Go-6976 Reverses Hyperglycemia-Induced Insulin Resistance Independently of cPKC Inhibition in AdipocytesReport as inadecuate


Go-6976 Reverses Hyperglycemia-Induced Insulin Resistance Independently of cPKC Inhibition in Adipocytes


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Publication Date: 2014-10-15

Journal Title: PLOS ONE

Publisher: PLOS

Volume: 9

Number: 10

Pages: e108963

Language: English

Type: Article

Metadata: Show full item record

Citation: Robinson, K. A., Hegyi, K., Hannun, Y. A., Buse, M. G., & Sethi, J. K. (2014). Go-6976 Reverses Hyperglycemia-Induced Insulin Resistance Independently of cPKC Inhibition in Adipocytes. PLOS ONE, 9 (10), e108963.

Description: This paper was originally published in PLOS ONE (Robinson KA, Hegyi K, Hannun YA, Buse MG, Sethi JK, PLoS ONE 2014, 9(10): e108963. doi:10.1371/journal.pone.0108963).

Abstract: 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, PKCa, (but not –b) 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 PKCa, and PKCa 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.

Sponsorship: This work was supported by grants from the Biotechnology and Biological Sciences Research Council (David Phillips Fellowship, JF16994), Diabetes UK (BDA:RD06/0003237) and British Heart Foundation (PG/10/38/28359) to J.K. Sethi and also from National Institute of Diabetes and Digestive and Kidney Diseases (DK-02001) to M.G. Buse.

Identifiers:

This record's URL: http://dx.doi.org/10.1371/journal.pone.0108963http://www.repository.cam.ac.uk/handle/1810/247297

Rights: Attribution 2.0 UK: England & Wales

Licence URL: http://creativecommons.org/licenses/by/2.0/uk/





Author: Robinson, Katherine A.Hegyi, KrisztinaHannun, Yusuf A.Buse, Maria G.Sethi, Jaswinder K.

Source: https://www.repository.cam.ac.uk/handle/1810/247297



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