title: Regulation of insulin signal transduction pathway by a small-molecule insulin receptor activator.
abstract: Insulin regulates cellular metabolism and growth through activation of insulin receptors (IRs). We recently identified a non-peptide small-molecule IR activator (compound 2), which induced human IR tyrosine kinase activity in Chinese-hamster ovary cells expressing human IR [Qureshi, Ding, Li, Szalkowski, Biazzo-Ashnault, Xie, Saperstein, Brady, Huskey, Shen et al. (2000) J. Biol. Chem. 275, 36590-36595]. Oral treatment with this compound resulted in correction of hyperglycaemia, hypertriacylglycerolaemia and hyperinsulinaemia in several rodent models of diabetes. In the present study, we have found that this compound increased tyrosine phosphorylation of the IR beta-subunit and IR substrate 1 in primary rat adipocytes as well as induced phosphorylation of Akt, the 70 kDa ribosomal protein S6 kinase and glycogen synthase-3 (deactivation) in Chinese-hamster ovary cells expressing human IR. Similar to insulin, compound 2 stimulated glucose uptake, glycogen synthesis and inhibited isoprenaline-stimulated lipolysis in adipocytes. A structurally related analogue (compound 3) was devoid of the above activities suggesting that the activity of compound 2 is specifically mediated by targeted IR activation. The effects of compound 2 on stimulation of glucose uptake, glycogen synthesis and inhibition of lipolysis were blocked by wortmannin, consistent with the involvement of a phosphoinositide 3-kinase-dependent pathway. In addition, compound 2, but not compound 3, exhibited additive or synergistic effects with sub-maximal concentrations of insulin in rat adipocytes. Thus the IR activator was capable of activating insulin-mediated signalling and metabolic pathways in primary adipocytes. These results demonstrate that IR activators have implications for the future development of new therapeutic approaches to Type I and Type II diabetes.
authors.affiliation: Department of Molecular Endocrinology, Merck Research Laboratories, PO Box 2000, 126 East Lincoln Avenue, Rahway, NJ 07065, U.S.A. victor_ding@merck.com
authors.forename: Victor D H
authors.initials: VD
authors.lastname: Ding
authors.forename: Sajjad A
authors.initials: SA
authors.lastname: Qureshi
authors.forename: Deborah
authors.initials: D
authors.lastname: Szalkowski
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Li
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Biazzo-Ashnault
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
authors.forename: Kun
authors.initials: K
authors.lastname: Liu
authors.forename: A Brian
authors.initials: AB
authors.lastname: Jones
authors.forename: David E
authors.initials: DE
authors.lastname: Moller
authors.forename: Bei B
authors.initials: BB
authors.lastname: Zhang
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D005990:Glycerol / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D004791:Enzyme Inhibitors; D007328:Insulin; D006006:Glycogen Synthase; D011972:Receptor, Insulin; D019893:Ribosomal Protein S6 Kinases; D005947:Glucose; D007545:Isoproterenol; D005990:Glycerol; D000077191:Wortmannin