title: The phosphatidylethanolamine derivative diDCP-LA-PE mimics intracellular insulin signaling.
abstract: Insulin facilitates glucose uptake into cells by translocating the glucose transporter GLUT4 towards the cell surface through a pathway along an insulin receptor (IR)/IR substrate 1 (IRS-1)/phosphatidylinositol 3 kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt axis. The newly synthesized phosphatidylethanolamine derivative 1,2-O-bis-[8-{2-(2-pentyl-cyclopropylmethyl)-cyclopropyl}-octanoyl]-sn-glycero-3-phosphatidylethanolamine (diDCP-LA-PE) has the potential to inhibit protein tyrosine phosphatase 1B (PTP1B) and to directly activate PKCζ, an atypical isozyme, and PKCε, a novel isozyme. PTP1B inhibition enhanced insulin signaling cascades downstream IR/IRS-1 by preventing tyrosine dephosphorylation. PKCζ and PKCε directly activated Akt2 by phosphorylating at Thr309 and Ser474, respectively. diDCP-LA-PE increased cell surface localization of GLUT4 and stimulated glucose uptake into differentiated 3T3-L1 adipocytes, still with knocking-down IR or in the absence of insulin. Moreover, diDCP-LA-PE effectively reduced serum glucose levels in type 1 diabetes (DM) model mice. diDCP-LA-PE, thus, may enable type 1 DM therapy without insulin injection.
authors.affiliation: Innovative Bioinformation Research Organization, Kobe, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nishizaki
authors.affiliation: Laboratory of Cell and Gene Therapy, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Gotoh
authors.affiliation: Laboratory of Chemical Biology, Advanced Medicinal Research Center, Hyogo University of Health Sciences, Kobe, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Laboratory of Chemical Biology, Advanced Medicinal Research Center, Hyogo University of Health Sciences, Kobe, Japan.
authors.forename: Akito
authors.initials: A
authors.lastname: Tanaka
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D010714:Phosphatidylethanolamines / Q000008:administration & dosage* / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D000099221:Protein Kinase C zeta
chemical_list: D001786:Blood Glucose; D005947:Glucose; D007328:Insulin; D010714:Phosphatidylethanolamines; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D000099221:Protein Kinase C zeta; C000607905:1,2-O-bis(8-(2-(2-pentylcyclopropylmethyl)cyclopropyl)octanoyl)-sn-glycero-3-phosphatidylethanolamine; C516609:Ptpn1 protein, mouse