A computational model to define the molecular causes of type 2 diabetes mellitus.
BACKGROUND
Metabolic abnormalities associated with type 2 diabetes mellitus (DM2) are caused in part by inadequate insulin action and resulting changes in gene expression in the skeletal muscle. Two recent, independent studies of human skeletal muscle biopsies from ethnically diverse DM2 patients have identified coordinated reductions in the expression of the oxidative phosphorylation (OXPHOS) genes. Whether these reductions are a consequence or a cause of impaired insulin sensitivity remains an open question.


METHODS
To address this question and to define the underlying molecular causes consistent with the expression changes reported in the muscle studies, we created a large-scale computable model to analyze the molecular actions and effects of insulin on muscle gene expression. The model enables computer-aided reasoning using over 210,000 molecular relationships assembled from the DM2 literature.


RESULTS
We integrated the data from these muscle biopsy studies into the model and used computer-aided causal reasoning to discover mechanisms that can link alterations in OXPHOS genes to decreases in glucose transport, insulin signaling, and risk factors associated to post-transplant diabetes mellitus.


CONCLUSIONS
The emerging hypotheses describe biologic effects in DM2 and offer important cues for molecular targeted therapy.
Pollard
Jack
J
Genstruct, Inc., Cambridge, Massachusetts 02140, USA. jpollard@genstruct.com
Butte
Atul J
AJ
Hoberman
Steve
S
Joshi
Monica
M
Levy
Josh
J
Pappo
Jacques
J
D000465:Algorithms; D001786:Blood Glucose / Q000378:metabolism; D003198:Computer Simulation; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D016678:Genome; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D017058:Mexican Americans; D015233:Models, Statistical; D018482:Muscle, Skeletal / Q000378:metabolism; D010085:Oxidative Phosphorylation; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D012537:Scandinavian and Nordic Countries; D013844:Thiazoles / Q000627:therapeutic use
D001786:Blood Glucose; D013844:Thiazoles; D012313:RNA