Potential use of botanicals in diabetes: A review of stevia By Oluwole A. Williams, B.Sc., Pharm.D., R.PH.

pharmacy

Medicinal plants and drugs of biological origin have a place in the treatment of chronic diseases. Drugs of biological origin, such as penicillin, morphine and senna, have been used consistently and are still in use globally in medical and pharmaceutical practices. A significant number of antimicrobial agents, such as vancomycin, griseofulvin, streptomycin, erythromycin, and gentamycin, were originally obtained from natural origin.

Stevia is a medicinal plant belonging to the botanical family Asteraceae. The leaf extracts of Stevia rebaudiana (Bertoni) contain eight potent diterpene glycosides: Stevioside, Rebaudosides A to E, Steviolbioside and Dulcoside A, which have been studied elaborately for use as sweeteners.

Three of the stevia glycosides listed above (Stevioside, Rebaudoside A, and Rebaudoside D) are well studied and recognised to be 250–300 times sweeter than sucrose. Animal studies in mammalian species, using rats, dogs and mice by researchers, have examined the pharmacological and toxicological properties of stevia glycosides. Ulbricht C, Isaac R et al, in an evidence-based systematic review, courtesy of the Natural Standard Research Collaboration, assessed the effects of stevia on two indications – hypertension and hyperglycaemia – from two long-term studies. The result showed stevia possesses hypoglycaemic and blood pressure lowering effects in mammals.

Shibata et al, have postulated that the anti-diabetic effects of stevioside may be from a suppression of glucagon secretion from the alpha cells of the pancreas. Wheeler et al (2008), have conducted human studies showing a similar but different metabolic and elimination pathways for Rebaudoside A and Stevioside. The insulin-like effects of stevia extracts in stimulating glucose uptake were demonstrated by Stone et al, using two cell types, HL-60 human leukaemia and SH-SY5Y human neuroblastoma cells. Stevia extract was found to enhance glucose uptake in both cellular lines.

In the United States, purified forms of Rebaudoside A were granted GRAS (Generally Recognised As Safe) status by the FDA and are available under low-calorie sweetener brand names as natural sugar substitutes for people living with diabetes, and for obese patients on strict diets/exercise regimen. They are also available for patients diagnosed with pre-diabetes and or metabolic syndrome.

Natural stevia leaf extracts are obtainable as diet supplements and may not be added to commercial beverages as a food additive, though current research is evaluating its potency in diabetes, obesity and hypertension. In regard to diabetes, some studies identified stevia’s trophic effects on pancreatic beta cells, insulin secretion and insulin sensitivity in rats.

Stevia is not recommended in pregnant patients, and its effect is not yet evaluated in juveniles. It is inapplicable in Type 1 diabetes since its potential effects appear connected to functional pancreatic cells. In one case report of adverse reactions, four patients who were given 500mg of stevia powder experienced symptoms of abdominal fullness, nausea, asthenia, and myalgia; but their symptoms disappeared after one week of treatment.

In vitro studies shows marked anti-inflammatory and antibacterial properties of stevia glycosides; though there have been warnings of weak mutagenic activity in laboratory animals given high doses. According to The JECFA (Joint FAO/WHO Expert Committee on Food Additives), brand name products labelled as a stevia sweetener must contain at least 95 per cent of the stevia glycoside Rebaudoside A, and the suggested acceptable daily intake(ADI) per JECFA is 0–2mg/kgbw/day of a steviol content that is equivalent to 0-6mg/kgbw/day of Rebaudoside A.

Stevia glycosides are metabolised initially in the gut to steviol (the aglycone moiety) and are excreted in the urine as steviol glucuronide. Stevia was shown to have additive antihypertensive effects with verapamil, and blood sugar lowering effects with antidiabetic drugs; therefore caution must be exercised in its use and recommendation in patients taking prescription drugs for chronic ailments.

Section 201(ff){1} of the Federal Food, Drug & Cosmetic Act permits the sale of stevia leaf extracts in the US as a diet supplement only, and not for the treatment of any manner of disease. Stevia shows promise as a potential source of important phytochemical ingredients that may serve as precursors of new drugs for diabetes in just the same way as a derivative of guanidine extracts from Galega officinalis (Goat’s rue or French lilac), Galegine, became the precursor of metformin.

Oluwole Williams wrote from Glenside, Pennsylvania, USA

REFERENCES

• Ulbritch, C; Isaac, R; Milkin, T; Poole, EA; Rusie, E. et al.(April 2010). “An evidenced-based systematic review of stevia by the Natural Standard Research Collaboration”. Cardiovascular Hematol Agents Med Chem 8(2): 113 – 127. PMID 20370653.
• Joint FAO/WHO Expert Committee on food additives, sixty-ninth Meeting. World Health Organisation 4 July 2008.
• FDA GRAS notification database; Stevia search in FDA GRAS Database.
• Misra, H; Soni M; Silawat, N; Mehta, D; Mehta, B.K; “Antidiabetic activity of medium-polar extract from the leaves of stevia rebaudiana Bet(Bertoni) on alloxan-induced diabetic rats” Pharm Bioallied Sci. 3(2): 242 – 8.
• “Diabetic Supplement Health and Education Act of 1994”. FDA.gov. 2011.
• Koyama, E.et al. “In vitro metabolism of the glycosidic sweeteners in stevia mixture and enzymatically modified stevia in human intestinal microflora. “Food and Chemical Toxicology 41”.3(2003) 359 – 374.
• Kujur, R.S; Singh, V; Ram, M; Yadava, N.H; Singh, K.K; Kumari, S; and Roy, B.K. Antidiabetic activity and phytochemical screening of crude extract of stevia rebaudiana in alloxan-induced diabetic rats. Pharmacognosy Res. 2010 Jul – Aug; 2(4): 258 – 263 PMC3141138.
• Shibata H, Sawa Y, Oka T, Sonoke S, Kim, K.K, Yoshioka M. Steviol and steviol glycosides: glucosyl tranferase activities in stevia rebadiana Bertoni – purification and partial characterization. Arch Biochem Biophys. 1995; 321(2): 390 – 396.
• Chen TH, Chen SC, Chan P et al. Mechanism of the hypoglycemic effect of stevioside, a glycoside of stevia rebaudiana. Planta Med.2005; 71(2): 108 – 113.
• Wheeler A, Bioleau AC, Winkler PC, Compton JC, Prakash I et al. Pharmacokinetics of rebaudoside A and stevioside after single dose in healthy men. Food Chem Toxicology, 2008:04.041.
• Gregersen S, Jeppensen PB, Holst JJ, Hermansen K. Antihyperglycemic effects of stevioside in type 2 diabetic subjects. Metabolism.2004; 53:73-6.
• Melis, M.S. et al. “Effect of calcium and verapamil on renal function of rats during treatment with stevioside” : J. Etnopharmacol. 1991; 33(3): 257-62.