Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 44, Pages 18745-18750Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0903032106
Keywords
muscle and adipose tissue; transcriptional mechanisms; diabetes; branched chain amino acid (BCAA); inflammation
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Funding
- National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [K01-DK62025]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development and NIH [U54-HD012303]
- NIH [P01-DK074868, R01DK033651, R33-HL087375]
- National Institute of General Medical Sciences [U54-GM69338]
- NIDDK [P01-DK074868]
- University of California Discovery [bio03-10383]
- Pfizer, Inc.
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Cellular and tissue defects associated with insulin resistance are coincident with transcriptional abnormalities and are improved after insulin sensitization with thiazolidinedione (TZD) PPAR gamma 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.
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