Cross-Talk Between Iron Metabolism and Diabetes

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


Diabetes. 2002;51(8) 

In This Article

Iron Overload and Type 2 Diabetes

Five additional pieces of scientific evidence favor the hypothesis that iron plays a role in type 2 diabetes. First, increased prevalence of hemochromatosis was found among unselected patients with type 2 diabetes. Phelps et al.[29] and Conte et al.[30] reported that diabetes confers increased risk for hereditary hemochromatosis, which was 2.4% and 1.34% higher in Australian and Italian populations, respectively.

This evidence, however, is not always consistent. The recent characterization of HFE has allowed a more direct study of the prevalence of its mutations in type 2 diabetes. Homozygosity for the C282Y change is generally associated with clinically evident hereditary hemochromatosis (83% of hemochromatosis patients are YY homozygotes). Compound heterozygotes for H63D mutation(C282Y/H63D) succumb to the disease, although with reduced penetrance. An increased frequency of C282Y mutations in subjects with type 2 diabetes has been described in some studies.[31,32] Notwithstanding, at least four additional studies reported nosignificant differences in the prevalence of C282Y mutations between patients with type 2 diabetes and control subjects of Caucasian origin.[33,34,35,36] In the Spanish population, the frequency of the H63D mutation was significantly higher in type 2 diabetic subjects.[36] The H63D mutation is also associated with other nonclassical conditions of iron overload. On the other hand, it is interesting to mention that genetic hemochromatosis contributed to 1% of late-onset type 1 diabetes.[37]

Second, frequent blood donations, leading to decreasing iron stones, have been demonstrated to constitute a protective factor for the development of diabetes.[13] This finding is especially important given the high prevalence of increased iron stores in the general population of western countries[10] and the observation that increased iron stores appear to predict an increased incidence of type 2 diabetes.[5] In experimental models, the incidence of diabetes was reduced from 78 to 22%at 120 days of age after serial blood withdrawals in the BBrat.[38]

Third, a recent randomized study also suggests that iron stores may influence insulin action in type 2 diabetes.[15] In this report, 28 type 2 diabetic patients with increased serum ferritin concentration and negative for C282Y mutation of hereditary hemochromatosis were randomized to blood letting (three 500ml phlebotomies at 2-week intervals) or to observation. Insulin secretion and sensitivity were tested at baseline and at 4 and 12 months thereafter. The two groups were matched for age, BMI, pharmacological treatment, and chronic diabetes complications.[15] Baseline glycated hemoglobin and insulin sensitivity were not significantly different between the two groups. A statistically significant increase in insulin sensitivity was observed in the blood-letting group (from 2.30 ± 1.81 to 3.08 ±2.55 mg · dl-1 · min-1 at 4 months to 3.16 ±1.85 mg · dl-1 · min-1 at 12 months, P = 0.045) in contrast to patients subjected to observation in whom insulin sensitivity did not significantly change (from 3.24 ±1.9 to 3.26 ± 2.05 mg · dl-1 · min-1 at 4 months to 2.31 ± 1.35 mg · dl-1 · min-1at 12 months). Accordingly, blood HbA1c decreased significantly only in the blood-letting group at 4 months (mean differences-0.61, 95% CI -0.17 to -1.048, P = 0.01).

Fourth, a novel syndrome of hepatic iron overload has been described that associates hyperferritinemia with normal transferrin saturation and is not linked to the HLA-A3 antigen, a common marker for hereditary hemochromatosis.[39] This condition is known as insulin resistance-associated hepatic iron overload (IR-HIO) and combines abnormalities in iron metabolism (isolated hyperferritinemia with normal transferrin saturation), steatohepatitis, and the insulin resistance syndrome (obesity, hyperlipidemia, abnormal glucose metabolism, and hypertension).[39,40,41] In IR-HIO, iron overload occurs in both hepatocytes and sinusoid cells, being higher in the latter cells in 45% of cases, a finding seen in only 3% of subjects with hemochromatosis.[42] Approximately two-thirds of these patients develop steatosis, whereas the remaining third show isolated signs of inflammation.[42] Thus, these patients are at high risk for developing liver fibrosis, a complication observed in 60% of all cases, even in the presence of moderate iron overload. In contrast, liver fibrosis affects only 33% of patients with hemocromatosis. Because patients with IR-HIO are prone to experience significant tissue damage and because this can be prevented with simple and inexpensive therapies (i.e., phlebotomy), higher awareness in order to diagnose the disease has been suggested.

It cannot be ruled out, however, that IR-HIO is the same process of iron overload-related insulin resistance that associate sliver steatosis and fibrosis in susceptible patients. It is important to recognize that in one study, liver iron stores were found within the normal range in patients with type 2 diabetes[43] in contrast to other studies.[29,30] Under this assumption, IR-HIO would be at one end of the spectrum of iron overload-related insulin resistance.

Fifth, insulin resistance features are frequently seen in patients chronically infected with the hepatitis C virus. In these subjects, BMI, elderliness, iron stores, and family history of diabetes and advanced liver fibrosis were found to predict the development of diabetes.[44]