Selective Glycogen Synthase Kinase 3 Inhibitors Potentiate Insulin Activation of Glucose Transport and Utilization In Vitro and In Vivo
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 (Ki < 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.
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:.
Received for publication 30 April 2002 and accepted in revised form 20 November 2002.
D.B.R., S.T.M., J.W.R., T.S., A.S.W., and S.D.H. are employed by and own stock in Chiron, a corporation that is involved in the research and development of potential therapeutics for the treatment of diabetes. K.W.J., J.M.N., D.G., I.S., and M.-E.W.H. are former employees of and hold stock in Chiron. E.J.H. and T.R.K. have received research support from Chiron.
K.J.W.’s current affiliation is Genesoft Inc., South San Francisco, California. J.N.’s current affiliation is Exelixis, Inc., South San Francisco, California. D.G.’s current affiliation is Rigel, Inc., South San Francisco, California; I.S.’s current affiliation is Bayer Biotech, Berkeley, California.
GS, glycogen synthase; GSK-3, glycogen synthase kinase 3; GTT, glucose tolerance test; ipGTT, intraperitoneal glucose tolerance test; IRS-1, insulin receptor substrate 1; oGTT, oral glucose tolerance test; PI, phosphatidylinositol; PKC, protein kinase C; RTK, receptor tyrosine kinase.