Proteomics analysis of human skeletal muscle reveals novel abnormalities in obesity and type 2 diabetes.
OBJECTIVE
Insulin resistance in skeletal muscle is an early phenomenon in the pathogenesis of type 2 diabetes. Studies of insulin resistance usually are highly focused. However, approaches that give a more global picture of abnormalities in insulin resistance are useful in pointing out new directions for research. In previous studies, gene expression analyses show a coordinated pattern of reduction in nuclear-encoded mitochondrial gene expression in insulin resistance. However, changes in mRNA levels may not predict changes in protein abundance. An approach to identify global protein abundance changes involving the use of proteomics was used here.


METHODS
Muscle biopsies were obtained basally from lean, obese, and type 2 diabetic volunteers (n = 8 each); glucose clamps were used to assess insulin sensitivity. Muscle protein was subjected to mass spectrometry-based quantification using normalized spectral abundance factors.


RESULTS
Of 1,218 proteins assigned, 400 were present in at least half of all subjects. Of these, 92 were altered by a factor of 2 in insulin resistance, and of those, 15 were significantly increased or decreased by ANOVA (P < 0.05). Analysis of protein sets revealed patterns of decreased abundance in mitochondrial proteins and altered abundance of proteins involved with cytoskeletal structure (desmin and alpha actinin-2 both decreased), chaperone function (TCP-1 subunits increased), and proteasome subunits (increased).


CONCLUSIONS
The results confirm the reduction in mitochondrial proteins in insulin-resistant muscle and suggest that changes in muscle structure, protein degradation, and folding also characterize insulin resistance.
Hwang
Hyonson
H
Center for Metabolic Biology, Arizona State University, Tempe, Arizona, USA.
Bowen
Benjamin P
BP
Lefort
Natalie
N
Flynn
Charles R
CR
De Filippis
Elena A
EA
Roberts
Christine
C
Smoke
Christopher C
CC
Meyer
Christian
C
Højlund
Kurt
K
Yi
Zhengping
Z
Mandarino
Lawrence J
LJ
D000328:Adult; D001706:Biopsy; D015992:Body Mass Index; D056404:Chaperonin Containing TCP-1 / Q000235:genetics; D018833:Chaperonins / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015309:Glucose Clamp Technique; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism; D018482:Muscle, Skeletal / Q000503:physiopathology*; D009765:Obesity / Q000235:genetics*; D010447:Peptide Hydrolases / Q000235:genetics; D040901:Proteomics / Q000379:methods*; D012016:Reference Values
D003598:Cytoskeletal Proteins; C533304:TCP1 protein, human; D010447:Peptide Hydrolases; D056404:Chaperonin Containing TCP-1; D018833:Chaperonins