Circulating Soluble Transferrin Receptor According to Glucose Tolerance Status and Insulin Sensitivity

Abstract

OBJECTIVE -The relationships between iron metabolism and type 2 diabetes are bidirectional: iron affects glucose metabolism and glucose metabolism impinges on several iron metabolic pathways. The mechanisms of these interactions depend on poorly known factors. We aimed to study the contribution of the serum soluble transferrin receptor (sTfR). RESEARCH DESIGN AND METHODS -Circulating sTfR was evaluated in 221 men(97 with normal glucose tolerance [NGT], 36 with impaired glucose tolerance, and 88 with type 2 diabetes). In a subset of these subjects, glucose tolerance (oral glucose tolerance test [OGTT]), minimal model-derived insulin sensitivity, and sTfR during the OGTT were also evaluated.RESULTS -Men with altered glucose tolerance showed significantly increased sTfR (9.4 Ϯ 4.4 vs. 8.2 Ϯ 2.6 g/ml, P ϭ 0.02) and higher serum ferritin than men with NGT. Serum sTfR was negatively associated with serum ferritin (r ϭ Ϫ0.16, P ϭ 0.02). sTfR correlated with several clinical and metabolic variables such as systolic blood pressure, glycated hemoglobin, and glucose and insulin values during OGTT. Insulin sensitivity was also negatively associated with sTfR in NGT and nonobese subjects. BMI (P ϭ 0.01), serum ferritin (P ϭ 0.025), and insulin sensitivity (P Ͻ 0.0001) contributed independently to 21% of sTfR variance. Serum sTfR concentration did not significantly change during the OGTT.CONCLUSIONS -Both insulin sensitivity and glucose tolerance status are significantly associated with serum sTfR concentrations, although insulin sensitivity predicts independently circulating sTfR, mainly in subjects with NGT. The implications of the interrelationships between iron and glucose metabolism should be investigated further. Diabetes Care 30:604 -608, 2007I nsulin is an anabolic hormone that stimulates the cellular uptake of many nutrients, including hexoses, amino acids, cations, and anions. In the steady state, iron circulates bound to transferrin and is taken up from the blood by a highaffinity specific transferrin receptor (TfR) (1). The TfR complex is internalized by endocytosis and released into a nonacidic cellular compartment, where it can be used in the synthesis of essential cellular components. Insulin is known to cause a rapid and marked stimulation of iron uptake by fat cells, redistributing TfRs from an intracellular membrane compartment to the cell surface (2). Insulin also induces iron transport and accumulation in hepatocytes by a similar mechanism (2) and is responsible for increased ferritin synthesis in cultured rat glioma cells (3). TfRs have been shown to colocalize with insulin-responsive glucose transporters and IGF-II receptors in the microsomal membranes of cultured adipocytes, suggesting that regulation of iron uptake by insulin parallels its effects on glucose transport (4).The synthesis of TfR and the iron storage protein ferritin is regulated reciprocally at the posttranscriptional level according to the cellular iron status (5). As a result of the externalization of TfR during the endocytic cycle, a s...

Role of androgen-mediated enhancement of erythropoiesis in the increased body iron stores of patients with polycystic ovary syndrome

“…Our data rule out any direct association of sTfR concentrations with indexes of insulin metabolism, obesity, and abnormal glucose tolerance, in sharp contrast with previous findings in older men in whom sTfR levels were higher in the subgroup presenting with altered glucose tolerance (28). Aside from the obvious sex differences in iron metabolism, the fact that the population studied here was older and that the diabetic patients were under pharmacologic treatment with several drugs, including insulin, sulfonylureas, and insulin sensitizers, may contribute to explain the discrepancies with our present data in much younger and untreated premenopausal women.…”

Circulating soluble transferrin receptor concentration decreases after exercise-induced improvement of insulin sensitivity in obese individuals

“…6 We observed that the lower the insulin sensitivity, the higher the sTfR concentration. Furthermore, insulin sensitivity, independently of age, obesity and iron status, contributed independently to the variance of circulating sTfR concentration.…”

“…Furthermore, insulin sensitivity, independently of age, obesity and iron status, contributed independently to the variance of circulating sTfR concentration. 6 As insulin injection increases serum sTfR concentration in animal models, 7 hyperinsulinaemia may contribute to the inappropriately high sTfR concentration detected in individuals with altered glucose tolerance.…”

“…6 Recently, resistance training (RT) has been shown to improve insulin sensitivity in individuals with type 2 diabetes. 8 Taking into account these observations, 26 obese women were randomized to follow a structured RT program and a hypocaloric diet (n ¼ 11), compared with hypocaloric diet alone (n ¼ 8) and a group of individuals in whom no action was implemented (n ¼ 7).…”

Biomarkers of iron metabolism are independently associated with impaired glucose metabolism and type 2 diabetes: the KORA F4 study

“…These studies in general reported positive associations, although transferrin is inversely related to body iron stores and ferritin (8). In addition, while increased ferritin is quite consistently associated with hyperglycemia or insulin resistance, existing results on the soluble transferrin receptor (sTfR) and transferrin saturation (TSAT) are much more controversial (4,9,10,11,12,13).…”