title: Identification of a molecular activator for insulin receptor with potent anti-diabetic effects.
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.
authors: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors: Kunyan
authors: K
authors: He
authors: Chi-Bun
authors: CB
authors: Chan
authors: Xia
authors: X
authors: Liu
authors: Yonghui
authors: Y
authors: Jia
authors: Hongbo R
authors: HR
authors: Luo
authors: Stefan A
authors: SA
authors: France
authors: Yang
authors: Y
authors: Liu
authors: W David
authors: WD
authors: Wilson
authors: Keqiang
authors: K
authors: Ye
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000818:Animals; D040761:Biomimetic Materials / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D020536:Enzyme Activators / Q000494:pharmacology*; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin; D051379:Mice; D008820:Mice, Obese; D011972:Receptor, Insulin / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: D020536:Enzyme Activators; D007004:Hypoglycemic Agents; D007328:Insulin; D011972:Receptor, Insulin; D005947:Glucose