{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T23:54:10Z","timestamp":1791158050850,"version":"4.1.0"},"reference-count":34,"publisher":"American Diabetes Association","issue":"8","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2002,8,1]]},"abstract":"<jats:p>SH-2-containing inositol 5\u2032-phosphatase 2 (SHIP-2) is a physiologically important lipid phosphatase that functions to hydrolyze phosphatidylinositol (PI) 3-kinase product PI(3,4,5)P3 to PI(3,4)P2 in the negative regulation of insulin signaling. We investigated whether SHIP-2 is associated with the insulin resistance of diabetic db\/db mice. The amount of SHIP-2 protein was elevated in quadriceps muscle and epididymal fat tissue, but not in the liver, of db\/db mice relative to that in control db\/+m mice. In accordance with the enhanced expression of SHIP-2, its localization at the membrane preparation was increased in the skeletal muscle and fat tissue of db\/db mice. Insulin stimulation of PI 3-kinase activity was modestly decreased in skeletal muscle, fat tissue, and liver of db\/db mice compared with that of db\/+m mice. In addition to the modest decrease at the level of PI 3-kinase, the activity of Akt and protein kinase C (PKC)-\u03b6\/\u03bb, which are downstream molecules of PI 3-kinase, was more severely reduced in the skeletal muscle and fat tissue, but not in liver of db\/db mice. Treatment with the insulin-sensitizing agent rosiglitazone decreased the elevated expression of SHIP-2 in the skeletal muscle and fat tissue of db\/db mice. Insulin-induced Akt activation and PKC-\u03b6\/\u03bb phosphorylation were restored to the control level, although insulin-stimulated PI 3-kinase activation was minimally affected in the skeletal muscle and fat tissue of db\/db mice. These results indicate that SHIP-2 is a novel molecule associated with insulin resistance in the skeletal muscle and fat tissue, and that insulin-induced activity of the downstream molecules of PI 3-kinase is decreased, at least in part, by the elevated expression of SHIP-2 in diabetic db\/db mice.<\/jats:p>","DOI":"10.2337\/diabetes.51.8.2387","type":"journal-article","created":{"date-parts":[[2007,3,6]],"date-time":"2007-03-06T19:04:22Z","timestamp":1173207862000},"page":"2387-2394","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":79,"title":["Association of SH2-Containing Inositol Phosphatase 2 With the Insulin Resistance of Diabetic <i>db<\/i>\/<i>db<\/i> Mice"],"prefix":"10.2337","volume":"51","author":[{"given":"Hiroyuki","family":"Hori","sequence":"first","affiliation":[{"name":"First Department of Internal Medicine, Toyama Medical & Pharmaceutical University, Toyama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiyasu","family":"Sasaoka","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Toyama Medical & Pharmaceutical University, Toyama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajime","family":"Ishihara","sequence":"additional","affiliation":[{"name":"First Department of Internal Medicine, Toyama Medical & Pharmaceutical University, Toyama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsutomu","family":"Wada","sequence":"additional","affiliation":[{"name":"First Department of Internal Medicine, Toyama Medical & Pharmaceutical University, Toyama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shihou","family":"Murakami","sequence":"additional","affiliation":[{"name":"First Department of Internal Medicine, Toyama Medical & Pharmaceutical University, Toyama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Ishiki","sequence":"additional","affiliation":[{"name":"First Department of Internal Medicine, Toyama Medical & Pharmaceutical University, Toyama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"First Department of Internal Medicine, Toyama Medical & Pharmaceutical University, Toyama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022031206450446700_R1","doi-asserted-by":"crossref","unstructured":"Saltiel AR: New perspectives into the molecular pathogenesis and treatment of type 2 diabetes. Cell\u2008104:517\u2013529,2001","DOI":"10.1016\/S0092-8674(01)00239-2"},{"key":"2022031206450446700_R2","doi-asserted-by":"crossref","unstructured":"Virkama\u0308ki A, Ueki K, Kahn CR: Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J Clin Invest\u2008103:931\u2013943,1999","DOI":"10.1172\/JCI6609"},{"key":"2022031206450446700_R3","doi-asserted-by":"crossref","unstructured":"Czech MP, Corvera S: Signaling mechanisms that regulate glucose transport. J Biol Chem\u2008274:1865\u20131868,1999","DOI":"10.1074\/jbc.274.4.1865"},{"key":"2022031206450446700_R4","doi-asserted-by":"crossref","unstructured":"Stephens LR, Hughes KT, Irvine RF: Pathway of phosphatidylinositol(3,4,5)-triphosphate synthesis in activated neutrophils. Nature\u2008351:33\u201339,1991","DOI":"10.1038\/351033a0"},{"key":"2022031206450446700_R5","doi-asserted-by":"crossref","unstructured":"Funaki M, Katagiri H, Kanda A, Anai M, Nawano M, Ogihara T, Inukai K, Fukushima Y, Ono H, Yazaki Y, Kikuchi M, Oka Y, Asano T: p85\/p110-type phosphatidylinositol kinase phosphorylates not only the D-3, but also the D-4 position of the inositol ring. J Biol Chem\u2008274:22019\u201322024,1999","DOI":"10.1074\/jbc.274.31.22019"},{"key":"2022031206450446700_R6","doi-asserted-by":"crossref","unstructured":"Toker A, Cantley LC: Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature\u2008387:673\u2013676,1997","DOI":"10.1038\/42648"},{"key":"2022031206450446700_R7","doi-asserted-by":"crossref","unstructured":"Majerus PW, Kisseleva MV, Norris FA: The role of phosphatases in inositol signaling reactions. J Biol Chem\u2008274:10669\u201310672,1999","DOI":"10.1074\/jbc.274.16.10669"},{"key":"2022031206450446700_R8","doi-asserted-by":"crossref","unstructured":"Standaert ML, Galloway L, Karnam P, Bandyopadhyay G, Moscat J, Farese RV: Protein kinase C-\u03b6 as a downstream effector of phosphatidylinositol 3-kinase during insulin stimulation in rat adipocytes: potential role in glucose transport. J Biol Chem\u2008272:30075\u201330082,1997","DOI":"10.1074\/jbc.272.48.30075"},{"key":"2022031206450446700_R9","doi-asserted-by":"crossref","unstructured":"Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter GF, Holmes AB, Gaffney PRJ, Reese CB, McCormick F, Tempst P, Coadwell J, Hawkins PT: Protein kinase B: kinases that mediate phosphatidylinositol 3,4,5-triphosphate-dependent activation of protein kinase B. Science\u2008279:710\u2013714,1998","DOI":"10.1126\/science.279.5351.710"},{"key":"2022031206450446700_R10","doi-asserted-by":"crossref","unstructured":"Stokoe D, Stephens LR, Copeland T, Gaffney PRJ, Reese CB, Painter GF, Holmes AB, McCormick F, Hawkins PT: Dual role of phosphatidylinositol-3,4,5-triphosphate in the activation of protein kinase B. Science\u2008277:567\u2013570,1997","DOI":"10.1126\/science.277.5325.567"},{"key":"2022031206450446700_R11","doi-asserted-by":"crossref","unstructured":"Pesesse X, Deleu S, Smedt FD, Drayer L, Erneux C: Identification of a second SH2-domain-containing protein closely related to the phosphatidylinositol polyphosphate 5-phosphatase SHIP. Biochem Biophys Res Commun\u2008239:697\u2013700,1997","DOI":"10.1006\/bbrc.1997.7538"},{"key":"2022031206450446700_R12","doi-asserted-by":"crossref","unstructured":"Ishihara H, Sasaoka T, Hori H, Wada T, Hirai H, Haruta T, Langlois WJ, Kobayashi M: Molecular cloning of rat SH2-containing inositol phosphatase 2 (SHIP-2) and its role in the regulation of insulin signaling. Biochem Biophys Res Commun\u2008260:265\u2013272,1999","DOI":"10.1006\/bbrc.1999.0888"},{"key":"2022031206450446700_R13","doi-asserted-by":"crossref","unstructured":"Wada T, Sasaoka T, Funaki M, Hori H, Murakami S, Ishiki M, Haruta T, Asano T, Ogawa W, Ishihara H, Kobayashi M: Overexpression of SH2-containing inositol phosphatase 2 results in negative regulation of insulin-induced metabolic actions in 3T3-L1 adipocytes via its 5\u2032-phosphatase catalytic activity. Mol Cell Biol\u200821:1633\u20131646,2001","DOI":"10.1128\/MCB.21.5.1633-1646.2001"},{"key":"2022031206450446700_R14","doi-asserted-by":"crossref","unstructured":"Sasaoka T, Hori H, Wada T, Ishiki M, Haruta T, Ishihara H, Kobayashi M: SH2-containing inositol phosphatase 2 negatively regulates insulin-induced glycogen synthesis in L6 myotubes. Diabetologia\u200844:1258\u20131267,2001","DOI":"10.1007\/s001250100645"},{"key":"2022031206450446700_R15","doi-asserted-by":"crossref","unstructured":"Clement S, Krause U, Desmedt F, Tanti JF, Behrends J, Pesesse X, Sasaki T, Penninger J, Doherty M, Malaisse W, Dumont JE, Marchand-Brustel YL, Erneux C, Hue L, Schurmans S: The lipid phosphatase SHIP-2 controls insulin sensitivity. Nature\u2008409:92\u201397,2001","DOI":"10.1038\/35051094"},{"key":"2022031206450446700_R16","doi-asserted-by":"crossref","unstructured":"Kim YB, Zhu JS, Zierath JR, Shen HQ, Baron AD, Kahn BB: Glucosamine infusion in rats rapidly impairs insulin stimulation of phosphoinositide 3-kinase but does not alter activation of Akt\/protein kinase B in skeletal muscle. Diabetes\u200848:310\u2013320,1999","DOI":"10.2337\/diabetes.48.2.310"},{"key":"2022031206450446700_R17","doi-asserted-by":"crossref","unstructured":"Kim YB, Nikoulina SE, Ciaraldi TP, Henry RR, Kahn BB: Normal insulin-dependent activation of Akt\/protein kinase B, with diminished activation of phosphoinositide 3-kinase, in muscle in type 2 diabetes. J Clin Invest\u2008104:733\u2013741,1999","DOI":"10.1172\/JCI6928"},{"key":"2022031206450446700_R18","doi-asserted-by":"crossref","unstructured":"Song XM, Kawano Y, Krook A, Ryder JW, Efendic S, Roth RA, Wallberg-Henriksson H, Zierath JR: Muscle fiber type-specific defects in insulin signal transduction to glucose transport in diabetic GK rats. Diabetes\u200848:664\u2013670,1999","DOI":"10.2337\/diabetes.48.3.664"},{"key":"2022031206450446700_R19","doi-asserted-by":"crossref","unstructured":"Nawano M, Ueta K, Oku A, Arakawa K, Saito A, Funaki M, Anai M, Kikuchi M, Oka Y, Asano T: Hyperglycemia impairs the insulin signaling step between PI 3-kinase and Akt\/PKB activations in ZDF rat liver. Biochem Biophys Res Commun\u2008266:252\u2013256,1999","DOI":"10.1006\/bbrc.1999.1797"},{"key":"2022031206450446700_R20","doi-asserted-by":"crossref","unstructured":"Kurowski TG, Lin Y, Luo Z, Tsichlis PN, Buse MG, Heydrick SJ, Ruderman NB: Hyperglycemia inhibits insulin activation of Akt\/protein kinase B but not phosphatidylinositol 3-kinase in rat skeletal muscle. Diabetes\u200848:658\u2013663,1999","DOI":"10.2337\/diabetes.48.3.658"},{"key":"2022031206450446700_R21","doi-asserted-by":"crossref","unstructured":"Krook A, Roth RA, Jiang XJ, Zierath JR, Wallberg-Henriksson H: Insulin-stimulated Akt kinase activity is reduced in skeletal muscle from NIDDM subjects. Diabetes\u200847:1281\u20131286,1998","DOI":"10.2337\/diab.47.8.1281"},{"key":"2022031206450446700_R22","doi-asserted-by":"crossref","unstructured":"Carvalho E, Eliasson B, Wesslau C, Smith U: Impaired phosphorylation and insulin-stimulated translocation to the plasma membrane of protein kinase B\/Akt in adipocytes from type II diabetic subjects. Diabetologia\u200843:1107\u20131115,2000","DOI":"10.1007\/s001250051501"},{"key":"2022031206450446700_R23","doi-asserted-by":"crossref","unstructured":"Kanoh Y, Bandyopadhyay G, Sajan MP, Standaert ML, Farese RV: Thiazolidinedione treatment enhances insulin effects on protein kinase C-\u03b6\/\u03bb activation and glucose transport in adipocytes of non diabetic and Goto-Kakizaki type II diabetic rats. J Biol Chem\u2008275:16690\u201316696,2000","DOI":"10.1074\/jbc.M000287200"},{"key":"2022031206450446700_R24","doi-asserted-by":"crossref","unstructured":"Kanoh Y, Bandyopadhyay G, Sajan MP, Standaert ML, Farese RV: Rosiglitazone, insulin treatment, and fasting correct defective activation of protein kinase C-\u03b6\/\u03bb by insulin in vastus lateralis muscles and adipocytes of diabetic rats. Endocrinology\u2008142:1595\u20131605,2001","DOI":"10.1210\/endo.142.4.8066"},{"key":"2022031206450446700_R25","doi-asserted-by":"crossref","unstructured":"Tremblay F, Lavigne C, Jacques H, Marette A: Defective insulin-induced Glut4 translocation in skeletal muscle of high fat-fed rats is associated with alterations in both Akt\/protein kinase B and atypical protein kinase C (\u03b6\/\u03bb) activities. Diabetes\u200850:1901\u20131910,2001","DOI":"10.2337\/diabetes.50.8.1901"},{"key":"2022031206450446700_R26","doi-asserted-by":"crossref","unstructured":"Friedman JM, Halaas JL: Leptin and the regulation of body weight in mammals. Nature\u2008395:763\u2013770,1998","DOI":"10.1038\/27376"},{"key":"2022031206450446700_R27","doi-asserted-by":"crossref","unstructured":"Shao J, Yamashita H, Qiao L, Friedman JE: Decreased Akt kinase activity and insulin resistance in C57BL\/KsJ-Leprdb\/db mice. J Endocrinol\u2008167:107\u2013115,2000","DOI":"10.1677\/joe.0.1670107"},{"key":"2022031206450446700_R28","doi-asserted-by":"crossref","unstructured":"Ikemoto S, Thompson KS, Takahashi M, Itakura H, Lane MD, Ezaki O: High fat diet-induced hyperglycemia: prevention by low level expression of a glucose transporter (Glut4) minigene in transgenic mice. Proc Natl Acad Sci U S A\u200892:3096\u20133099,1995","DOI":"10.1073\/pnas.92.8.3096"},{"key":"2022031206450446700_R29","doi-asserted-by":"crossref","unstructured":"Tang Y, Osawa H, Onuma H, Nishimiya T, Ochi M, Makino H: Improvement in insulin resistance and the restoration of reduced phosphodiesterase 3B gene expression by pioglitazone in adipose tissue of obese diabetic KKAy mice. Diabetes\u200848:1830\u20131835,1999","DOI":"10.2337\/diabetes.48.9.1830"},{"key":"2022031206450446700_R30","doi-asserted-by":"crossref","unstructured":"Taylor V, Wong M, Brandts C, Reilly L, Dean NM, Cowsert LM, Moodie S, Stokoe D: 5\u2032 phospholipid phosphatase SHIP-2 causes protein kinase B inactivation and cell cycle arrest in glioblastoma cells. Mol Cell Biol\u200820:6860\u20136871,2000","DOI":"10.1128\/MCB.20.18.6860-6871.2000"},{"key":"2022031206450446700_R31","doi-asserted-by":"crossref","unstructured":"Pesesse X, Dewaste V, Smedt FD, Laffargue M, Giuriato S, Moreau C, Payrastre B, Erneux C: The src homology 2 domain containing inositol 5-phosphatase SHIP-2 is recruited to the epidermal growth factor (EGF) receptor and dephosphorylates phoshatidylinositol 3,4,5-triphosphate in EGF-stimulated Cos-7 cells. J Biol Chem\u2008276:28348\u201328355,2001","DOI":"10.1074\/jbc.M103537200"},{"key":"2022031206450446700_R32","doi-asserted-by":"crossref","unstructured":"Kitamura T, Ogawa W, Sakaue H, Hino Y, Kuroda S, Takata M, Matsumoto M, Maeda T, Konishi H, Kikkawa U, Kasuga M: Requirement for activation of the serine-threonine kinase Akt (protein kinase B) in insulin stimulation of protein synthesis but not glucose transport. Mol Cell Biol\u200818:3708\u20133717,1998","DOI":"10.1128\/MCB.18.7.3708"},{"key":"2022031206450446700_R33","doi-asserted-by":"crossref","unstructured":"Wang Q, Somwar R, Bilan PJ, Liu Z, Jin J, Woodgett JR, Klip A: Protein kinase B\/Akt participates in Glut4 translocation by insulin in L6 myotubes. Mol Cell Biol\u200819:4008\u20134018,1999","DOI":"10.1128\/MCB.19.6.4008"},{"key":"2022031206450446700_R34","doi-asserted-by":"crossref","unstructured":"Kotani K, Ogawa W, Matsumoto M, Kitamura T, Sakaue H, Hino Y, Miyake K, Sano W, Akimoto K, Ohno S, Kasuga M: Requirement of atypical protein kinase C\u03bb for insulin stimulation of glucose uptake but not for Akt activation in 3T3-L1 adipocytes. Mol Cell Biol\u200818:6971\u20136982,1998","DOI":"10.1128\/MCB.18.12.6971"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/51\/8\/2387\/657853\/db0802002387.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/51\/8\/2387\/657853\/db0802002387.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:15:17Z","timestamp":1667405717000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/51\/8\/2387\/11911\/Association-of-SH2-Containing-Inositol-Phosphatase"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2002,8,1]]},"references-count":34,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2002,8,1]]}},"URL":"https:\/\/doi.org\/10.2337\/diabetes.51.8.2387","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2002,8,1]]}}}