Plasma retinol-binding protein-4 concentrations are elevated in human subjects with impaired glucose tolerance and type 2 diabetes.

OBJECTIVE: The dysregulation of adipokines is closely associated with the pathogenesis of insulin resistance and type 2 diabetes. Retinol-binding protein-4 (RBP4), a new adipokine, was recently reported to provide a link between obesity and insulin resistance. Here, we examined the relation between plasma RBP4 concentrations and various metabolic parameters in humans. RESEARCH DESIGN AND METHODS: An enzyme-linked immunosorbent assay was developed to measure human RBP4 plasma concentrations, which were then compared with various parameters related to insulin resistance in subjects with normal glucose tolerance (NGT; n = 57), impaired glucose tolerance (IGT; n = 48), and type 2 diabetes (n = 49). RESULTS: Plasma RBP4 concentrations were higher in the IGT and type 2 diabetic groups than in the NGT group (median 18.9 [range 11.2-45.8], 20.9 [9.9-48.5], and 18.1 microg/ml [9.3-30.5], respectively). However, no difference was found between plasma RBP4 concentrations in the IGT and type 2 diabetic groups. Plasma RBP4 concentrations were found to be associated with sex, waist circumference, fasting plasma glucose, and insulin resistance. Of these, sex and fasting plasma glucose levels were found to be independent determinants of plasma RBP4 concentration. CONCLUSIONS: Plasma RBP4 concentrations were found to be elevated in subjects with IGT or type 2 diabetes and to be related to various clinical parameters known to be associated with insulin resistance.

The role of adipocytokines in adipocyte-related pathological processes.

It is becoming clear that adipose tissue is not merely a storage for excess energy but that it secretes a number of biologically active soluble factors collectively termed adipocytokines that control glucose and fatty acid metabolism. Of these adipocytokines, adiponectin and resistin have been the objects of intensive research, as they are implicated in obesity and diabetes-related diseases. In this review, we summarize recent advances in understanding the roles of adiponectin and resistin in the causation of metabolic diseases and consider the prospects for treating metabolic disorders by targeting these two adipocytokines.

Plasma resistin concentrations measured by enzyme-linked immunosorbent assay using a newly developed monoclonal antibody are elevated in individuals with type 2 diabetes mellitus.

Resistin is an adipocyte-derived peptide that might play a role in obesity and insulin resistance. However, its role in humans is largely unclear. Although many studies have measured the expression of human resistin in tissues, the circulating concentrations of resistin and its relation to metabolic parameters in humans are unknown. We developed an ELISA for human resistin and measured plasma concentrations in aged individuals with or without type 2 diabetes mellitus. To validate the results of plasma resistin concentrations in our subjects, plasma adiponectin concentrations were also determined, which were higher in nondiabetic subjects than in type 2 diabetic patients and correlated with the homeostasis model assessment for insulin resistance (HOMA-IR). Log-transformed plasma resistin concentrations (log-resistin) were higher in diabetic patients compared with normal individuals (0.50 +/- 0.39 vs. 0.28 +/- 0.51 ng/ml; P < 0.001), and this difference was significant after controlling for gender and body mass index. Log-resistin did not show a significant correlation with HOMA-IR, waist circumference, body mass index, blood pressure, or total cholesterol. The plasma glucose concentration was an independent factor associated with log-resistin. In conclusion, plasma resistin concentrations are elevated in patients with type 2 diabetes, but are not associated with insulin resistance or obesity.

Identification of a ligand for glucocorticoid-induced tumor necrosis factor receptor constitutively expressed in dendritic cells.

Glucocorticoid-induced tumor necrosis receptor (GITR) has been implicated in regulation of T cell suppression by CD25(+)CD4(+) regulatory T cells (Tregs). We isolated a cDNA encoding GITR ligand (GITRL) from mouse endothelioma cells. When stably expressed in HEK293 cells, its specific interaction with GITR was confirmed by flow cytometry with the use of GITR-Fc. The interaction was greatly diminished by the addition of soluble GITRL. Consistent with this, soluble GITRL bound to the cell surface of the GITR-expressing HEK293 cells. Coexpression of GITR with GITRL or stimulation of the GITR-expressing cells with soluble GITRL led to activation of NF-kappaB, which was significantly reduced by anti-GITR. More importantly, GITRL was expressed by both immature and mature dendritic cells, suggesting that the interaction between GITR and GITRL may contribute to immune regulation of Tregs by dendritic cells. This isolated TNFRL represents a bona fide GITRL whose presence has been elusive until this time.