Cross-Talk Between Iron Metabolism and Diabetes

Iron Stores are Associated With Insulin Sensitivity, Insulin Secretion, and Type 2 Diabetes

Iron stores, expressed as serum ferritin concentration, have been proposed to be a component of the insulin-resistance syndrome. Indeed, the concentration of circulating ferritin was significantly associated with centrally distributed body fatness as well as with several other measurements of obesity.^[19] In the apparently healthy general population, serum levels of ferritin were also positively correlated with baseline serum glucose and with the area under the curve for glucose during the glucose oral tolerance test.^[20,21] In gestational diabetes, both BMI and serum ferritin levels were found to be independent predictors of 2-h glucose during an oral glucose tolerance test.^[8,9] Ferritin levels also correlated with diastolic arterial blood pressure, even after adjustment for BMI. Of note is the beneficial effect of blood letting, a means of reducing iron stores, in the treatment of resistant hypertension^[22] and in posttrans plant hypertension associated with erythrocytosis.^[23] Serum ferritin concentration was also directly associated with uric acid (another component of the insulin resistance syndrome) and inversely related with HDL cholesterol and the HDL₂-to-HDL₃ ratio.^[21]

Insulin resistance itself, assessed by either the euglycemic clamp ^[24] or the minimal model,^[25,26] was found to be associated with total body iron stores, even in the presence of normal glucose tolerance. Dmochowski et al.^[25] reported that serum concentrations of ferritin were negatively correlated with insulin sensitivity (r = -0.58) in subjects with hemosiderosis. Cavallo-Perinet al.^[26] reported that insulin sensitivity, which correlated closely with iron overload (r = -0.70), was reduced by 40% in thalassemia patients. Insulin resistance also appeared to be closely linked to total body iron stores in the general population.^[21] Serum ferritin levels could be a useful marker of insulin resistance beyond a given threshold.^[20,21] In the study by Toumainen et al.,^[20] the increase in serum insulin concentrations was clearly apparent in the upper two quintiles of ferritin levels. In a different study, the correlation between circulating ferritin and insulin resistance was only observed in the upper two quartiles of ferritin levels.^[21] Below this threshold, the potential tissue effects of siderosis would be negligible.

Some comments on the specifity of serum ferritin as an indicatorof iron stores seem necessary. The relationship between serum ferritin and histochemical assessment of stainable tissue iron contributes to define threshold values for serum ferritin, indicating exhausted, small, normal, ample, and increased iron stores. However, the barrier between "normal" and " small" or "ample" iron stores is not well defined and remains controversial. Approximately 10% of type 2 diabetic patients with high ferritin levels had transferrin saturations greater than normal (40%). On the other hand, serum ferritin should be cautiously evaluated in patients with type 2 diabetes, because it may falsely indicate "normal iron stores." It should not be ignored that chronic inflammation could contribute, to some extent, to increased ferritin concentration (see below).