Selective Glycogen Synthase Kinase 3 Inhibitors Potentiate Insulin Activation of Glucose Transport and Utilization In Vitro and In Vivo

Selective Glycogen Synthase Kinase 3 Inhibitors Potentiate Insulin Activation of Glucose Transport and Utilization In Vitro and In Vivo David B. Ring 1 , Kirk W. Johnson 1 , Erik J. Henriksen 2 , John M. Nuss 1 , Dane Goff 1 , Tyson R. Kinnick 2 , Sylvia T. Ma 1 , John W. Reeder 1 , Isa Samuels 1 , Trina Slabiak 1 , Allan S. Wagman 1 , Mary-Ellen Wernette Hammond 1 and Stephen D. Harrison 1 1 From the Chiron Corporation, Emeryville, California 2 Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona Abstract Insulin resistance plays a central role in the development of type 2 diabetes, but the precise defects in insulin action remain to be elucidated. Glycogen synthase kinase 3 (GSK-3) can negatively regulate several aspects of insulin signaling, and elevated levels of GSK-3 have been reported in skeletal muscle from diabetic rodents and humans. A limited amount of information is available regarding the utility of highly selective inhibitors of GSK-3 for the modification of insulin action under conditions of insulin resistance. In the present investigation, we describe novel substituted aminopyrimidine derivatives that inhibit human GSK-3 potently (K i < 10 nmol/l) with at least 500-fold selectivity against 20 other protein kinases. These low molecular weight compounds activated glycogen synthase at ∼100 nmol/l in cultured CHO cells transfected with the insulin receptor and in primary hepatocytes isolated from Sprague-Dawley rats, and at 500 nmol/l in isolated type 1 skeletal muscle of both lean Zucker and ZDF rats. It is interesting that these GSK-3 inhibitors enhanced insulin-stimulated glucose transport in type 1 skeletal muscle from the insulin-resistant ZDF rats but not from insulin-sensitive lean Zucker rats. Single oral or subcutaneous doses of the inhibitors (30–48 mg/kg) rapidly lowered blood glucose levels and improved glucose disposal after oral or intravenous glucose challenges in ZDF rats and db / db mice, without causing hypoglycemia or markedly elevating insulin. Collectively, our results suggest that these selective GSK-3 inhibitors may be useful as acute-acting therapeutics for the treatment of the insulin resistance of type 2 diabetes. Footnotes Address correspondence and reprint requests to Dr. Erik J. Henriksen, Department of Physiology, University of Arizona College of Medicine, P.O. Box 210093, Tucson, AZ 85721-0093. E-mail: ejhenrik{at}u.arizona.edu . Received for publication 30 April 2002 and accepted i