Mechanisms of human insulin resistance and thiazolidinedione-mediated insulin sensitization

D. D. Sears, G. Hsiao, A. Hsiao, J. G. Yu, C. H. Courtney, J. M. Ofrecio, J. Chapman, S. Subramaniam

Research output: Contribution to journalArticle

119 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)18745-18750
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number44
DOIs
StatePublished - Nov 3 2009
Externally publishedYes

Keywords

  • Branched chain amino acid (BCAA)
  • Diabetes
  • Inflammation
  • Muscle and adipose tissue
  • Transcriptional mechanisms

ASJC Scopus subject areas

  • General

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