Abstract | AIMS/HYPOTHESIS: METHODS: The endogenous function of SHIP2 was inhibited by expressing a catalytically inactive SHIP2 (DeltaIP-SHIP), and compared with the effect of treatments designed to restore the levels of IRS-1 in insulin signalling systems of 3T3-L1 adipocytes. RESULTS: Chronic insulin treatment induced the large (86%) down-regulation of IRS-1 and the modest (36%) up-regulation of SHIP2. Subsequent stimulation by insulin of Akt phosphorylation, PKClambda activity, and 2-deoxyglucose (2-DOG) uptake was markedly decreased by the chronic insulin treatment. Coincubation with the mTOR inhibitor, rapamycin, effectively inhibited the proteosomal degradation of IRS-1 caused by the chronic insulin treatment. Although the coincubation with rapamycin and advanced overexpression of IRS-1 effectively ameliorated subsequent insulin-induced phosphorylation of Akt, insulin stimulation of PKClambda activity and 2-DOG uptake was partly restored by these treatments. Similarly, expression of DeltaIP-SHIP2 effectively ameliorated the insulin-induced phosphorylation of Akt without affecting the amount of IRS-1. Furthermore, the decreased insulin-induced PKClambda activity and 2-DOG uptake following chronic insulin treatment were ameliorated by the expression of DeltaIP-SHIP2 more effectively than by the treatment with rapamycin. CONCLUSIONS/INTERPRETATION: Our results indicate that the inhibition of endogenous SHIP2 is effective in improving the state of insulin resistance caused by chronic insulin treatment.
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Authors | T Sasaoka, K Fukui, T Wada, S Murakami, J Kawahara, H Ishihara, M Funaki, T Asano, M Kobayashi |
Journal | Diabetologia
(Diabetologia)
Vol. 48
Issue 2
Pg. 336-44
(Feb 2005)
ISSN: 0012-186X [Print] Germany |
PMID | 15654601
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Insulin
- Insulin Receptor Substrate Proteins
- Irs1 protein, mouse
- Isoenzymes
- Phosphoproteins
- Deoxyglucose
- Protein Kinase C
- protein kinase C lambda
- Phosphoric Monoester Hydrolases
- INPPL1 protein, human
- Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
- Sirolimus
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Topics |
- 3T3 Cells
- Adipocytes
(drug effects, physiology)
- Animals
- Biological Transport
(drug effects)
- Deoxyglucose
(metabolism)
- Insulin
(pharmacology)
- Insulin Receptor Substrate Proteins
- Insulin Resistance
(physiology)
- Isoenzymes
(metabolism)
- Mice
- Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
- Phosphoproteins
(metabolism)
- Phosphoric Monoester Hydrolases
(antagonists & inhibitors)
- Protein Kinase C
(metabolism)
- Signal Transduction
(drug effects, physiology)
- Sirolimus
(pharmacology)
- src Homology Domains
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