Does Iron Overload Cause Diabetes and Heart Disease?

Iron plays an essential role in many physiological processes, including oxygen transport and mitochondrial energy production. However, more iron is not necessarily better! The overaccumulation of iron in the body, a condition referred to as iron overload, has been implicated in the development of several chronic diseases, including diabetes and heart disease. Read on to learn why iron overload promotes the development of diabetes and heart disease and how iron reduction strategies can be used to beneficially alter the course of these diseases.

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What Is Iron Overload?

Iron overload occurs when excess iron accumulates in the body. The most common cause of iron overload is hereditary hemochromatosis (HH), an autosomal recessive genetic disorder that affects between one in 200 and one in 400 individuals and is caused by mutations in the HFE C282Y and H63D genes. (1) HH is characterized by significantly enhanced intestinal iron absorption and the abnormal accumulation of iron in bodily organs. Excess iron oxidatively damages cells and tissues, essentially “rusting” the body. This generates organ toxicity and promotes chronic disease processes.

However, a negative test result for the C282Y and H63D mutations does not mean a person is “off the hook” for iron overload. In fact, carriers of HFE mutations and people with moderately elevated iron levels also have an increased risk of health complications associated with iron overload. (2) Alarmingly, research indicates that iron overload may be a significant but greatly underappreciated cause of two widely prevalent chronic diseases, diabetes and heart disease.

Iron Overload Is a Risk Factor for Metabolic Syndrome and Diabetes

The association between iron overload and diabetes was first noted in people with hereditary hemochromatosis. However, the effects of iron overload on glucose and insulin homeostasis are not limited to those with hemochromatosis. A growing body of research indicates that moderately elevated serum ferritin levels, well within the normal laboratory reference range, are associated with abnormal blood sugar, insulin resistance, metabolic syndrome, and diabetes. (3, 4, 5, 6) In fact, the constellation of high serum ferritin, insulin resistance, and glucose dysregulation has become common enough among the general population to warrant its own name—dysmetabolic iron overload syndrome (DIOS).

Have you had your iron levels checked? If you have heart disease or diabetes you should.

While serum ferritin is the most well-studied biomarker in relation to metabolic syndrome and diabetes, another important iron regulatory hormone, hepcidin, has also been associated with these conditions. (7) Hepcidin inhibits intestinal iron absorption, and in people without HFE mutations, it is upregulated in the presence of high body iron. However, elevated hepcidin may also detrimentally alter genes that govern insulin production, thus causing this protective function to backfire. Altogether, the available evidence suggests that “normal” iron levels may not be ideal and that iron overload may affect far more people than once believed.

There are several mechanisms by which iron physiologically impacts glucose and insulin homeostasis. Iron is catalytically reactive and readily interacts with endogenously produced hydrogen peroxide in a process called the Fenton reaction. This reaction produces hydroxyl free radicals, which oxidatively damage cells and tissues, including pancreatic beta-cells. The iron-induced free radical damage sustained by pancreatic beta-cells decreases insulin synthesis and secretion, contributing to insulin resistance. (8, 9) Iron overload also decreases glucose oxidation, impairing the utilization of glucose for fuel, and increases hepatic glucose production. (10, 11) Finally, iron has a proclivity for adipocytes; the accumulation of iron in fat cells reduces their production of the insulin-sensitizing hormone adiponectin, thus inducing insulin resistance.

While the harmful effects of iron overload on glucose and insulin homeostasis are concerning, it is possible to mediate the damage. Interestingly, the induction of near iron deficiency through therapeutic phlebotomy has been found to significantly lower postprandial blood glucose, improve glucose tolerance, and increase adiponectin, indicating that reduction of iron stores may be beneficial for the treatment of metabolic syndrome and diabetes. (12, 13)

Excess Iron Harms the Cardiovascular System

Cardiovascular disease (CVD) is the single largest cause of mortality in the world, and a growing body of evidence indicates that iron overload may play a significant role in its pathogenesis. Iron overload was first correlated with CVD in people with hereditary hemochromatosis. However, current evidence indicates that even moderately elevated body iron levels confer an increased risk of cardiovascular disease. (14)

Several epidemiological studies have revealed that men with serum ferritin levels above 200 µg/L have a significantly increased risk of atherosclerosis and ischemic cardiovascular disease. (15, 16) A similar association has been discovered in postmenopausal women, with high serum ferritin conferring an increased risk of cardiovascular complications. The risk for women appears to increase after menopause because the regular iron losses associated with menstruation have ceased, leading to iron accumulation. (17) Serum ferritin is also positively associated with increased carotid arterial plaque, coronary artery calcium content, and carotid arterial thickness, factors that promote the progression of atherosclerosis. (18, 19, 20)

Several studies have noted that the relationship between iron levels and CVD is stronger in people with elevated LDL concentrations and the ApoE4 gene variant, which has been linked to higher levels of oxidized LDL; this suggests that LDL may interact with ferritin, potentially through the process of lipid peroxidation, to increase the risk of CVD.

The primary mechanism by which iron harms the cardiovascular system is through the production of free radicals. In the Fenton reaction, mentioned previously in the context of iron and diabetes, iron reacts with hydrogen peroxide to create hydroxyl free radicals. Hydroxyl free radicals oxidize LDL particles and free fatty acids, contributing to the development of atherosclerosis and CVD. (21) Elevated hepcidin may also contribute to iron-induced cardiovascular damage by promoting the destabilization of fatty arterial plaques, a phenomenon implicated in the development of atherosclerosis. (22, 23)

How to Assess Iron Overload

Serum ferritin and hepcidin are two key markers for diagnosing iron overload; however, they are also acute-phase reactants that are elevated in the inflammatory response. To distinguish between iron overload and inflammation, a handful of other tests should be performed. These include measurements of iron saturation, soluble transferrin receptor, C-reactive protein and A1-acid glycoprotein, and HFE genetic testing. An elevated iron saturation measurement is indicative of iron overload, whereas the soluble transferrin receptor level will be low when iron is present in excess. C-reactive protein and A1-acid glycoprotein are acute-phase reactants that are elevated in the inflammatory response and can be used to distinguish between iron overload and inflammation—though it’s important to note that a normal C-reactive protein does not rule out inflammation as a cause of high ferritin. HFE genetic testing can reveal whether a patient possesses HFE C282Y or H63D variants.

What Treatment Options Are Available for Iron Overload?

Within the scientific community, the role of iron as a risk factor for diabetes and cardiovascular disease has drawn significant attention because it may be easily modifiable through dietary modification and other iron reduction strategies. Historically, phlebotomy and iron-chelating pharmaceuticals have been the frontline treatment for iron overload in people with hereditary hemochromatosis. However, recent research indicates that iron reduction may also be beneficial for people with mild to moderate iron overload. Iron chelation and phlebotomy produce improvements in insulin secretion and sensitivity, decrease glycated hemoglobin, and improve endothelial function in patients with and without hemochromatosis. (24, 25, 26, 27) For patients with severe iron overload, a prescription for therapeutic phlebotomy from a hematologist may be required; for those with milder cases, regular blood donations may be sufficient for lowering iron levels.

Specific dietary guidelines have been created for patients with hemochromatosis, and some of the recommendations may also be useful for people with mild to moderate iron overload. (28) The guidelines, developed by the Iron Disorders Institute, include the following:

• Avoid organ meats, venison, and shellfish. These foods are all very high in heme iron.
• Limit consumption of beef and lamb, which are also high in heme iron, to two or three times per week. Heme iron is more bioavailable than non-heme iron, present in plant foods such as legumes, grains, nuts, and seeds.
• Limit supplemental vitamin C to 200 mg/day. Supplemental vitamin C enhances intestinal iron absorption, but vitamin C from foods is fine.
• Avoid alcohol and sugar. Alcohol and sugar enhance intestinal iron absorption.
• Avoid supplements/multivitamins that contain iron.
• Eat a wide variety of fruits and vegetables. Plant foods contain polyphenols and oxalates that inhibit iron absorption and antioxidants that counteract iron-induced free radical damage.
• Drink tea or coffee with meals. The tannins in these beverages inhibit iron absorption.

While phlebotomy, pharmaceutical iron chelators, and dietary changes are currently the prevailing treatment options for iron overload, a wide variety of natural compounds have also been investigated for their iron-reducing potential. Green tea catechins have been found to chelate iron and scavenge free radicals; these dual roles may be beneficial for simultaneously reducing iron-overload and combating free radical damage in people with diabetes and CVD. (29, 30) Quercetin, a phytochemical found in a wide variety of fruits and vegetables, also inhibits intestinal iron absorption and reduces iron-induced free radical damage. (31, 32) Curcumin, an herb that has been lauded for its many health-promoting properties, has also demonstrated an ability to chelate iron. (33, 34) A handful of other herbs and plant compounds have demonstrated iron-chelating and free radical-scavenging activity, including Chinese skullcap, pycnogenol, and Ligusticum wallichi. (35, 36, 37) Finally, the iron-binding protein apolactoferrin binds and sequesters iron outside of the bloodstream and is protective against iron-mediated free radical damage. This protein occurs naturally in the body but can be supplemented in a form derived from cow’s milk. (38) While more research is needed to determine the clinical efficacy of these natural iron-binding compounds, the available evidence is promising and suggests that non-pharmaceutical iron-reduction strategies may soon be viable treatment options for patients with moderate iron overload.