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Diabetologia
Published in: Diabetologia 3/2008

01-03-2008 | Article

Isoform-specific defects of insulin stimulation of Akt/protein kinase B (PKB) in skeletal muscle cells from type 2 diabetic patients

Authors: D. Cozzone, S. Fröjdö, E. Disse, C. Debard, M. Laville, L. Pirola, H. Vidal

Published in: Diabetologia | Issue 3/2008

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Abstract

Aims/hypothesis

The serine/threonine kinase Akt/protein kinase B (PKB) is required for the metabolic actions of insulin. Controversial data have been reported regarding Akt defective activation in the muscle of type 2 diabetic patients. Because three Akt isoforms exist, each having a distinct physiological role, we investigated the contribution of isoform-specific defects to insulin signalling in human muscle.

Methods

The phosphorylation pattern and kinase activity of each Akt isoform were compared in primary myotubes from healthy control participants and type 2 diabetic patients. Phosphorylation of Ser473 and of Thr308 in each isoform was determined after immunoprecipitation in myotubes treated or not with insulin.

Results

Muscle cells from diabetic patients displayed defective insulin action and a drastic reduction of insulin-stimulated activity of all Akt isoforms. This was associated with specific defects of their phosphorylation pattern in response to insulin, with impaired Akt2- (and to a lower extent Akt3-) Ser473 phosphorylation, and with altered Akt1-Thr308 phosphorylation. These defects were not due to faulty phosphoinositide-dependent protein kinase 1 (PDK1) production or activation. Rather, we found higher levels of the Akt2-Ser473-specific protein phosphatase PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) in muscle from diabetic patients, which may contribute to the alteration of Akt2-Ser473 phosphorylation.

Conclusions/interpretation

These results suggest that several mechanisms affecting Akt isoforms, including deregulated production of PHLPP1, could underlie the alterations of skeletal muscle insulin signalling in type 2 diabetes. Taking into account the recently described isoform-specific metabolic functions of Akt, our results provide mechanistic insight that may contribute to the defective regulation of glucose and lipid metabolisms in the muscle of diabetic patients.
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Metadata
Title
Isoform-specific defects of insulin stimulation of Akt/protein kinase B (PKB) in skeletal muscle cells from type 2 diabetic patients
Authors
D. Cozzone
S. Fröjdö
E. Disse
C. Debard
M. Laville
L. Pirola
H. Vidal
Publication date
01-03-2008
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 3/2008
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-007-0913-8

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