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.

Dioleoylphosphoethanolamine Retains Cell Surface GLUT4 by Inhibiting PKCα-Driven Internalization

“…PKC serves as transducers and modulators of insulin signaling [14], and PKCι/ζ and -ε participate in the regulation of GLUT4 translocation [11, 15]. To see the direct effect of PKC on intracellular GLUT4 trafficking, the PKC isozymes were knocked-down.…”

“…PKCλ/ι, -ζ, and -ε are recognized to stimulate GLUT4 translocation and exocytosis [11, 14, 15], but little is known about the implication of PKCα in the regulation of GLUT4 trafficking. One of the major findings in the present study is that cell surface localization of GLUT4 is increased by knocking-down PKCα, but not other PKC isozymes, that occludes the effect of DOPE.…”

“…PKC activity in the cell-free systems was quantified by the method previously described [11]. Briefly, synthetic PKC substrate peptide (10 µM) was reacted with novel PKC isozymes such as PKCδ and -ε in Ca 2+ -free medium and the other PKC isozymes in C 2+ -containing medium.…”

“…OGTT was carried out in mice fasted for 12 h. DOPE was orally administered 30 min prior to loading glucose (2 g/kg body weight) using a feeding needle. After collection of blood (10 µL) from the tail vein, the serum was prepared from collected blood, and the serum glucose levels were measured by the method previously described [11]. …”

“…PE is shown to regulate membrane fusion, cell cycle, autophagy, apoptosis, cognitive function, and glucose homeostasis [5-10]. We have earlier found that the PE derivative 1, 2- O -bis-[8-{2-(2-pentyl-cyclopropylmethyl)-cyclopropyl}-octanoyl]- sn - glycero-3-phosphatidylethanolamine (diDCP-LA-PE) is capable of mimicking intracellular insulin signaling [11]. This prompted assessing the effects of natural PEs on GLUT4 trafficking and glucose homeostasis.…”