SH2-containing inositol phosphatase 2 negatively regulates insulin-induced glycogen synthesis in L6 myotubes

Sasaoka, Toshiyasu; Hori, Hiroyuki; Wada, Tsutomu; Ishiki, Manabu; Haruta, Tetsuro; Ishihara, Hajime; Kobayashi, Masaki

doi:10.1007/s001250100645

Cited by 77 publications

(66 citation statements)

References 31 publications

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“…that PI 3-kinase is activated normally, it is possible that modulation of 3-PIP content occurs by enhanced degradation. This is exemplified by recent papers demonstrating that overexpression of SHIP2, which decreases the PI-3,4,5-P3 : PI-3,4-P2 ratio, leads to impaired activation of Akt/PKB and aPKC and to metabolic insulin resistance [33,44]. Overexpression of other PIP phosphatases, either of the 3′ position [32] or of the 5′ position of the inositol ring [45], was also shown to induce insulin resistance.…”

Section: Discussionmentioning

confidence: 84%

Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-?

et al. 2004

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Aims/hypothesis. Chronic exposure of 3T3-L1 adipocytes to the HIV protease inhibitor nelfinavir induces insulin resistance, recapitulating key metabolic alterations of adipose tissue in the lipodystrophy syndrome induced by these agents. Our goal was to identify the defect in the insulin signal transduction cascade leading to nelfinavir-induced insulin resistance. Methods. Fully differentiated 3T3-L1 adipocytes were exposed to 30 µmol/l nelfinavir for 18 h, after which the amount, the phosphorylation and the localisation of key proteins in the insulin signalling cascade were evaluated.Results. Insulin-induced interaction of phosphatidylinositol 3′-kinase (PI 3-kinase) with IRS proteins was normal in cells treated with nelfinavir, as was IRS-1-associated PI 3-kinase activity. Yet insulin-induced phosphorylation of Akt/protein kinase B (PKB), p70S6 kinase and extracellular signal-regulated kinase 1/2 was significantly impaired. This could not be attributed to increased protein phosphatase 2A activity or to increased expression of phosphoinositide phosphatases (SHIP2 or PTEN). However, insulin failed to induce translocation of the PI 3-kinase effectors Akt/PKB and protein kinase C-ζ (PKC-ζ) to plasma membrane fractions of nelfinavir-treated adipocytes. Conclusions/interpretation. We therefore conclude that nelfinavir induces a defect in the insulin signalling cascade downstream of the activation of PI 3-kinase. This defect manifests itself by impaired insulin-mediated recruitment of Akt/PKB and PKC-ζ to the plasma membrane.

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Section: Discussionmentioning

confidence: 84%

Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-?

et al. 2004

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“…The membranes were then probed with the specified antibodies for 2 h at 20°C or for 16 h at 4°C. After washing the membranes in a buffer containing 50 mmol/l Tris, 150 mmol/l NaCl, and 0.1% Tween 20 (pH 7.5), blots were incubated with horseradish peroxidaseϪlinked second antibody and then examined by enhanced chemiluminescence (ECL) detection using an ECL reagent according to the manufacturer's instructions (Amersham) (13,14). PI 3-kinase assay.…”

Section: Methodsmentioning

confidence: 99%

“…The organic phase was removed and spotted on a silica gel thin-layer chromatography plate (Merck), and the plates were developed and dried. The phosphorylated inositol was visualized by autoradiography and quantitated with the BAS 2000 image analyzer (Fuji Film, Tokyo, Japan) (13,14). Akt activity assay.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we and others have cloned a novel 5Ј-phosphatase named SH-2Ϫcontaining inositol 5Ј-phosphatase 2 (SHIP-2), which is predominantly expressed in target tissues of insulin (11,12). Overexpression of SHIP-2 inhibits insulin-induced glucose uptake and glycogen synthesis via its 5Ј-phosphatase activity in 3T3-L1 adipocytes and L6 myotubes (13,14). Targeted disruption of the SHIP-2 gene in mice results in increased insulin sensitivity with no effect on biological systems other than insulin signaling (15).…”

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Association of SH2-Containing Inositol Phosphatase 2 With the Insulin Resistance of Diabetic db/db Mice

et al. 2002

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SH-2؊containing inositol 5-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)-/, 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. Insulininduced Akt activation and PKC-/ phosphorylation were restored to the control level, although insulinstimulated 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. Diabetes 51:2387-2394, 2002

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“…The function of SHIP2 in differentiated L6 myotubes and 3T3-L1 adipocytes was extensively studied by inhibition of the endogenous SHIP2 via overexpression of a dominantnegative SHIP2 mutant (dnSHIP2). SHIP2 inhibition increases phosphorylation of Akt (also known as protein kinase B) and glycogen synthesis in both cell lines (6,7). The liver-specific overexpression of dnSHIP2 in db/db mice results in dramatically decreased fasting glucose levels due to the reduced expression of the gluconeogenic genes glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) (8).…”

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confidence: 99%

Normalization of Prandial Blood Glucose and Improvement of Glucose Tolerance by Liver-Specific Inhibition of SH2 Domain–Containing Inositol Phosphatase 2 (SHIP2) in Diabetic KKAy Mice

et al. 2007

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Type 2 diabetes is characterized by a progressive resistance of peripheral tissues to insulin. Recent data have established the lipid phosphatase SH2 domain-containing inositol phosphatase 2 (SHIP2) as a critical negative regulator of insulin signal transduction. Mutations in the SHIP2 gene are associated with type 2 diabetes. Here, we used hyperglycemic and hyperinsulinemic KKA y mice to gain insight into the signaling events and metabolic changes triggered by SHIP2 inhibition in vivo. Liver-specific expression of a dominant-negative SHIP2 mutant in KKA y mice increased basal and insulin-stimulated Akt phosphorylation. Protein levels of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase were significantly reduced, and consequently the liver produced less glucose through gluconeogenesis. Furthermore, SHIP2 inhibition improved hepatic glycogen metabolism by modulating the phosphorylation states of glycogen phosphorylase and glycogen synthase, which ultimately increased hepatic glycogen content. Enhanced glucokinase and reduced pyruvate dehydrogenase kinase 4 expression, together with increased plasma triglycerides, indicate improved glycolysis. As a consequence of the insulin-mimetic effects on glycogen metabolism, gluconeogenesis, and glycolysis, the liverspecific inhibition of SHIP2 improved glucose tolerance and markedly reduced prandial blood glucose levels in KKA y mice. These results support the attractiveness of a specific inhibition of SHIP2 for the prevention and/or treatment of type 2 diabetes. Diabetes 56:2235-2241, 2007 A key event in insulin signal transduction is the increase in phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P 3 ], which recruits and activates downstream effectors at the plasma membrane (1). The lipid phosphatase SH2 domain-containing inositol phosphatase 2 (SHIP2) is expressed in insulin target tissues and dephosphorylates PI(3,4,5)P 3 at the D5 position (2,3). Activating mutations in the SHIP2 gene contribute to the genetic susceptibility to type 2 diabetes in humans (4). Mice lacking the SHIP2 gene (Inppl1 Ϫ/Ϫ mice) are viable and have normal glucose and insulin levels with normal insulin and glucose tolerances. However, Inppl1Ϫ/Ϫ mice are protected from diet-induced obesity, hyperglycemia, and insulin resistance (5). The function of SHIP2 in differentiated L6 myotubes and 3T3-L1 adipocytes was extensively studied by inhibition of the endogenous SHIP2 via overexpression of a dominantnegative SHIP2 mutant (dnSHIP2). SHIP2 inhibition increases phosphorylation of Akt (also known as protein kinase B) and glycogen synthesis in both cell lines (6,7). The liver-specific overexpression of dnSHIP2 in db/db mice results in dramatically decreased fasting glucose levels due to the reduced expression of the gluconeogenic genes glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) (8). However, the strong reduction in fasting blood glucose concentration confounds the interpretation of an improved glucose tolerance test in this model. Furthermore, an effect o...

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SH2-containing inositol phosphatase 2 negatively regulates insulin-induced glycogen synthesis in L6 myotubes

Cited by 77 publications

References 31 publications

Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-?

Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-?

Association of SH2-Containing Inositol Phosphatase 2 With the Insulin Resistance of Diabetic db/db Mice

Normalization of Prandial Blood Glucose and Improvement of Glucose Tolerance by Liver-Specific Inhibition of SH2 Domain–Containing Inositol Phosphatase 2 (SHIP2) in Diabetic KKAy Mice

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