Stevia (family Asteraceae) is a perennial herb native to northern Paraguay. It was discovered by Moises Santiago Bertoni in 1877. Its leaves have traditionally been used by South American Guarani Indians due to their sweet taste and effectiveness in treating diabetes. Leaves of Stevia produce tetracyclic diterpene Steviol Glycosides (SGs), which are 200–300 times sweeter than table sugar [1]. Steviol glycosides, due to their complex structure, are not metabolised in the human body and are thus non-caloric [2]. Other bioactive compounds found in leaves include terpenoids (amyrin, limonene, kaurenoic acid, carvacrol), phenols (catechin, apigenin, chlorogenic acid, quercetin, trans-ferulic acid, cinnamic acid, leteolin-7-O-rutinoside), carbohydrates (L-arabinose, D-mannose, D-xylose, L-rhamnose), lipids (palmitic acid, stearic acid, linoleic acid), protein (serine), vitamins (ascorbic acid, niacin, riboflavin, thiamine) and minerals (calcium, magnesium, manganese, sodium, selenium, cobalt, phosphorus, zinc and potassium) ^[3][4][5][3,4,5]. Stevia extracts have hypotensive, hypoglycaemic, anti-inflammatory, and antimicrobial properties [6]. Studies have demonstrated that Stevia leaf extracts are hypoglycaemic [7], antimicrobial [8], antioxidant [9], antiviral [10], and anti-inflammatory [11]. With increasing rates of diabetes and obesity globally and the risks associated with artificial sweeteners, people are turning to natural sweeteners. As a result, Stevia-based sweeteners and medications are now available on the market and are in high demand. 

This articlentry provides information about the various applications of SGs in brief, however detailed information on other aspects of SGs including their biosynthesis and elicitation through biotechnological interventions has been provided in the review 10.3390/agriculture13020475.

Stevia is well known for its antidiabetic potential. Several reports have demonstrated the antihyperglycaemic effects of Stevia leaf extracts (aqueous, ether, ethanolic, and methanolic), purified steviol, stevioside, and rebaudioside A, in in vitro and in vivo models including human subjects ^{[12][13][14][15][16][17][18][19][20]}[29,30,31,32,33,34,35,36,37]. Further, steviol glucuronide, isolated from human urine, showed dose and glucose-dependent stimulation of insulin secretion on mouse islets ^[18][35]. A number of studies have been carried out to understand the underlying mechanism of SG antidiabetic activity, and the following modes of action have been proposed: (i) enhancement of insulin secretion and sensitivity ^{[12][13][14][19][21][22]}[29,30,31,36,38,39], (ii) glucose transport modulation ^[23][40] (iii) inhibition of glucagon secretion ^[12][21][29,38], (iv) upregulation of gene expression (PPAR-γ, GLUT4, GLUT 2, Gcgr) ^{[14][15][16][18]}[31,32,33,35]. In a study proposed by Chen, Jeppesen, Nordentoft and Hermansen ^[14][31] and Bugliani, Tavarini, Grano, Tondi, Lacerenza, Giusti, Ronci, Maidecchi, Marchetti and Tesi ^[20][37], SGs protected mouse pancreatic beta cells from lipotoxicity and from the amelioration of glyburide-induced desensitization.

Stevioside, rebaudioside A, and steviol can potentially aid in the treatment of type 2 diabetes by increasing insulin production, lowering postprandial blood glucose, and protecting beta cells from damage.

Many studies have revealed the effectiveness of stevioside in combating hypertension. Stevioside has been reported to reduce blood pressure (BP) in animals (rats and dogs) and humans ^{[24][25][26][27][28][29]}[41,42,43,44,45,46]. When stevioside (95% purity) was administered intravenously to hypertensive rats, a marked reduction in BP was observed. Stevioside had a dose-dependent effect, with the maximum hypotensive activity at 200 mg/kg stevioside content ^[24][41]. Early reports have indicated that the hypotensive activity of stevioside is through a calcium antagonist mechanism (like verapamil) ^[30][47] and that its effect is prostaglandin activity-dependent ^[31][48], while other studies have shown the vasorelaxation activity of stevioside ^[24][32][41,49]. Further, studies on human patients have shown discrepancies in the effectiveness of stevioside ^[25][26][27][42,43,44]. Oral intake of capsules (500 mg stevioside) for two years showed a decrease in both systolic and diastolic blood pressure in mildly hypertensive patients as compared to placebo ^[26][43]. Other studies have reported that stevioside has no effect or a lower effect than other hypotensive drugs in human subjects ^[25][27][42,44]. GlucoMedix^®, a suspension prepared from 15% volume/volume (v/v) of Uncaria bark extract and 11.67% weight/volume (w/v) of Stevia leaf extract powder (8.18% w/v SGs content), has been demonstrated to be safe and effective against hyperglycaemia, hyperlipidemia, and hypertension in rats ^[29][46]. Further, the safety and tolerability of stevioside allow it to be used as an alternative or supplementary therapy for hypertension ^[25][27][42,44].

Many studies have been done to understand the activity and mechanisms mediating the anticancerous effects of SGs in both in vivo and in vitro models. Various SGs and their derivatives, like steviol, stevioside, rebaudioside A, steviolbioside, and isosteviol, have been explored to study their effect on cancer cell lines ^{[33][34][35][36][37]}[50,51,52,53,54]. SGs are effective against cell lines and models of leukaemia, gastrointestinal cancer, lung cancer, cervical cancer, breast cancer, and prostate cancer ^{[33][34][35][36][38]}[50,51,52,53,55]. Ref. ^[39][56] investigated the effects of Stevia extracts in a variety of solvents, including chloroform, acetone, water, ethanol, petroleum ether, and methanol, and assessed their potential cytotoxicity towards MCF-7 cell lines. All the extracts were effective, but petroleum ether produced the best results. In another in vitro study, Stevia leaf extracts in ethyl acetate and acetone exhibited more cytotoxicity on human laryngeal epithelioma cells in vitro ^[40][57]. Mechanistically, Stevia and its derivatives increase cytotoxicity, decrease cell viability, inhibit cell proliferation, arrest cells in the G1/G2 phase, and induce reactive oxygen-mediated apoptosis in different cell lines ^{[33][34][35][36][38]}[50,51,52,53,55].To sum up, SGs are ideal candidates for cancer therapy or prevention since they exhibit anticancer activity and are less toxic to non-cancerous cells ^[41][58].

Stevia extracts have been traditionally used in treating bacterial and fungal infections ^[32][49]. The antimicrobial activity of leaf extracts (aqueous, ethanol, ethyl acetate, acetone, methanol, chloroform, hexane, and acetone) has been investigated in several studies ^{[3][40][42][43][44][45]}[3,57,59,60,61,62]. Bibi, Sarwar, Sabir, Nisa and Khan ^[42][59] evaluated the antimicrobial activity of Stevia leaf extracts (water and ethanol) against microorganisms including Aspergillus flavus (fungi), Staphylococcus aureus, Lactobacillus acidophilus (gram-positive bacteria), Salmonella typhi, and Escherichia coli (gram-negative bacteria). Ethanolic extract showed better antibacterial activity, while no antifungal activity was detected. In another study, antibacterial, antifungal, antiyeast, and antitumour activities were detected in leaf extracts (ethyl acetate, acetone, chloroform, and water) of Stevia ^[40][57]. These extracts can also be used against tooth decaying bacteria because they effectively inhibit the growth of cariogenic bacteria (16 strains of Streptococcus and Lactobacillus) ^[43][60].

Many sweeteners are available on the market, like aspartame, saccharin, and cyclamate ^[46][63]. But these sweeteners produce toxic substances inside the body that are often associated with many health risks ^[47][48][64,65]. Stevia has emerged as an alternative sweetener as it is reported to be safe for consumption ^[47][49][64,66]. Stevioside and rebaudioside A are the main sweetening substances in Stevia and account for 90% w/w of SGs in leaves ^[50][67]. Additionally, SGs are heat resistant, pH stable, and non-fermentative, with high solubility and stability in aqueous solutions [5].

Therefore, Stevia has become an indispensable part of food products and dietary supplements such as beverages, dairy products, bakery products, medicines, and many more ^{[3][40][47][50][51][52][53]}[3,57,64,67,68,69,70]. A high-purity rebaudioside A sweetener, Rebiana, has been jointly commercialised by Cargill, Incorporation and The Coca-Cola Company; it has been successfully used in the preparation of food, beverages, confectionaries, nutraceuticals, and pharmaceuticals ^[54][71]. Some of the Stevia-based beverages with brand names such as Sprite Green, Zevia, Virgil Diet Soda, Virgil Zero, Virgil Coca, and Thomas Kemper Natural Diet Soda are also available on the market ^[55][72].

3. Toxicological studies

The safety of steviol glycosides for human consumption has been controversial assteviol glycosides have been associated with various acute, subacute, reproductive, andgenotoxicities ^[56][73]. The contradictory reviews on the safety of SG consumption publishedby Geuns ^[57][74] and Huxtable ^[58] [75] led to clinical studies on the risk assessment of these naturalsweeteners, which confirmed their non-genotoxic and non-carcinogenic nature ^[59][60][69,76].Studies conducted in the early 1900s demonstrated that SGs pose no reproductive ordevelopmental hazards to animal subjects ^[61][62][77,78]. In the investigation of plasma profiles,metabolism, and excretion characteristics of intact and bile duct-cannulated rats,administered with radiolabelled rebaudioside A (reb-A), stevioside (stv), and steviol weredetermined. Many in vitro and in vivo studies have confirmed that SGs are neither digestednor absorbed by the upper gastrointestinal tract, thus making them safe for humanconsumption ^[63][1]. The United States Food and Drug Administration (USFDA) designatedStevia as generally recognised as safe (GRAS) in December 2008 ^[64][79], following whichthe Food Safety and Standards Authority of India (FSSAI) also lifted the ban on Stevia in2015. The European Food Safety Authority (EFSA) and the United States Food and DrugAdministration (USFDA) recommended high-purity leaf extracts of Stevia to be safe with anacceptable daily intake dose of 4 mg “steviol equivalents” per kilogram of body weight per day ^[65][66][80,81].

4. Conclusion

Based on the information provided above, it can be concluded that SGs are not only useful as zero calorie (natural) sweeteners, but can also be used as therapeutics for treatment of various metabolic disorders and chronic diseases. Moreover, its natural source of biosynthesis makes it even more useful for applications in both food and medicine without any worries for side-effects on the end users.