application in food industry. Food Eng Rev 6:150–162

    Article  Google Scholar 

  22. 22.

    Gregersen S, Jeppesen PB, Holst JJ, Hermansen K (2004) Antihyperglycemic effects of stevioside in type 2 diabetic subjects. Metabolism 53(1):73–76

    Article  Google Scholar 

  23. 23.

    Jan SA, Shinwari ZK, Malik M, Ilyas M (2018) Antioxidant and anticancer activities of Brassica rapa: a review. MOJ Biol Med 3(5):175–178

    Google Scholar 

  24. 24.

    Jeppesen PB, Gregersen S, Poulsen CR, Hermansen K (2000) Stevioside acts directly on pancreatic beta cells to secrete insulin:actions independent of cyclic adenosine monophosphate and adenosine triphosphate-sensitive K+-channel activity. Metabolism 49(2):208–214

    Article  Google Scholar 

  25. 25.

    Jideani V, Onwubali F (2009) Optimisation of wheat-sprouted soybean flour bread using response surface methodology. Afr J Biotechnol 8:6364–6373

    Article  Google Scholar 

  26. 26.

    Kujur, RS, Singh V, Ram M, Yadava HN, Singh KK, Kumari S, Roy, BK (2010) Antidiabetic activity and phytochemical screening of crude extract of Stevia rebaudiana in alloxan-induced diabetic rats. Pharm Res 2(4):258–263

  27. 27.

    Lasekan O, Naidu RM (2013) Changes in the volatile constituents of the leaves of Stevia rebaudiana Bertoni caused by different drying procedures. J Food Agri Environ 11(3):190–194

    Google Scholar 

  28. 28.

    Lemus-Mondaca R, Vega-Galvez A, Zura-Bravo L, Ahhen K (2012) Stevia rebaudiana Bertoni, source of a high-potency natural sweetener. A comprehensive review on the biochemical, nutritional and functional aspects. Food Chem 132(1):1121–1132

    Article  Google Scholar 

  29. 29.

    Li G, Zhang P, Wang J, Gregg EW, Yang W, Gong Q (2008) The long-term effect of life style interventions to prevent diabetes in the China Da Qing diabetes prevention study: a 20-year follow-up study. Lancet 371:1783–1789

    Article  Google Scholar 

  30. 30.

    Mathers CD, Loncar D (2006) Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 3(11):e442

    Article  Google Scholar 

  31. 31.

    Mayasari NR, Susetyowati, Wahyuningsih MSH, Probosuseno (2018) Antidiabetic effect of Rosella-Stevia tea on prediabetic women in Yogyakarta, Indonesia. J Am College Nut 37(5):1–7

  32. 32.

    Mishra N (2011) An Analysis of antidiabetic activity of Stevia rebaudiana extract on diabetic patient. J Nat Sci Res 1(3):1–9

    Google Scholar 

  33. 33.

    Prata C, Zambonin L, Rizzo B, Maraldi T, Angeloni C, Vieceli Dalla Sega F, Hrelia S (2017) Glycosides from Stevia rebaudiana Bertoni possess insulin-mimetic and antioxidant activities in rat cardiac fibroblasts. Oxid Med Cel Long. https://doi.org/10.1155/2017/3724545

    Article  Google Scholar 

  34. 34.

    Preethi D, Sridhar TM, Josthna P, Naidu CV (2011) Studies on antibacterial activity, phytochemical analysis of Stevia rebaudiana (Bert.). An important calorie free biosweetner. J Ecobiotechnol 3(7):5–10

    Google Scholar 

  35. 35.

    Pól J, Hohnová B, Hyötyläinen T (2007) Characterization of Stevia rebaudiana by comprehensive two-dimensional liquid chromatography time-of-flight massspectrometry. J. Chromatography A 1150:85–92

    Article  Google Scholar 

  36. 36.

    Ruiz-Ruiz JC, Moguel-Ordoñez YB, Matus-Basto AJ, Segura-Campos MR (2015) Antidiabetic and antioxidant activity of Stevia rebaudiana extracts (Var. Morita) and their incorporation into a potential functional bread. J Food Sci Technol 52(12):7894–7903

    Article  Google Scholar 

  37. 37.

    Shinwari ZK, Jan SA, Khalil AT, Khan A, Ali M, Qaiser M, Zahra NB (2018) Identification and phylogenetic analysis of selected medicinal plant species from Pakistan: DNA barcoding approach. Pak J Bot 50(2):553–560

    Google Scholar 

  38. 38.

    Shivanna N, Naika M, Khanum F, Kaul VK (2013) Antioxidant, anti-diabetic and renal protective properties of Stevia rebaudiana. J Diabetes Comp 27(2):103–113

    Article  Google Scholar 

  39. 39.

    Soejarto DD, Kinghorn AD, Farnsworth NR (1982) Potential sweetening agent of plant origin III: organo leptic evaluation of Stevia leaf herbarium samples for sweetness. J Nat Prod 45:590–599

    Article  Google Scholar 

  40. 40.

    Suanarunsawat T, Chaiyabutr N (1997) The effect of steviosides on glucose metabolism in rat. Can J Physiol Pharmacol 75:976–982

    Article  Google Scholar 

  41. 41.

    Thiyagarajan M, Venkatachalam P (2012) Large scale in vitro propagation of Stevia rebaudiana (Bert.) for commercial application: pharmaceutically important and antidiabetic medicinal herb. Indust Crops Prod. 37(1):111–117

    Article  Google Scholar 

  42. 42.

    Toskulkao C, SutheeraWatananon M, Wanichanon C, Saitongdee P, Suttajit M (1995) Effects of stevioside and steviol on intestinal glucose absorption in hamsters. J Nutr Sci Vitaminol 41(1):105–113

    Article  Google Scholar 

  43. 43.

    Ullah I, Wakeel A, Shinwari ZK, Jan SA, Khalil AT, Ali M (2017) Antibacterial and antifungal activity of Isatis tinctoria l using micro-plate method. Pak J Bot 49(5):1949–1957

    Google Scholar 

  44. 44.

    Wang T, Guo M, Song X, Zhang Z, Jiang H, Wang W (2014) Stevioside plays an anti-inflammatory role by regulating the NFkappaB and MAPK pathways in S. aureus-infected mouse mammary glands. Inflammation 37(5):1837–1846

    Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Sohail Ahmad Jan.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Jan, S.A., Habib, N., Shinwari, Z.K. et al. The anti-diabetic activities of natural sweetener plant Stevia: an updated review. SN Appl. Sci. 3, 517 (2021). https://doi.org/10.1007/s42452-021-04519-2

Download citation

Keywords

  • Anti-diabetic
  • Animal model
  • Diabetes
  • Stevia
  • Oxidative stress