Impaired Akt phosphorylation in insulin-resistant human muscle is accompanied by selective and heterogeneous downstream defects

• DOI: 10.1007/s00125-012-2811-y
• Publication Date: 2013-01-23T07:26:01Z
• Authors: K. T. Tonks; Y. Ng; S. Miller; A. C. F. Coster; D. Samocha-Bonet; T. J. Iseli; A. Xu; E. Patrick; J. Y. H. Yang; J. R. Junutula; Z. Modrusan; G. Kolumam; J. Stöckli; D. J. Chisholm; D. E. James; J. R. Greenfield
• Keywords: Adult; Male; 0301 basic medicine; anzsrc-for: 1114 Paediatrics and Reproductive Medicine; anzsrc-for: 4206 Public health; 610; 32 Biomedical and Clinical Sciences; anzsrc-for: 1103 Clinical Sciences; 03 medical and health sciences; anzsrc-for: 32 Biomedical and Clinical Sciences; Clinical Research; Insulin Secretion; Diabetes Mellitus; 2.1 Biological and endogenous factors; Humans; Insulin; Obesity; Phosphorylation; 3202 Clinical Sciences; Metabolic and endocrine; Nutrition; Aged; Metabolic Syndrome; Forkhead Box Protein O1; Gene Expression Profiling; Muscles; Diabetes; 600; Forkhead Transcription Factors; Middle Aged; Diabetes Mellitus, Type 2; anzsrc-for: 0601 Biochemistry and Cell Biology; anzsrc-for: 3202 Clinical Sciences; Female; Insulin Resistance; Proto-Oncogene Proteins c-akt; Type 2; Biotechnology; anzsrc-for: 1117 Public Health and Health Services; Signal Transduction

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.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.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.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.