The University of Southampton
University of Southampton Institutional Repository

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.

This record has no associated files available for download.

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

Catalogue record

Date deposited: 06 Nov 2017 17:30
Last modified: 16 Mar 2024 04:31

Export record

Altmetrics

Contributors

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

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×