Circulating retinol-binding protein-4 concentration might reflect insulin resistance-associated iron overload.
OBJECTIVE
The mechanisms behind the association between retinol-binding protein-4 (RBP4) and insulin resistance are not well understood. An interaction between iron and vitamin A status, of which RBP4 is a surrogate, has long been recognized. We hypothesized that iron-associated insulin resistance could be behind the impaired insulin action caused by RBP4.


METHODS
Serum ferritin and RBP4 concentration and insulin resistance were evaluated in a sample of middle-aged men (n = 132) and in a replication independent study. Serum RBP4 was also studied before and after iron depletion in patients with type 2 diabetes. Finally, the effect of iron on RBP4 release was evaluated in vitro in adipose tissue.


RESULTS
A positive correlation between circulating RBP4 and log serum ferritin (r = 0.35 and r = 0.61, respectively; P < 0.0001) was observed in both independent studies. Serum RBP4 concentration was higher in men than women in parallel to increased ferritin levels. On multiple regression analyses to predict serum RBP4, log serum ferritin contributed significantly to RBP4 variance after controlling for BMI, age, and homeostasis model assessment value. Serum RBP4 concentration decreased after iron depletion in type 2 diabetic patients (percent mean difference -13.7 [95% CI -25.4 to -2.04]; P = 0.024). The iron donor lactoferrin led to increased dose-dependent adipose tissue release of RBP4 (2.4-fold, P = 0.005) and increased RBP4 expression, while apotransferrin and deferoxamine led to decreased RBP4 release.


CONCLUSIONS
The relationship between circulating RBP4 and iron stores, both cross-sectional and after iron depletion, and in vitro findings suggest that iron could play a role in the RBP4-insulin resistance relationship.
Fernández-Real
José Manuel
JM
Diabetes, Endocrinology, and Nutrition Unit, Dr. Josep Trueta Hospital, Girona Institute for Biomedical Research, Girona, Spain. uden.jmfernandezreal@htrueta.scs.es
Moreno
José María
JM
Ricart
Wifredo
W
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D015415:Biomarkers / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood; D005293:Ferritins / Q000097:blood*; D006801:Humans; D007333:Insulin Resistance; D007501:Iron / Q000378:metabolism*; D000090463:Iron Deficiencies; D019190:Iron Overload / Q000097:blood*; D007781:Lactoferrin / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D054839:Retinol-Binding Proteins, Plasma / Q000187:drug effects / Q000378:metabolism*; D014168:Transferrin / Q000494:pharmacology; D014801:Vitamin A / Q000097:blood
D015415:Biomarkers; C101326:RBP4 protein, human; D054839:Retinol-Binding Proteins, Plasma; D014168:Transferrin; D014801:Vitamin A; D005293:Ferritins; D007501:Iron; D007781:Lactoferrin