Discovery of a Small Molecule Insulin Mimetic with Antidiabetic Activity in Mice
- 7 May 1999
- journal article
- other
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 284 (5416) , 974-977
- https://doi.org/10.1126/science.284.5416.974
Abstract
Insulin elicits a spectrum of biological responses by binding to its cell surface receptor. In a screen for small molecules that activate the human insulin receptor tyrosine kinase, a nonpeptidyl fungal metabolite (L-783,281) was identified that acted as an insulin mimetic in several biochemical and cellular assays. The compound was selective for insulin receptor versus insulin-like growth factor I (IGFI) receptor and other receptor tyrosine kinases. Oral administration of L-783,281 to two mouse models of diabetes resulted in significant lowering in blood glucose levels. These results demonstrate the feasibility of discovering novel insulin receptor activators that may lead to new therapies for diabetes.Keywords
This publication has 17 references indexed in Scilit:
- Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analogThe EMBO Journal, 1997
- Visualization of intermediate and transition-state structures in protein-tyrosine phosphatase catalysis.Proceedings of the National Academy of Sciences, 1996
- The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinaseCell, 1995
- Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects.Journal of Clinical Investigation, 1995
- Potentiation of insulin stimulation of phosphatidylinositol 3-kinase by thiazolidinedione-derived antidiabetic agents in Chinese hamster ovary cells expressing human insulin receptors and L6 myotubes.Journal of Biological Chemistry, 1994
- Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor.Proceedings of the National Academy of Sciences, 1993
- Divergent mechanisms for the insulin resistant and hyperresponsive glucose transport in adipose cells from fasted and refed rats. Alterations in both glucose transporter number and intrinsic activity.Journal of Clinical Investigation, 1988
- Expression of a functional human insulin receptor from a cloned cDNA in Chinese hamster ovary cells.Proceedings of the National Academy of Sciences, 1985
- The human insulin receptor cDNA: The structural basis for hormone-activated transmembrane signallingCell, 1985
- Human insulin receptor and its relationship to the tyrosine kinase family of oncogenesNature, 1985