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Diabetologia
Published in: Diabetologia 9/2010

01-09-2010 | Article

Differential aetiology and impact of phosphoinositide 3-kinase (PI3K) and Akt signalling in skeletal muscle on in vivo insulin action

Authors: M. Friedrichsen, P. Poulsen, E. A. Richter, B. F. Hansen, J. B. Birk, R. Ribel-Madsen, K. Stender-Petersen, E. Nilsson, H. Beck-Nielsen, A. Vaag, J. F. P. Wojtaszewski

Published in: Diabetologia | Issue 9/2010

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Abstract

Aims/hypothesis

Insulin resistance in skeletal muscle is a key factor in the development of type 2 diabetes and although some studies indicate that this could be partly attributed to reduced content and activity of various proximal and distal insulin signalling molecules, consensus is lacking. We therefore aimed to investigate the regulation of proximal insulin signalling in skeletal muscle and its effect on glucose metabolism in a large non-diabetic population.

Methods

We examined 184 non-diabetic twins with gold-standard techniques including the euglycaemic–hyperinsulinaemic clamp. Insulin signalling was evaluated at three key levels, i.e. the insulin receptor, IRS-1 and V-akt murine thymoma viral oncogene (Akt) levels, employing kinase assays and phospho-specific western blotting.

Results

Proximal insulin signalling was not associated with obesity, age or sex. However, birthweight was positively associated with IRS-1-associated phosphoinositide 3-kinase (PI3K; IRS-1-PI3K) activity (p = 0.04); maximal aerobic capacity \( \left( {\mathop {V}\limits^\cdot {{\hbox{O}}_{\rm{2max}}}} \right) \), paradoxically, was negatively associated with IRS-1-PI3K (p = 0.02) and Akt2 activity (p = 0.01). Additionally, we found low heritability estimates for most measures of insulin signalling activity. Glucose disposal was positively associated with Akt-308 phosphorylation (p < 0.001) and Akt2 activity (p = 0.05), but not with insulin receptor tyrosine kinase or IRS-1-PI3K activity.

Conclusions/interpretation

With the exception of birthweight, ‘classical’ modifiers of insulin action, including genetics, age, sex, obesity and \( \mathop {V}\limits^\cdot {{\hbox{O}}_{\rm{2max}}} \), do not seem to mediate their most central effects on whole-body insulin sensitivity through modulation of proximal insulin signalling in skeletal muscle. We also demonstrated an association between Akt activity and in vivo insulin sensitivity, suggesting a role of Akt in control of in vivo insulin resistance and potentially in type 2 diabetes.
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Metadata
Title
Differential aetiology and impact of phosphoinositide 3-kinase (PI3K) and Akt signalling in skeletal muscle on in vivo insulin action
Authors
M. Friedrichsen
P. Poulsen
E. A. Richter
B. F. Hansen
J. B. Birk
R. Ribel-Madsen
K. Stender-Petersen
E. Nilsson
H. Beck-Nielsen
A. Vaag
J. F. P. Wojtaszewski
Publication date
01-09-2010
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 9/2010
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-010-1795-8

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