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Go-6976 reverses hyperglycemia-induced insulin resistance independently of cPKC inhibition in adipocytes

Go-6976 reverses hyperglycemia-induced insulin resistance independently of cPKC inhibition in adipocytes
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 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.

1932-6203
Robinson, Katherine A.
5cc32ce8-e130-47f1-afe3-e8253381583c
Hegyi, Krisztina
ba174082-24e9-4b49-abec-b35f68269a79
Hannun, Yusuf A.
b89a0b1f-006e-4e76-947e-de213df9d2f9
Buse, Maria G.
2c7d89f7-3ea6-4ffc-a856-06ac5b9d42d5
Sethi, Jaswinder K.
923f1a81-91e4-46cd-8853-bb4a979f5a85
Robinson, Katherine A.
5cc32ce8-e130-47f1-afe3-e8253381583c
Hegyi, Krisztina
ba174082-24e9-4b49-abec-b35f68269a79
Hannun, Yusuf A.
b89a0b1f-006e-4e76-947e-de213df9d2f9
Buse, Maria G.
2c7d89f7-3ea6-4ffc-a856-06ac5b9d42d5
Sethi, Jaswinder K.
923f1a81-91e4-46cd-8853-bb4a979f5a85

Robinson, Katherine A., Hegyi, Krisztina, Hannun, Yusuf A., Buse, Maria G. and Sethi, Jaswinder K. (2014) Go-6976 reverses hyperglycemia-induced insulin resistance independently of cPKC inhibition in adipocytes. PLoS ONE, 9 (10), [A1306]. (doi:10.1371/journal.pone.0108963).

Record type: Article

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, 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.

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More information

Accepted/In Press date: 5 September 2014
e-pub ahead of print date: 15 October 2014
Published date: 15 October 2014

Identifiers

Local EPrints ID: 415249
URI: http://eprints.soton.ac.uk/id/eprint/415249
ISSN: 1932-6203
PURE UUID: 4f6b2263-017e-4d9e-8deb-4048420ea1ae
ORCID for Jaswinder K. Sethi: ORCID iD orcid.org/0000-0003-4157-0475

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Date deposited: 06 Nov 2017 17:30
Last modified: 06 Jun 2024 01:59

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Contributors

Author: Katherine A. Robinson
Author: Krisztina Hegyi
Author: Yusuf A. Hannun
Author: Maria G. Buse

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