Effects of Stevioside on Glucose Transport Activity in Insulin-Sensitive and Insulin-Resistant Rat Skeletal Muscle Narissara Lailerd, Vitoon Saengsirisuwan, Julie A. Sloniger, Chaivat Toskulkao, and Erik J. Henriksen Stevioside (SVS), a natural sweetener extracted from Stevia rebaudiana, has been used as an antihyperglycemic agent. However, little is known regarding its potential action on skeletal muscle, the major site of glucose disposal. Therefore, the purpose of the present study was to determine the effect of SVS treatment on skeletal muscle glucose transport activity in both insulin-sensitive lean (Fa/-) and insulin-resistant obese (fa/fa) Zucker rats. SVS was administered (500 mg/kg body weight by gavage) 2 hours before an oral glucose tolerance test (OGTT). Whereas the glucose incremental area under the curve (IAUC glucose ) was not affected by SVS in lean Zucker rats, the insulin incremental area under the curve (IAUC insulin ) and the glucose-insulin index (product of glucose and insulin IAUCs and inversely related to whole-body insulin sensitivity) were decreased (P< .05) by 42% and 45%, respectively. Interestingly, in the obese Zucker rat, SVS also reduced the IAUC insulin by 44%, and significantly decreased the IAUC glucose (30%) and the glucose-insulin index (57%). Muscle glucose transport was assessed following in vitro SVS treatment. In lean Zucker rats, basal glucose transport in type I soleus and type IIb epitrochlearis muscles was not altered by 0.01 to 0.1 mmol/L SVS. In contrast, 0.1 mmol/L SVS enhanced insulin-stimulated (2 mU/mL) glucose transport in both epitrochlearis (15%) and soleus (48%). At 0.5 mmol/L or higher, the SVS effect was reversed. Similarly, basal glucose transport in soleus and epitrochlearis muscles in obese Zucker rats was not changed by lower doses of SVS (0.01 to 0.1 mmol/L). However, these lower doses of SVS significantly increased insulin-stimulated glucose transport in both obese epitrochlearis and soleus (15% to 20%). In conclusion, acute oral SVS increased whole-body insulin sensitivity, and low concentrations of SVS (0.01 to 0.1 mmol/L) modestly improved in vitro insulin action on skeletal muscle glucose transport in both lean and obese Zucker rats. These results indicate that one potential site of action of SVS is the skeletal muscle glucose transport system. © 2004 Elsevier Inc. All rights reserved. D IABETES MELLITUS is a group of metabolic diseases characterized by abnormally elevated levels of glucose in blood and urine. More than 90% of the cases of diabetes worldwide are classified as type 2 diabetes. The etiology of type 2 diabetes is complex and is associated with multiple defects, including impaired insulin secretion from pancreatic  cells and insulin resistance in peripheral tissues, primarily skeletal muscle. 1 Type 2 diabetes is a progressive disease, such that the initial development of hyperinsulinemia and skeletal muscle insulin resistance ultimately leads to a relative hypoin- sulinemia and hyperglycemia. In order to regulate plasma glu- cose levels as close to normal as possible, dietary restrictions, exercise, and blood glucose–lowering agents are required. However, the present pharmacological approaches for the man- agement of type 2 diabetes are far from ideal. Therefore, newer and safer agents for treatment of type 2 diabetes are needed. Currently, there is an enormous increase in the use of herbal and other alternative medicines for the treatment of diabetes. Stevia rebaudiana is a shrub native to Brazil and Paraguay. The leaves from this plant contain a large amount of the glycoside stevioside (SVS), a noncaloric sweetener 300 times sweeter than sucrose. SVS is formed by 3 molecules of glucose and 1 molecule of steviol, a diterpenic carboxylic alcohol. Extracts from Stevia rebaudiana have been used for many years in South America in the treatment of diabetes. However, little is known regarding its action, especially in peripheral insulin-sensitive tissues, such as skeletal muscle. Several stud- ies have reported that ingestion of extracts of Stevia rebaudiana causes a slight suppression of plasma glucose levels and a significantly increased glucose tolerance in normal adult hu- mans. 2,3 Recently, Jeppesen et al 4 reported that SVS and steviol stimulate insulin secretion via a direct action on isolated  cells of rats. The insulinotropic action of SVS and steviol are independent of cyclic adenosine monophosphate and adenosine triphosphate-sensitive K + channel activity. This action is de- pendent on the prevailing glucose concentrations and dimin- ishes when blood glucose levels decrease toward normal. 4 It is clear that additional potential mechanisms for the antihyper- glycemic action of SVS and steviol need to be investigated. The obese Zucker (fa/fa) rat is a well-defined animal model of glucose intolerance, dyslipidemia, and central obesity, and exhibits severe skeletal muscle insulin resistance attributable to defects in insulin signaling 5 and GLUT-4 glucose transporter protein translocation. 6,7 In order to evaluate the effect of SVS on whole-body and skeletal muscle insulin action in conditions of normal insulin sensitivity and insulin resistance, we exam- ined the effect of in vivo and in vitro SVS treatment on glucose tolerance and skeletal muscle glucose transport activity in both insulin-sensitive lean Zucker rats and insulin-resistant obese Zucker rats. From the Muscle Metabolism Laboratory, Department of Physiol- ogy, University of Arizona College of Medicine, Tucson, AZ; and the Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand. Submitted May 5, 2003; accepted July 22, 2003. Supported by a grant from the Ministry of University Affairs of Thailand to N.L., the Faculty of Graduate Studies, Mahidol University, and by a Grant-in-Aid from the Pacific Mountain Affiliate of the American Heart Association to E.J.H. Address reprint requests to Erik J. Henriksen, PhD, Department of Physiology, Ina E. Gittings Building #93, University of Arizona, Tuc- son, AZ 85721-0093. © 2004 Elsevier Inc. All rights reserved. 0026-0495/04/5301-0039$30.00/0 doi:10.1016/j.metabol.2003.07.014 101 Metabolism, Vol 53, No 1 (January), 2004: pp 101-107