C282Y and H63D mutations of the hemochromatosis candidate gene in type 2 diabetes.

Fernández‐Real, José Manuel; Vendrell, Joan; Baiget, Montserrat; Gimferrer, E; Ricart, Wifredo

doi:10.2337/diacare.22.3.525

Cited by 36 publications

(24 citation statements)

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“…Serum ferritin is now proposed to be a component of the metabolic syndrome (49). Interestingly, Moirand et al (51) described a new non-HLA-linked iron over- Data for intake are median (range).…”

Section: Resultsmentioning

confidence: 99%

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Iron Intake and the Risk of Type 2 Diabetes in Women

et al. 2006

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OBJECTIVE -Epidemiological studies suggest that high body iron stores are associated with insulin resistance and type 2 diabetes. The aim of this study was to evaluate the association between dietary intake of iron and the risk of type 2 diabetes.RESEARCH DESIGN AND METHODS -We conducted a prospective cohort study within the Nurses' Health Study. We followed 85,031 healthy women aged 34 -59 years from 1980 to 2000. Dietary data were collected every 4 years, and data on medical history and lifestyle factors were updated biennially.RESULTS -During the 20 years of follow-up, we documented 4,599 incident cases of type 2 diabetes. We found no association between total, dietary, supplemental, or nonheme iron and the risk of type 2 diabetes. However, heme iron intake (derived from animal products) was positively associated with risk; relative risks (RRs) across increasing quintiles of cumulative intake were 1.00, 1.08 (95% CI 0.97-1.19), 1.20 (1.09 -1.33), 1.27 (1.14 -1.41), and 1.28 (1.14 -1.45) (P trend Ͻ 0.0001) after controlling for age, BMI, and other nondietary and dietary risk factors. In addition, when we modeled heme iron in seven categories, the multivariate RR comparing women who consumed Ն2.25 mg/day and those with intake Ͻ0.75 mg/day was 1.52 (1.22-1.88). The association between heme iron and the risk of diabetes was significant in both overweight and lean women.CONCLUSIONS -This large cohort study suggests that higher heme iron intake is associated with a significantly increased risk of type 2 diabetes. Diabetes Care 29:1370 -1376, 2006D iet and lifestyle play a major role in the prevention of type 2 diabetes. The quality and quantity of macronutrients (especially fat and carbohydrates) are known to have an impact on the risk of type 2 diabetes; however, the role of micronutrients is not well established (1). Several studies have suggested a possible role of minerals such as magnesium (2,3), chromium (4,5), calcium (6), and iron (7) in insulin resistance or diabetes.Iron is a transitional metal and a potential catalyst in many cellular reactions that produce reactive oxygen species. Such reactions contribute to tissue damage and increase oxidative stress, thereby potentially altering the risk of type 2 diabetes (8). Several studies have suggested a possible link between high body iron stores and metabolic parameters (9 -13) (serum insulin and glucose) as well as hyp e r t e n s i o n ( 9 , 1 4 ) , d y s l i p i d e m i a (9,15,16), and obesity (9,17). In addition, epidemiological studies have reported an association between high iron stores and increased risk of cardiovascular disease (18), metabolic syndrome (10,12,19), gestational diabetes (20,21), and type 2 diabetes (22-27). The major source of body iron is derived from the diet. Dietary iron exists as either heme (derived from meat and meat products) or nonheme iron. In two recent prospective cohort studies (28,29), intake of total or nonheme iron was not associated with the risk of type 2 diabetes, but heme iron was associated with elevated risk. Th...

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Section: Resultsmentioning

confidence: 99%

“…Another potential mechanism is direct iron deposition in the pancreatic ␤-cells that can impair insulin secretion (48). In addition, the hemochromatosis C282Y and H63D mutations in the HFE gene (chromosome 6) that are associated with high iron stores may also play a role in the development of diabetes (49,50).…”

Section: Resultsmentioning

confidence: 99%

Iron Intake and the Risk of Type 2 Diabetes in Women

et al. 2006

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“…Excess iron storage in patients with type 2 diabetes unrelated to primary hemochromatosis is increasingly recognized. Moreover, patients with diabetes showed increased prevalence for mutations of hereditary hemochromatosis in some studies (30,31). An adequate and safe therapy will be needed for these patients, and blood letting might be one of them.…”

Section: Discussionmentioning

confidence: 99%

Blood Letting in High-Ferritin Type 2 Diabetes

Fernández‐Real¹,

Peñarroja²,

Castro³

et al. 2002

Diabetes

312

199

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Iron-related insulin-resistance is improved by iron depletion or treatment with iron chelators. The aim of this study was to evaluate insulin sensitivity and insulin secretion after blood letting in patients who had highferritin type 2 diabetes and were randomized to blood letting (three phlebotomies [500 ml of blood] at 2-week intervals, group 1) or to observation (group 2). Insulin secretion and sensitivity were tested at baseline and 4 and 12 months thereafter. The two groups were matched for age, BMI, pharmacologic treatment, and chronic diabetic complications. All patients were negative for C282Y mutation of hereditary hemochromatosis. Baseline glycated hemoglobin (6.27 ؎ 0.9% vs. 6.39 ؎ 1.2%), insulin sensitivity (2.75 ؎ 1.8 vs. 3.2 ؎ 2.1 mg ⅐ dl ؊1 ⅐ min ؊1 ), and area under the curve for C-peptide (AUC C-peptide ; 38.7 ؎ 11.6 vs. 37.6 ؎ 14.1 ng ⅐ ml ؊1 ⅐ min ؊1 ) were not significantly different between the two groups of patients. Body weight, blood pressure, blood hematocrit levels, and drug treatment remained essentially unchanged during the study period. As expected, serum ferritin, transferrin saturation index, and blood hemoglobin decreased significantly at 4 months only in patients who received blood letting. In parallel to this changes, blood HbA 1c decreased significantly only in group 1 subjects (mean differences, ؊0.61; 95% CI, ؊0.17 to ؊1.048; P ‫؍‬ 0.01). AUC C-peptide decreased by ؊10.2 ؎ 6.3% after blood letting. In contrast, a 10.4 ؎ 6.4% increase in AUC C-peptide was noted in group 2 subjects at 4 months (P ‫؍‬ 0.032). At 12 months, AUC C-peptide returned to values not significantly different from baseline in the two groups of subjects. At 4 months, the change in insulin sensitivity from baseline was significantly different between the two groups (80.6 ؎ 43.2% vs. ؊8.6 ؎ 9.9% in groups 1 and 2, respectively, P ‫؍‬ 0.049). At 12 months, the differences between the two groups were even more marked (55.5 ؎ 24.8% vs. ؊26.8 ؎ 9.9%; P ‫؍‬ 0.005). When the analysis was restricted to those subjects who completed the follow-up until 12 months, results did not show differences compared with the changes observed at 4 months, except for insulin sensitivity. 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 ⅐ dl ؊1 ⅐ min ؊1 at 4 months, to 3.16 ؎ 1.85 mg ⅐ dl ؊1 ⅐ min ؊1 at 12 months; P ‫؍‬ 0,045) in contrast with group 2 subjects (from 3.24 ؎ 1.9 to 3.26 ؎ 2.05 mg ⅐ dl ؊1 ⅐ min ؊1 at 4 months, to 2.31 ؎ 1.35 mg ⅐ dl ؊1 ⅐ min ؊1 at 12 months). In summary, blood letting led simultaneously to decreased blood HbA 1c levels and to changes in insulin secretion and insulin resistance that were significantly different from those observed in a matched observational group of subjects with high-ferritin type 2 diabetes. The mechanisms for improvement in peripheral insulin sensitivity after blood letting should be investigated further.

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“…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 no significant differences in the prevalence of C282Y mutations between patients with type 2 diabetes and control subjects of Caucasian origin (33)(34)(35)(36).…”

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confidence: 98%

Cross-Talk Between Iron Metabolism and Diabetes

Fernández‐Real¹,

López‐Bermejo²,

Ricart³

2002

Diabetes

593

411

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Emerging scientific evidence has disclosed unsuspected influences between iron metabolism and type 2 diabetes. The relationship is bi-directional-iron affects glucose metabolism, and glucose metabolism impinges on several iron metabolic pathways. Oxidative stress and inflammatory cytokines influence these relationships, amplifying and potentiating the initiated events. The clinical impact of these interactions depends on both the genetic predisposition and the time frame in which this network of closely related signals acts. In recent years, increased iron stores have been found to predict the development of type 2 diabetes while iron depletion was protective. Iron-induced damage might also modulate the development of chronic diabetes complications. Iron depletion has been demonstrated to be beneficial in coronary artery responses, endothelial dysfunction, insulin secretion, insulin action, and metabolic control in type 2 diabetes. Here, we show that iron modulates insulin action in healthy individuals and in patients with type 2 diabetes. The extent of this influence should be tested in large-scale clinical trials, searching for the usefulness and cost-effectiveness of therapeutic measures that decrease iron toxicity. The study of individual susceptibility and of the mechanisms that influence tissue iron deposition and damage are proposed to be valuable in anticipating and treating diabetes complications. Diabetes 51:2348 -2354, 2002

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C282Y and H63D mutations of the hemochromatosis candidate gene in type 2 diabetes.

Cited by 36 publications

References 0 publications

Iron Intake and the Risk of Type 2 Diabetes in Women

Iron Intake and the Risk of Type 2 Diabetes in Women

Blood Letting in High-Ferritin Type 2 Diabetes

Cross-Talk Between Iron Metabolism and Diabetes

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