title: Identification of a small molecular insulin receptor agonist with potent antidiabetes activity.
abstract: Insulin replacement therapy is a widely adopted treatment for all patients with type 1 diabetes and some with type 2 diabetes. However, injection of insulin has suffered from problems such as tissue irritation, abscesses, discomfort, and inconvenience. The use of orally bioactive insulin mimetics thus represents an ideal treatment alternative. Here we show that a chaetochromin derivative (4548-G05) acts as a new nonpeptidyl insulin mimetic. 4548-G05 selectively activates an insulin receptor (IR) but not insulin-like growth factor receptor-I or other receptor tyrosine kinases. Through binding to the extracellular domain of the IR, 4548-G05 induces activation of the receptor and initiates the downstream Akt and extracellular signal-related kinase pathways to trigger glucose uptake in C2C12 myotubes. Moreover, it displays a potent blood glucose-lowering effect when administrated orally in normal, type 1 diabetic, and type 2 diabetic mice models. Therefore, 4548-G05 may represent a novel pharmacological agent for antidiabetes drug development.
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA.
authors.forename: Guifen
authors.initials: G
authors.lastname: Qiang
authors.forename: Shenghui
authors.initials: S
authors.lastname: Xue
authors.forename: Jenny J
authors.initials: JJ
authors.lastname: Yang
authors.forename: Guanhua
authors.initials: G
authors.lastname: Du
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Pang
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Li
authors.forename: Devrishi
authors.initials: D
authors.lastname: Goswami
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
authors.forename: Eric A
authors.initials: EA
authors.lastname: Ortlund
authors.forename: Chi Bun
authors.initials: CB
authors.lastname: Chan
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D016466:CHO Cells; D003412:Cricetulus; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009285:Naphthoquinones / Q000627:therapeutic use*; D011972:Receptor, Insulin / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C588315:(9,9'-Bi-4H-naphtho(2,3-b)pyran)-4,4'-dione,2,2',3,3'-tetrahydro-5,5',6,6',8,8'-hexahydroxy-2,2',3,3'-tetramethyl; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D009285:Naphthoquinones; D011972:Receptor, Insulin