Go-6976 reverses hyperglycemia-induced insulin resistance independently of cPKC inhibition in adipocytes.
Chronic hyperglycemia induces insulin resistance by mechanisms that are incompletely understood. One model of hyperglycemia-induced insulin resistance involves chronic preincubation of adipocytes in the presence of high glucose and low insulin concentrations. We have previously shown that the mTOR c...
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2014-01-01
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| Online Access: | https://doi.org/10.1371/journal.pone.0108963 |
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| author | Katherine A Robinson Krisztina Hegyi Yusuf A Hannun Maria G Buse Jaswinder K Sethi |
| author_facet | Katherine A Robinson Krisztina Hegyi Yusuf A Hannun Maria G Buse Jaswinder K Sethi |
| author_sort | Katherine A Robinson |
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| description | Chronic hyperglycemia induces insulin resistance by mechanisms that are incompletely understood. One model of hyperglycemia-induced insulin resistance involves chronic preincubation of adipocytes in the presence of high glucose and low insulin concentrations. We have previously shown that the mTOR complex 1 (mTORC1) plays a partial role in the development of insulin resistance in this model. Here, we demonstrate that treatment with Go-6976, a widely used "specific" inhibitor of cPKCs, alleviates hyperglycemia-induced insulin resistance. However, the effects of mTOR inhibitor, rapamycin and Go-6976 were not additive and only rapamycin restored impaired insulin-stimulated AKT activation. Although, PKCα, (but not -β) was abundantly expressed in these adipocytes, our studies indicate cPKCs do not play a major role in causing insulin-resistance in this model. There was no evidence of changes in the expression or phosphorylation of PKCα, and PKCα knock-down did not prevent the reduction of insulin-stimulated glucose transport. This was also consistent with lack of IRS-1 phosphorylation on Ser-24 in hyperglycemia-induced insulin-resistant adipocytes. Treatment with Go-6976 did inhibit a component of the mTORC1 pathway, as evidenced by decreased phosphorylation of S6 ribosomal protein. Raptor knock-down enhanced the effect of insulin on glucose transport in insulin resistant adipocytes. Go-6976 had the same effect in control cells, but was ineffective in cells with Raptor knock-down. Taken together these findings suggest that Go-6976 exerts its effect in alleviating hyperglycemia-induced insulin-resistance independently of cPKC inhibition and may target components of the mTORC1 signaling pathway. |
| format | Article |
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| institution | OA Journals |
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| language | English |
| publishDate | 2014-01-01 |
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| spelling | doaj-art-3d83709382a64172a8bdd5ff2bb961242025-08-20T02:34:07ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-01910e10896310.1371/journal.pone.0108963Go-6976 reverses hyperglycemia-induced insulin resistance independently of cPKC inhibition in adipocytes.Katherine A RobinsonKrisztina HegyiYusuf A HannunMaria G BuseJaswinder K SethiChronic hyperglycemia induces insulin resistance by mechanisms that are incompletely understood. One model of hyperglycemia-induced insulin resistance involves chronic preincubation of adipocytes in the presence of high glucose and low insulin concentrations. We have previously shown that the mTOR complex 1 (mTORC1) plays a partial role in the development of insulin resistance in this model. Here, we demonstrate that treatment with Go-6976, a widely used "specific" inhibitor of cPKCs, alleviates hyperglycemia-induced insulin resistance. However, the effects of mTOR inhibitor, rapamycin and Go-6976 were not additive and only rapamycin restored impaired insulin-stimulated AKT activation. Although, PKCα, (but not -β) was abundantly expressed in these adipocytes, our studies indicate cPKCs do not play a major role in causing insulin-resistance in this model. There was no evidence of changes in the expression or phosphorylation of PKCα, and PKCα knock-down did not prevent the reduction of insulin-stimulated glucose transport. This was also consistent with lack of IRS-1 phosphorylation on Ser-24 in hyperglycemia-induced insulin-resistant adipocytes. Treatment with Go-6976 did inhibit a component of the mTORC1 pathway, as evidenced by decreased phosphorylation of S6 ribosomal protein. Raptor knock-down enhanced the effect of insulin on glucose transport in insulin resistant adipocytes. Go-6976 had the same effect in control cells, but was ineffective in cells with Raptor knock-down. Taken together these findings suggest that Go-6976 exerts its effect in alleviating hyperglycemia-induced insulin-resistance independently of cPKC inhibition and may target components of the mTORC1 signaling pathway.https://doi.org/10.1371/journal.pone.0108963 |
| spellingShingle | Katherine A Robinson Krisztina Hegyi Yusuf A Hannun Maria G Buse Jaswinder K Sethi Go-6976 reverses hyperglycemia-induced insulin resistance independently of cPKC inhibition in adipocytes. PLoS ONE |
| title | Go-6976 reverses hyperglycemia-induced insulin resistance independently of cPKC inhibition in adipocytes. |
| title_full | Go-6976 reverses hyperglycemia-induced insulin resistance independently of cPKC inhibition in adipocytes. |
| title_fullStr | Go-6976 reverses hyperglycemia-induced insulin resistance independently of cPKC inhibition in adipocytes. |
| title_full_unstemmed | Go-6976 reverses hyperglycemia-induced insulin resistance independently of cPKC inhibition in adipocytes. |
| title_short | Go-6976 reverses hyperglycemia-induced insulin resistance independently of cPKC inhibition in adipocytes. |
| title_sort | go 6976 reverses hyperglycemia induced insulin resistance independently of cpkc inhibition in adipocytes |
| url | https://doi.org/10.1371/journal.pone.0108963 |
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