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Clinical Trial
. 2009 Nov 3;106(44):18745-50.
doi: 10.1073/pnas.0903032106. Epub 2009 Oct 19.

Mechanisms of human insulin resistance and thiazolidinedione-mediated insulin sensitization

D D Sears  1 , G Hsiao, A Hsiao, J G Yu, C H Courtney, J M Ofrecio, J Chapman, S Subramaniam
Affiliations
Clinical Trial

Mechanisms of human insulin resistance and thiazolidinedione-mediated insulin sensitization

D D Sears et al. Proc Natl Acad Sci U S A. .

Abstract

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Study design and subject insulin sensitivity distribution. (A) Schematic of human insulin-resistance study. (B) Distribution of baseline insulin sensitivity and TZD-mediated insulin sensitization response of study subjects. NRd (insulin sensitive subjects with normal Rd, >8 mg/kg per min, blue square symbols), IRdall (insulin resistant subjects with impaired Rd, <8 mg/kg per min, triangle symbols), IRd+ (subgroup of insulin resistant subjects that are TZD responders, in upper quartile of post-TZD fractional Rd change, pink triangles), IRd− (subgroup of insulin resistant subjects that are TZD nonresponders, in bottom quartile of post-TZD fractional Rd change, yellow triangles), IRdmid (subgroup of insulin resistant subjects in the middle two quartiles of post-TZD fractional Rd change, red triangles). RdFrac − fractional Rd change [(Rd2 − Rd1)/Rd1].
Fig. 2.
Fig. 2.
Differential expression of glucose metabolism genes in skeletal muscle. (A and B) Pre- and postclamp HK2 and PDK4 expression data from the subject groups before and after TZD treatment are shown. (A) Insulin-activated expression of HK2 in NRd subjects was completely blocked in IRdall subjects. After TZD-treatment, this defect was improved in IRdall subjects, normalized in IRd+ subgroup subjects and unaffected in IRd− subgroup subjects. (B) Insulin-induced repression of PDK4 expression in NRd subjects was blunted in IRdall subjects. After TZD-treatment, this defect was improved in IRdall subjects, normalized in IRd+ subgroup subjects and unaffected in IRd− subgroup subjects. NRd (blue), IRdall (red), IRd+ subgroup (pink), IRd− subgroup (yellow). (C) Glycolysis schematic highlighting defectively regulated genes by insulin in IRdall subjects compared with NRd subjects before TZD treatment. Green fill indicates significantly blunted insulin-induced expression in IRdall subjects, resulting in low postclamp expression. Red fill indicates significantly blunted insulin-repressed expression in IRdall subjects, resulting in high postclamp expression. *, significant difference between bracketed groups (αbonf = 0.05).
Fig. 3.
Fig. 3.
Inflammatory marker expression in adipose tissue of insulin resistant subjects. (A and B) Schematics of the antigen processing and presentation pathway highlighting genes that are overexpressed in IRdall subjects before TZD treatment (A) and down-regulated in IRd+ subjects after TZD treatment (B). (C and D) Schematics of the leukocyte transendothelial migration pathway that highlight genes that are overexpressed in IRdall subjects before TZD treatment (C) and down-regulated in IRd+ subjects after TZD treatment (D). White ovals – genes not differentially expressed between NRd and IRdall (A and C) or IRd+ (B and D) subjects. Red ovals – genes significantly overexpressed between NRd and IRdall (A and C) or IRd+ (B and D) subjects. Pink ovals – genes still significantly overexpressed in IRd+ subjects compared with NRd subjects but are significantly down-regulated compared with pre-TZD levels. Schematics are adapted from KEGG. (E) CD74 was significantly overexpressed in all IRd subject groups compared with NRd subjects. After TZD treatment, CD74 expression was significantly down-regulated in IRd+ subgroup subjects (pink) but not in IRdall subjects (red) or IRd− subgroup subjects (yellow). *, significant difference between bracketed groups (αbonf = 0.05). (F) Negative correlation between CD74 expression and Rd (r = −0.59). Graph includes pre- and post-TZD treatment data. IRdall subjects (pink, red, and yellow triangles). IRd+ subgroup subjects (pink), IRd− subgroup subjects (yellow), IRdmid subgroup subjects (red).
Fig. 4.
Fig. 4.
Mitochondrial metabolic function in adipose tissue is correlated with insulin sensitivity. Schematics of mitochondrial metabolic pathways highlighting genes whose adipose tissue expression (before and after TZD treatment) was positively correlated with Rd. (A) β-oxidation of fatty acids, TCA cycle, and branched chain amino acid degradation. (B) Oxidative phosphorylation. Dark orange ovals – genes with expression vs. Rd correlations of r > 0.5. Light orange ovals – genes with expression vs. Rd correlations of r = 0.45–0.50.
Fig. 5.
Fig. 5.
Gene expression predictors of TZD-mediated insulin sensitization. (A) Expression of MLXIP in pre-TZD skeletal muscle was positively correlated with fractional Rd change in IRdall subjects (r = 0.54) and significantly higher in IRd+ vs. IRd− subjects. (B) Expression of HLA-DRB1 in pre-TZD, basal adipose tissue was negatively correlated with fractional Rd change in IRdall subjects (r = −0.47) and significantly lower in IRd+ vs. IRd− subjects. Bars indicate the expression mean and range of fractional Rd change for the IRd+ (red) and IRd− (yellow) subject groups. IRdall subjects (pink, red, and yellow triangles), IRd+ subgroup subjects (pink), IRd− subgroup subjects (yellow), IRdmid subgroup subjects (red).
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