0944-7113/02/09/01-009 $ 15.00/0  Introduction Extracts of leaves from the plant Stevia rebaudiana Bertoni (SrB), have been used for many years in tradi- tional medicine in South America in the treatment of diabetes (Soejarto et al., 1983; Mosettig et al., 1955; Kohda et al., 1976). Interestingly, Curi et al. (1986) showed that oral intake of extracts of SrB for 3 days slightly suppressed plasma glucose during an oral glu- cose tolerance test in healthy subjects. A 35% reduction in blood glucose has also been observed in diabetic subjects after an oral intake of extracts from SrB (Ovei- do et al. 1979). Various substances are present in the leaves of SrB e.g. the glycoside Stevioside (Bridel and Lavielle, 1931; Wood et al., 1955), which we recently have demonstrated exerts a direct insulinotropic action in isolated mouse islets and in the clonal rat beta cell line, INS-1 (Jeppesen et al., 1996; 2000). Type 2 dia- Phytomedicine 9: 9–14, 2002 © Urban & Fischer Verlag http://www.urbanfischer.de/journals/phytomed Phytomedicine Stevioside induces antihyperglycaemic, insulinotropic and glucagonostatic effects in vivo: studies in the diabetic Goto-Kakizaki (GK) rats P. B. Jeppesen, S. Gregersen, K.K. Alstrup and K. Hermansen Department of Endocrinology and Metabolism C, Aarhus University Hospital, Aarhus C, Denmark Summary Extracts of leaves from the plant Stevia rebaudiana Bertoni have been used in the traditional treat- ment of diabetes in Paraguay and Brazil. Recently, we demonstrated a direct insulinotropic effect in isolated mouse islets and the clonal beta cell line INS-1 of the glycoside stevioside that is present in large quantity in these leaves. Type 2 diabetes is a chronic metabolic disorder that results from defects in both insulin and glucagon secretion as well as insulin action. In the present study we wanted to unravel if stevioside in vivo exerts an antihyperglycaemic effect in a nonobese animal model of type 2 diabetes. An i.v. glucose tolerance test ( IVGT ) was carried out with and without stevioside in the type 2 diabetic Goto-Kakizaki (GK) rat, as well as in the normal Wistar rat. Ste- vioside (0.2 g/kg BW) and D-glucose (2.0 g/kg BW) were administered as i.v. bolus injections in anaesthetized rats. Stevioside significantly suppressed the glucose response to the IVGT in GK rats (incremental area under the curve (IAUC): 648 ± 50 (stevioside) vs 958 ± 85 mM ×120 min (control); P < 0.05) and concomitantly increased the insulin response (IAUC: 51116 ± 10967 (ste- vioside) vs 21548 ± 3101 μU × 120 min (control); P<0.05). Interestingly, the glucagon level was sup- pressed by stevioside during the IVGT, (total area under the curve (TAUC): 5720 ± 922 (stevioside) vs 8713 ± 901 pg/ml × 120 min (control); P<0.05). In the normal Wistar rat stevioside enhanced in- sulin levels above basal during the IVGT (IAUC: 79913 ± 3107 (stevioside) vs 17347 ± 2882 μU × 120 min (control); P < 0.001), however, without altering the blood glucose response (IAUC: 416 ± 43 (stevioside) vs 417 ± 47 mM × 120 min (control)) or the glucagon levels (TAUC: 5493 ± 527 (ste- vioside) vs 5033 ± 264 pg/ml × 120 min (control)). In conclusion, stevioside exerts antihypergly- caemic, insulinotropic, and glucagonostatic actions in the type 2 diabetic GK rat, and may have the potential of becoming a new antidiabetic drug for use in type 2 diabetes. Key words: Stevioside, insulin, glucose, glucagon, type 2 diabetes, Goto-Kakizaki rat, Wistar rat