Mechanisms of human insulin resistance and thiazolidinedione-mediated insulin sensitization

DD Sears, G Hsiao, A Hsiao, JG Yu… - Proceedings of the …, 2009 - National Acad Sciences
DD Sears, G Hsiao, A Hsiao, JG Yu, CH Courtney, JM Ofrecio, J Chapman, S Subramaniam
Proceedings of the National Academy of Sciences, 2009National Acad Sciences
Cellular and tissue defects associated with insulin resistance are coincident with
transcriptional abnormalities and are improved after insulin sensitization with
thiazolidinedione (TZD) PPARγ 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 …
Cellular and tissue defects associated with insulin resistance are coincident with transcriptional abnormalities and are improved after insulin sensitization with thiazolidinedione (TZD) PPARγ 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.
National Acad Sciences