Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo

David B. Ring, Kirk W. Johnson, Erik J. Henriksen, John M. Nuss, Dane Goff, Tyson R. Kinnick, Sylvia T. Ma, John W. Reeder, Isa Samuels, Trina Slabiak, Allan S. Wagman, Mary Ellen Wernette Hammond, Stephen D. Harrison

Research output: Contribution to journalArticle

322 Scopus citations

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 (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.

Original languageEnglish (US)
Pages (from-to)588-595
Number of pages8
JournalDiabetes
Volume52
Issue number3
DOIs
StatePublished - Mar 1 2003

Keywords

  • GS, glycogen synthase
  • GSK-3, glycogen synthase kinase 3
  • GTT, glucose tolerance test
  • IRS-1, insulin receptor substrate 1
  • IpGTT, intraperitoneal glucose tolerance test
  • OGTT, oral glucose tolerance test
  • PI, phosphatidylinositol
  • PKC, protein kinase C

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Ring, D. B., Johnson, K. W., Henriksen, E. J., Nuss, J. M., Goff, D., Kinnick, T. R., Ma, S. T., Reeder, J. W., Samuels, I., Slabiak, T., Wagman, A. S., Hammond, M. E. W., & Harrison, S. D. (2003). Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes, 52(3), 588-595. https://doi.org/10.2337/diabetes.52.3.588