Safety evaluation of certain food additives - ipcs inchem

198 STEVIOL GLYCOSIDES (addendum)
of animals that consumed a high-fructose diet but no stevioside. Streptozotocininduced
diabetic rats were used to investigate the response to exogenous insulin.
These rats were given an intraperitoneal injection of long-acting human insulin (1
International Unit [IU]/kg bw) once a day for 3 days to normalize insulin sensitivity.
Rats were then divided into two groups, with one group receiving three daily doses
of 5 mg stevioside/kg bw by gavage for 10 days and the other group receiving the
same volume and number of doses of vehicle. After dosing, rats received an
intravenous insulin injection of short-acting human insulin, and blood samples were
taken at regular intervals to determine the change in plasma glucose. A positive
control used doses of metformin. Short-acting human insulin together with a dose
of 5 mg stevioside/kg bw caused 40.3% difference in plasma glucose–lowering
activity at an insulin dose of 1 IU/kg bw and 52.4% at a 2.5 IU/kg bw dose of insulin.
The authors concluded that stevioside has a significant effect on insulin resistance
and plasma glucose levels (Chang et al., 2005).
Diabetic male Zucker rats were randomized into four groups, 12 animals per
group, and fed the following test diets for 10 weeks: (A) standard carbohydrate-rich
laboratory chow, (B) chow plus stevioside (30 mg/kg bw per day, 91% stevioside,
4% rebaudioside A and 5% other glycosides; 11.2 mg/kg bw per day expressed as
steviol), (C) 50% soya + 50% chow (adjusted for vitamins and minerals) and (D)
50% soya + 50% chow + 30 mg stevioside/kg bw per day. Plasma glucose, blood
pressure, weight and food intake were measured weekly. At week 10, an intraarterial
glucose tolerance test was performed (2 g glucose/kg bw), with blood
samples taken 15 min and immediately before and 2, 5, 10, 15, 20, 30, 45, 60, 90,
120, 180 and 240 min after glucose infusion. Blood glucose, insulin and glucagon,
triglycerides, free fatty acids and total cholesterol were also measured. In group B,
blood glucose showed a 19% reduction compared with group A; in group D, a 12%
reduction was observed compared with group C. No effects were observed on
insulin or glucagon responses. After 2 weeks, a reduction in systolic blood pressure
was observed in the two stevioside-treated groups. No adverse effects were noted
(Dyrskog et al., 2005a).
Stevioside (99% purity) was administered to diabetic Wistar rats (numbers
not specified) at doses of 0, 0.5, 1 and 5 mg/kg bw per day by gavage for 2 weeks
along with a high-fructose diet. Blood insulin and glucose levels were measured
following the treatment. The animals in the test groups receiving stevioside were
found to have lower blood glucose and insulin levels compared with their diabetic
and control counterparts in the control groups. This effect was statistically significant
and dose dependent (Chen et al., 2005).
Rebaudioside A (97.8% purity) administered in the diet at a dose of 25 mg/kg
bw per day to male GK rats for 8 weeks did not cause any significant changes in
glucose tolerance or glycaemic control when compared with control animals
(Dyrskog et al., 2005b).
Isosteviol (purity 99.4%) was administered to Zucker diabetic rats at single
doses of 0, 1, 5 and 10 mg/kg bw and to normal Wistar rats at single doses of 0 and
10 mg/kg bw. Blood samples were taken at a number of time points after
administration, and plasma insulin and glucose levels were measured. In diabetic