Steviol glycosides in purified stevia leaf extract sharing the same metabolic fate

Purkayastha, Sidd; Markosyan, A. A.; Prakash, Indra; Bhusari, Sachin; Pugh, George; Lynch, Barry; Roberts, Ashley

doi:10.1016/j.yrtph.2016.02.015

Cited by 48 publications

(42 citation statements)

References 31 publications

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“…In contrast, elimination of administered steviol glycosides in humans, is primarily in the urine as steviol glucuronide with very small amounts of the unchanged glycoside or steviol (Kraemer and Maurer, 1994;Simonetti et al, 2004;Geuns et al, 2006Geuns et al, , 2007Wheeler et al, 2008). Recent studies using human fecal homogenates have demonstrated that regardless of the type of sugar moieties or linkages present on the steviol backbone, these are hydrolyzed to the common metabolite steviol (Purkayastha et al, 2014(Purkayastha et al, , 2015(Purkayastha et al, , 2016.…”

Section: Introductionmentioning

confidence: 99%

“…Although steviol glycosides share a common metabolic fate in both rats and humans (Wingard et al, 1980;Hutapea et al, 1997;Gardana et al, 2003;Koyama et al, 2003a;Geuns et al, 2007;Roberts and Renwick, 2008;Wheeler et al, 2008;Nikiforov et al, 2013;Purkayastha et al, 2014Purkayastha et al, , 2015Purkayastha et al, , 2016, some differences in pharmacokinetics have been noted. As evaluated by JECFA at their sixty-ninth meeting (JECFA, 2009), studies comparing the pharmacokinetics of steviol and steviol glucuronide following oral administration of steviol glycosides demonstrated substantial differences in the concentration of circulating plasma steviol and steviol glucuronide between rats and humans (Roberts and Renwick, 2008;Wheeler et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Chemical-specific adjustment factors (inter-species toxicokinetics) to establish the ADI for steviol glycosides

Roberts

Lynch

Rogerson

et al. 2016

Regulatory Toxicology and Pharmacology

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Abbreviations: λz, terminal elimination constant; ADI, acceptable daily intake; AUC0-last, area under the curve from time zero until the last sampling time point; AE, adverse events; AUC, area under the plasma concentration-time curve; AUC-0.75-inf, AUC from time zero to infinity; AUClast, AUC to the last quantifiable observation; BLQ, below the limit of quantification; BMI, body mass index; bw, body weight; Cmax, concentration maximum; CSAF, chemical-specific adjustment factor; EE, efficacy evaluable population; EKG, electrocardiogram; HBsAg, hepatitis B surface antigen; IQR, interquartile range; IRB, Institutional Review Board; JECFA, Joint FAO/WHO Expert Committee on Food Additives; LC-MS/MS, liquid chromatography-tandem mass spectrometry; LLOQ, lower limit of quantification, LOQ, limit of quantification; NOAEL, noobserved-adverse-effect level; PP, per protocol population; SD, standard deviation; T1/2, half-life; Tmax, time to maximum concentration; WHO, World Health Organization * Corresponding author: Tel: +1-905-542-2900 E-mail address: ashley.roberts@intertek.com AbstractThe acceptable daily intake (ADI) of commercially available steviol glycosides is currently 4 mg/kg body weight (bw)/day, based on application of a 100-fold uncertainty factor to a noobserved-adverse-effect-level value from a chronic rat study. Within the 100-fold uncertainty factor is a 10-fold uncertainty factor to account for inter-species differences in toxicokinetics (4-fold) and toxicodynamics (2.5-fold). Single dose pharmacokinetics of stevioside were studied in rats (40 and 1,000 mg/kg bw) and in male human subjects (40 mg/kg bw) to generate a chemical-specific, inter-species toxicokinetic adjustment factor. Tmax values for steviol were at ~8 and ~20 hours after administration in rats and humans, respectively. Peak concentrations of steviol were similar in rats and humans, while steviol glucuronide concentrations were significantly higher in humans. Glucuronidation in rats was not saturated over the dose range 40-1,000 mg/kg bw. The AUC0-last for steviol was approximately 2.8-fold greater in humans compared to rats. Chemical-specific adjustment factors for extrapolating toxicokinetics from rat to human of 1 and 2.8 were established based on Cmax and AUC0-last data respectively. Because these factors are lower than the default value of 4.0, a higher ADI for steviol glycosides of between 6 to 16 mg/kg bw/d is justified.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chemical-specific adjustment factors (inter-species toxicokinetics) to establish the ADI for steviol glycosides

Roberts

Lynch

Rogerson

et al. 2016

Regulatory Toxicology and Pharmacology

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“…1,2 Highly purified steviol glycosides have been permitted for use as food sweetener in numerous countries and regions, including Japan, the European Union and the United States. To date, more than 40 steviol glycosides have been identified from stevia leaf extracts, of which stevioside and rebaudioside A are the most abundant.…”

Section: Introductionmentioning

confidence: 99%

“…1,2 Highly purified steviol glycosides have been permitted for use as food sweetener in numerous countries and regions, including Japan, the European Union and the United States. 2,14 As previously unanimously described, 1,14-16 enzymes and acid present in the upper gastrointestinal tract are not able to hydrolyse the glycosidic bonds in steviol glycosides. A multitude of preclinical and clinical studies have demonstrated their antihyperglycaemic effects, including lowering postprandial blood glucose, 3,4 enhancing insulin secretion [5][6][7][8][9][10][11] and improving insulin sensitivity.…”

Section: Introductionmentioning

confidence: 99%

“…To date, more than 40 steviol glycosides have been identified from stevia leaf extracts, of which stevioside and rebaudioside A are the most abundant. 1,2 Highly purified steviol glycosides have been permitted for use as food sweetener in numerous countries and regions, including Japan, the European Union and the United States. Besides the sweet property, steviol glycosides also possess potential therapeutic benefits.…”

Section: Introductionmentioning

confidence: 99%

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Steviol glucuronide, a metabolite of steviol glycosides, potently stimulates insulin secretion from isolated mouse islets: Studies in vitro

Rebsdorf

Anker

et al. 2019

Endocrino Diabet & Metabol

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Aims Steviol glycosides are the sweet components extracted from medicinal plant Stevia rebaudiana Bertoni, which have antihyperglycaemic effects. Steviol glucuronide (SVG) is the metabolite excreted in human urine after oral administration of steviol glycosides. We aimed to clarify whether SVG exerts direct insulin stimulation from pancreatic islets and to explore its mode of action. Materials and Methods Insulin secretion was measured after 60 minutes static incubation of isolated mouse islets with (a) 10−9‐10−5 mol/L SVG at 16.7 mmol/L glucose and (b) 10−7 mol/L SVG at 3.3‐16.7 mmol/L glucose. Islets were perifused with 3.3 or 16.7 mmol/L glucose in the presence or absence of 10−7 mol/L SVG. Gene transcription was measured after 72 hours incubation in the presence or absence of 10−7 mol/L SVG. Results SVG dose‐dependently increased insulin secretion from mouse islets with 10−7 mol/L exerting the maximum effect in the presence of 16.7 mmol/L glucose (P < .001). The insulinotropic effect of SVG was critically dependent on the prevailing glucose concentration, and SVG (10−7 mol/L) enhanced insulin secretion at or above 11.1 mmol/L glucose (P < .001) and showed no effect at lower glucose concentrations. During perifusion of islets, SVG (10−7 mol/L) had a long‐acting and apparently reversible insulinotropic effect in the presence of 16.7 mmol/L glucose (P < .05). Gene‐transcript levels of B2m and Gcgr were markedly altered. Conclusion This is the first report to demonstrate that SVG stimulates insulin secretion in a dose‐ and glucose‐dependent manner from isolated mouse islets of Langerhans. SVG may be the main active metabolite after oral intake of steviol glycosides.

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Tinkering with Stevia rebaudiana Genome to Improve Its Sweetening Property and Productivity

Mondal,

Kundu,

Bandyopadhyay

2023

Genetic Engineering of Crop Plants for Food and Health Security

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Steviol glycosides in purified stevia leaf extract sharing the same metabolic fate

Cited by 48 publications

References 31 publications

Chemical-specific adjustment factors (inter-species toxicokinetics) to establish the ADI for steviol glycosides

Chemical-specific adjustment factors (inter-species toxicokinetics) to establish the ADI for steviol glycosides

Steviol glucuronide, a metabolite of steviol glycosides, potently stimulates insulin secretion from isolated mouse islets: Studies in vitro

Tinkering with Stevia rebaudiana Genome to Improve Its Sweetening Property and Productivity

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