Aims/hypothesis The molecular mechanisms underlying insulin resistance in skeletal muscle are incompletely understood. Here, we aimed to obtain a global picture of changes in protein abundance in skeletal muscle in obesity and type 2 diabetes, and those associated with whole-body measures of insulin action. Methods Skeletal muscle biopsies were obtained from ten healthy lean (LE), 11 obese non-diabetic (OB), and ten obese type 2 diabetic participants before and after hyperinsulinaemic-euglycaemic clamps. Quantitative proteome analysis was performed by two-dimensional differential-gel electrophoresis and tandem-mass-spectrometry-based protein identification.Results Forty-four protein spots displayed significant (p< 0.05) changes in abundance by at least a factor of 1.5 between groups. Several proteins were identified in multiple spots, suggesting post-translational modifications. Multiple spots containing glycolytic and fast-muscle proteins showed increased abundance, whereas spots with mitochondrial and slow-muscle proteins were downregulated in the OB and obese type 2 diabetic groups compared with the LE group. No differences in basal levels of myosin heavy chains were observed. The abundance of multiple spots representing glycolytic and fast-muscle proteins correlated negatively with insulin action on glucose disposal, glucose oxidation and lipid oxidation, while several spots with proteins J. Giebelstein, G. Poschmann and K. Højlund contributed equally to this work. involved in oxidative metabolism and mitochondrial function correlated positively with these whole-body measures of insulin action. Conclusions/interpretation Our data suggest that increased glycolytic and decreased mitochondrial protein abundance together with a shift in muscle properties towards a fasttwitch pattern in the absence of marked changes in fibretype distribution contribute to insulin resistance in obesity with and without type 2 diabetes. The roles of several differentially expressed or post-translationally modified proteins remain to be elucidated.
Unfortunately, "negatively" and "positively" were inadvertently reversed in the legend to Fig. 6. The third sentence of the legend should read: A complete dark red or dark blue label indicates proteins where combined spot volumes (combination of all spots where the respective protein was identified) were significantly positively (red) or negatively (blue) correlated with GDR (p<0.05).The online version of the original article can be found at http://dx
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