Cross-Talk Between Iron Metabolism and Diabetes

José Manuel Fernández-Real, Abel López-Bermejo, and Wifredo Ricart

Disclosures

Diabetes. 2002;51(8) 

In This Article

Clinical and Therapeutical Implications of Iron Depletion

There are historical notes regarding iron overload conditions that can be helpful in delineating the effects of iron depletion.[58,59,60] Phlebotomy was first used in the treatment of hemochromatosis in the 1950s. Interestingly, diabetic metabolic control improved in 35-45% of patients with hemochromatosis after iron depletion.[58] In 1969, Williams et al.[59] showed that diabetic patients treated with phlebotomy required less insulin than similar patients during the prephlebotomy period. In 1972, Dymock et al.[60] reported a significant reduction in total daily insulin dosage following phlebotomy.

Facchini[11] found significant reductions in insulin concentrations 1 month after performing a 550-ml phlebotomy in healthy volunteers. It has also been suggested that the increased insulin sensitivity observed in vegetarian subjects might be related to their low-iron diet. Recently, as stated above, blood letting of 1, 500 ml has been demonstrated to improve insulin sensitivity and to decrease C-peptide secretion in type 2 diabetic subjects who were negative for common hemochromatosis mutations but had increased serum ferritin concentration.[15]

Iron chelators also seem beneficial in optimizing diabetic metabolic control. In 1989, Cutler[61] administered deferoxamine to nine type 2 diabetic patients with hyperferritinemia who were negative for the most common hemochromatosis haplotypes. Major improvement in the metabolic control was observed in seven patients, and parallel reductions in baseline concentrations of glucose, triglycerides, and glycated hemoglobin were observed. Treatment with either insulin or oral hypoglycemic agents could be discontinued insome patients.[61] Subsequently, it was reported that subcutaneous deferoxamine caused an improvement in glycated hemoglobin in another nine patients,[62] although serum concentrations of C-peptide after glucose or arginine infusion did not improve significantly.[62]

Macrovascular Disease. The general effect of catalytic iron is to convert poorly reactive free radicals, such as H2O2, into highly reactive ones, such as OH- and O2. Free radicals and other oxidation by-products are well known factors that impair the mechanisms of vasodilatation[63] and cause endothelial depletion of endogenous antioxidants, such as ascorbic acid.[64] Iron chelation blocks oxidation of LDL, and iron released from heme and ferritin favors oxidation of this lipoprotein.[65] Increased iron availability is, theoretically, expected to contribute to macrovascular disease because iron has an adverse effect on endothelium[66] and accelerates the development of atherosclerosis.[67] In fact, ferritin gene expression increases in the course of atherosclerotic plaque formation.[68] Notwithstanding, studies performed in experimental models offer conflicting conclusions. For instance, an iron-deficient diet has been found to reduce atherosclerotic lesions,[69] whereas iron overload led to a decrease in atherosclerosis[70] in the same animal model. It should be noted, however, that the possible influence of obesity, insulin resistance, or diabetes has not been explored in experimental iron-modified atherosclerosis. Moreover, humans are the only species in which genetic iron overload has been described to induce significant parenchymal damage.[71]

In subjects with hemochromatosis, medium-sized arteries are characterized by an eccentric hypertrophy and decreased distensibility that are partially reversible after iron depletion.[72] These findings seem to be linked to iron-induced fibrogenesis, determining an increased total collagen content in arteries from these patients. There is also some evidence for iron-dependent growth of arterial wall tissue: iron chelation by deferoxamine inhibits vascular smooth muscle cell proliferation.[73]

Long-term use of the modified iron chelator hydroxyethyl starch conjugated-deferoxamine prevented endothelial dysfunction associated with experimental diabetes.[74] In type 2 diabetic patients, coronary artery responses to cold stress testing improved substantially after deferoxamine administration.[16] Similarly, iron chelation was shown to ameliorate the endothelial dysfunction of patients with coronary heart disease.[17]

Improvement of nitroglycerine-induced vasodilatation was also observed following phlebotomy in type 2 diabetic patients in a preliminary study. The improvement in vascular reactivity paralleled the decrease in serum transferrin saturation, total hemoglobin (markers of circulating iron), and blood glycated hemoglobin.[75] These observations suggest that diabetic vascular dysfunction seems partially reversible and that the circulating compartment acts as a reservoir of transition metals that directly affects vascular function.[76] Increased hemoglobin, an iron-enriched protein, is deleterious for endothelial function, as normal blood vessels exposed to total and glycated hemoglobin are known to experience impaired vascular relaxation.[77]

In the general population, the relationship between iron and atherosclerosis is, however, controversial.[78] Thus, some animal experimental data regarding the effect of manipulating iron stores on atherosclerosis and human data showing improvement of vascular structure and function following iron depletion[16,17,72,75] are both consistent with the theory that iron contributes to the development of vascular disease. However, the current epidemiological data associating iron stores with either atherosclerosis or coronary heart disease (reviewed i[78] do not fully support this hypothesis.

An early development and accelerated course of diabetic nephropathy has been observed in iron-loaded patients with -thalassemia, a condition with recognized iron overload.[79] Increased proximal tubular lysosomal iron concentration has been observed in patients with diabetic nephropathy.[80] These observations are pertinent to the finding that mutations for hereditary hemochromatosis appeared to predict the development of diabetic nephropathy.[32]

Deferoxamine administration restored motor and sensory nerve conduction velocity and improved nerve blood flow in experimental studies.[76] The possible extrapolation of these findings to human diabetes has not been explored.

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