Impaired Akt phosphorylation in insulin-resistant human muscle is accompanied by selective and heterogeneous downstream defects.
OBJECTIVE
Muscle insulin resistance, one of the earliest defects associated with type 2 diabetes, involves changes in the phosphoinositide 3-kinase/Akt network. The relative contribution of obesity vs insulin resistance to perturbations in this pathway is poorly understood.


METHODS
We used phosphospecific antibodies against targets in the Akt signalling network to study insulin action in muscle from lean, overweight/obese and type 2 diabetic individuals before and during a hyperinsulinaemic-euglycaemic clamp.


RESULTS
Insulin-stimulated Akt phosphorylation at Thr309 and Ser474 was highly correlated with whole-body insulin sensitivity. In contrast, impaired phosphorylation of Akt substrate of 160 kDa (AS160; also known as TBC1D4) was associated with adiposity, but not insulin sensitivity. Neither insulin sensitivity nor obesity was associated with defective insulin-dependent phosphorylation of forkhead box O (FOXO) transcription factor. In view of the resultant basal hyperinsulinaemia, we predicted that this selective response within the Akt pathway might lead to hyperactivation of those processes that were spared. Indeed, the expression of genes targeted by FOXO was downregulated in insulin-resistant individuals.


CONCLUSIONS
These results highlight non-linearity in Akt signalling and suggest that: (1) the pathway from Akt to glucose transport is complex; and (2) pathways, particularly FOXO, that are not insulin-resistant, are likely to be hyperactivated in response to hyperinsulinaemia. This facet of Akt signalling may contribute to multiple features of the metabolic syndrome.
Diabetes and Obesity Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, 2010 NSW, Australia.
K T
KT
Tonks
Y
Y
Ng
S
S
Miller
A C F
AC
Coster
D
D
Samocha-Bonet
T J
TJ
Iseli
A
A
Xu
E
E
Patrick
J Y H
JY
Yang
J R
JR
Junutula
Z
Z
Modrusan
G
G
Kolumam
J
J
Stöckli
D J
DJ
Chisholm
D E
DE
James
J R
JR
Greenfield
D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism; D008875:Middle Aged; D009132:Muscles / Q000378:metabolism / Q000503:physiopathology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007328:Insulin; D051057:Proto-Oncogene Proteins c-akt