Topiramate is an insulin-sensitizing compound in vivo with direct effects on adipocytes in female ZDF rats

1 Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego; and the Whittier Diabetes Institute, La Jolla, California; and 2 Johnson & Johnson Pharmaceutical Research & Development, Raritan, New Jersey Submitted 14 September 2004 ; accepted in final form 9 November 2004 We have studied the in vivo and in vitro effects of Topiramate (TPM) in female Zucker diabetic fatty (ZDF) rats. After weight matching, drug treatment had a marked effect to lower fasting glucose levels of relatively normoglycemic animals as well as during an oral glucose tolerance test. The glucose clamp studies revealed a 30% increased glucose disposal, increased hepatic glucose output (HGO) suppression from 30 to 60%, and an increased free fatty acid suppression from 40 to 75%. Therefore, TPM treatment led to enhanced insulin sensitivity at the level of tissue glucose disposal (increased ISGDR), liver (increased inhibition of HGO), and adipose tissue (enhanced suppression of lipolysis). When soleus muscle strips of control or TPM-treated ZDF rats were studied ex vivo, insulin-stimulated glucose transport was not enhanced in the drug-treated animals. In contrast, when isolated adipocytes were studied ex vivo, a marked increase (+55%) in insulin-stimulated glucose transport was observed. In vitro treatment of muscle strips and rat adipocytes showed no effect on glucose transport in muscle with a 40% increase in insulin-stimulated adipocyte glucose transport. In conclusion, 1 ) TPM treatment leads to a decrease in plasma glucose and increased in vivo insulin sensitivity; 2 ) insulin sensitization was observed in adipocytes, but not muscle, when tissues were studied ex vivo or in vitro; and 3 ) TPM directly enhances insulin action in insulin-resistant adipose cells in vitro. Thus the in vivo effects of TPM treatment appear to be exerted through adipose tissue. insulin sensitization; skeletal muscle; adipose tissue; Zucker diabetic fatty rat Address for reprint requests and other correspondence: J. Wilkes, Dept. of Medicine (0673), UCSD, 9500 Gilman Dr., La Jolla, CA 92093. (E-mail: wilkesjason{at}hotmail.com )