Identification of a Molecular Activator for Insulin Receptor with Potent Anti-diabetic Effects

• Type of Material: Article
• Authors: Kunyan He, Emory University; Chi Bun Chan, Emory University; Xia Liu, Emory University; Yonghui Jia, Harvard Medical School and Children's Hospital; Hongbo R. Luo, Harvard Medical School and Children's Hospital; Stefan A. France, Georgia Institute of Technology; Yang Liu, Georgia State University; W. David Wilson, Georgia State University; Keqiang Ye, Emory University
• Language: English
• Date: 2011-10-28
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1074%2Fjbc.M111.247387
• Title of Journal or Parent Work: Journal of Biological Chemistry
• Volume: 286
• Issue: 43
• Start Page: 37379
• End Page: 37388
• Grant/Funding Information: This work was supported, in whole or in part, by National Institutes of Health Grant CA127119 from NCI (to K. Y.).
• Keywords: Insulin Resistance; Signal Transduction; Insulin; Receptors; Diabetes
• Research Categories: Health Sciences, Pathology

Abstract

Insulin exerts its actions through the insulin receptor (IR) and plays an essential role in diabetes. The inconvenient daily injection and undesirable side-effects associated with insulin injection demand novel drugs for the diseases. To search for bioactive insulin mimetics, we developed an in vitro screening assay using phospho-IR ELISA. After screening the small molecule chemical libraries, we have obtained a compound (5,8-diacetyloxy-2,3-dichloro-1,4-naphthoquinone) that provokes IR activation by directly binding to the receptor kinase domain to trigger its kinase activity at micromolar concentrations. This compound selectively activates IR but not other receptors and sensitizes insulin's action. Moreover, it elevates glucose uptake in adipocytes and has oral hypoglycemic effect in wild-type C57BL/6J mice and db/db and ob/ob mice without demonstrable toxicity. Hence, this promising compound mimics the biological functions of insulin and is useful for further drug development for diabetes treatment.