Mechanisms of human insulin resistance and thiazolidinedione-mediated insulin sensitization.
|Title||Mechanisms of human insulin resistance and thiazolidinedione-mediated insulin sensitization.|
|Publication Type||Journal Article|
|Year of Publication||2009|
|Authors||Sears DD, Hsiao G, Hsiao A, Yu JG, Courtney CH, Ofrecio JM, Chapman J, Subramaniam S|
|Journal||Proc Natl Acad Sci U S A|
|Date Published||2009 Nov 3|
|Keywords||Adipocytes, Adipose Tissue, Biological Markers, Gene Expression Profiling, Gene Expression Regulation, Glucose, Humans, Inflammation, Insulin, Insulin Resistance, Mitochondria, Muscle, Skeletal, Thiazolidinediones|
Cellular and tissue defects associated with insulin resistance are coincident with transcriptional abnormalities and are improved after insulin sensitization with thiazolidinedione (TZD) PPARgamma ligands. We characterized 72 human subjects by relating their clinical phenotypes with functional pathway alterations. We transcriptionally profiled 364 biopsies harvested before and after hyperinsulinemic-euglycemic clamp studies, at baseline and after 3-month TZD treatment. We have identified molecular and functional characteristics of insulin resistant subjects and distinctions between TZD treatment responder and nonresponder subjects. Insulin resistant subjects exhibited alterations in skeletal muscle (e.g., glycolytic flux and intramuscular adipocytes) and adipose tissue (e.g., mitochondrial metabolism and inflammation) that improved relative to TZD-induced insulin sensitization. Pre-TZD treatment expression of MLXIP in muscle and HLA-DRB1 in adipose tissue from insulin resistant subjects was linearly predictive of post-TZD insulin sensitization. We have uniquely characterized coordinated cellular and tissue functional pathways that are characteristic of insulin resistance, TZD-induced insulin sensitization, and potential TZD responsiveness.
|Alternate Journal||Proc. Natl. Acad. Sci. U.S.A.|