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Over 38 million adults in the United States have diabetes, according to the Centers for Disease Control and Prevention. Furthermore, the prevalence of diabetes has been steadily rising, increasing from 9.7% in 1999-2000 to 14.7% today.

Traditional risk factors, such as obesity, heredity, and unhealthy lifestyle patterns cannot fully account for the dramatic increase in diabetes prevalence. This has prompted researchers to explore nontraditional risk factors, including metal ion exposure.

“Metal ions are essential inorganic elements for biological processes, entering the body mainly through diet and the environment,” Scott Isaacs, MD, president of the American Association of Clinical Endocrinology, told Medscape Medical News.

Ana Navas-Acien, MD, PhD, MPH, Leon Hess Professor and chair of Environmental Sciences, Mailman School of Public Health, Columbia University, New York City, explained that metal ions enter the body from the environment via transporters and other channels. “They can be readily absorbed through our membranes, such as the GI [gastrointestinal] tract or the respiratory tract,” she noted.

Metals can be classified as essential or nonessential, with the former playing vital roles in bodily functions and the latter having no known function. “Macrometals,” such as magnesium, are found in large quantities in the human body, while other metals, including copper, zinc, iron, manganese, and chromium, are required in small amounts and are referred to as trace elements or micronutrients.

A Delicate Balance

Metal ion metabolism “refers to the regulation of the absorption, distribution, storage, and removal of metal ions in cells,” according to a paper by Siyuan Liu and colleagues. Intracellular metal ion levels must be maintained within a certain range, sometimes described as “intracellular metal ion balance.”

“Mineral metabolism seems to be quite important in the development of diabetes because a good balance in essential metal ions is needed for insulin production as well as for insulin metabolic response in the peripheral tissues — such adipose tissue — as well as in the liver,” Navas-Acien said.

“An imbalance of metal ions can affect health in general and can affect diabetes in particular through worsening insulin resistance or decreasing insulin secretion,” added Isaacs, adjunct associate professor of medicine, Emory University, Atlanta. “These ions are vital for metabolism but harmful in excess or deficiency.”

Imbalances in certain essential metals may adversely affect the pancreas, resulting in the development of diabetes. For example, an association has been found between hemochromatosis — which can be caused by excess iron — and type 2 diabetes (T2D) development. This iron overload damages pancreatic beta-cells through oxidative stress, impairing insulin secretion and promoting insulin resistance.

On the other hand, iron deficiency and iron deficiency anemia can interfere with glucose homeostasis, negatively affect glycemic control, and lead to more complications in patients with both type 1 diabetes (T1D) and T2D. Some research has suggested that correcting iron deficiency can improve diabetes control and may delay or even prevent additional complications.

One method for addressing iron overload is chelation therapy, which promotes excretion of excess iron, reduces iron absorption, and blocks iron recycling. While iron chelators can enhance beta-cell function and insulin sensitivity, they also carry significant drawbacks and potential toxicity, Isaacs said. Phlebotomy can be a viable alternative treatment for iron overload in conditions such as hemochromatosis, according to Isaacs.

An Array of Essential Metals

Beyond iron, several other metal ions play important roles in diabetes and its complications. For example, copper is an essential cofactor of many enzymes. Its deficiency or overload can contribute to diabetes-related complications. Wilson disease, an autosomal recessive copper metabolism disorder, leads to decreased transport of copper from the liver to the bile and the deposition of excess copper in the liver. This results in hepatocellular damage, as well as damage to several other organs and oxidative stress. In turn, oxidative stress can result in peripheral insulin resistance and impairment of islet beta-cell function, triggering diabetes and diabetic complications.

Conversely, diabetes can predispose people to copper overload that similarly causes oxidative stress, resulting in the same type of damage, as well as large and small vascular complications. Tissue damage to the nerves, retina, kidneys, heart, and blood vessels can ensue as well. On the other hand, copper deficiency can lead to small vessel complications.

Zinc, an essential trace element involved in normal cell processing, is responsible for the catalytic activities of more than 300 enzymes. Zinc modulates oxidative stress, enhancing glycemic control and reducing insulin resistance. Its deficiency impairs insulin synthesis and storage, as well as immune regulation, increasing susceptibility to T1D, according to Isaacs. Individuals with diabetes often have suboptimal zinc status in their blood due to increased urinary depletion, making them vulnerable to zinc imbalances. By contrast, zinc overload can lead to anemia, neutropenia, zinc-induced copper deficiency, and zinc toxicity.

“Zinc and copper are required cofactors for important enzymes involved in the regulation of oxidative stress,” Navas-Acien said. “We know that in the early stages of diabetes, there can be severe dysregulation of oxidative stress and alterations in metal ion balance can exacerbate these processes.”

Magnesium also plays a critical role in an array of physiologic functions. Magnesium is involved in the activity of more than 300 enzymes, including those involved with glucose homeostasis. Magnesium deficiency may result in decreased insulin-mediated glucose uptake, and individuals with diabetes have been found to have higher urinary excretion of magnesium than healthy control individuals. Chronic latent magnesium deficit or even overt clinical hypomagnesemia is common in patients with T2D, especially in the setting of poorly controlled glycemic profiles. “Both chromium and magnesium deficiencies reduce insulin sensitivity and glucose uptake,” Isaacs said. On the other hand, magnesium overload (hypermagnesemia) — which is rarer and less studied — is also detrimental, as it can be associated with diabetic ketoacidosis.

Calcium is generally associated with bone health, and indeed, the role of calcium in bone mineralization is one of its most important physiologic functions. But calcium also plays a critical role in pancreatic islet cells and is involved in insulin secretion. In islet beta-cells, glucose induces a rapid increase in calcium, which serves as a major signaling messenger leading to insulin secretion. Diabetes can be associated with both hypo- and hypercalcemia. One reason is that deficiencies in magnesium, often seen in patients with diabetes, can contribute to hypocalcemia, while in T2D, reduced glucose transport through normal insulin stimulation can lead to increased intracellular free calcium concentration. In turn, this increases the demand for insulin, leading to excessive insulin production and secretion and insulin resistance.

Toxic Metals

Not all metal ions are beneficial to the body. Toxic metals such as lead, nickel, cadmium, and arsenic accumulate in tissues and are nondegradable. These harmful metals are found in air, water, and soil, posing risks to everyone but particularly to individuals with diabetes because they can interact with proteins in the body, leading to modification in function and kinetics.

Some toxic metals, including lead, arsenic, and cadmium, have been found in higher concentrations in biological samples of individuals with diabetes than in biological samples of their age-matched counterparts without diabetes, suggesting that individuals with diabetes may have greater vulnerability to their adverse effects. Moreover, they may be implicated in the pathogenesis of several diseases, including diabetes.

Achieving the Best Balance

Addressing and rectifying metal ion imbalances is “an active area of research, which is quite exciting right now because we’re trying to find the best way to restore our metal ion balance,” Navas-Acien said.

The problem is that “restoring this balance isn’t necessarily easy, and just taking mineral supplementation might not be enough,” she continued. “For this reason, there is research ongoing to identify which are the best metal ion forms that we could take to restore this balance and what other interventions might be helpful.”

Liu and colleagues reviewed potential approaches to balancing metal ions in diabetes research and treatment (Table).

Table. Interventions to Improve Metal Metabolism

Navas-Acien emphasized the importance of avoiding exposure to contaminant metals, such as lead and cadmium, which “could interfere with our essential metals.” In addition, “an adequate diet is also critical, as the natural forms of the metal ions found in food might be more readily absorbed than the supplemental forms.”

Isaacs agreed. “Zinc and chromium supplements are not usually recommended over a healthy, balanced diet rich in foods that are high in zinc and chromium.” He also suggested additional lifestyle modifications, such as limiting processed foods high in sodium, consuming iron-rich meats, and increasing the intake of foods abundant in magnesium and zinc.

Navas-Acien believes “we’re going to see substantial advances, which could help us delay or fully prevent the development of diabetes.” In addition to the potential benefits of balancing essential metal ions in preventing or delaying diabetes onset, “evidence also shows that a good balance of these ions could be quite important to prevent complications of diabetes, including cardiovascular outcomes and peripheral arterial disease.” For example, her group has conducted a study showing a connection between excess elimination of zinc via urine and the risk for amputation in patients with diabetes.

Understanding metal ions may inform future targets for diabetes treatment, according to Navas-Acien. “This is an area of research I want to focus on strongly, as I see major opportunities to help people and have a positive impact in society,” she stated. She anticipates “important breakthroughs in the coming years.”

Isaacs and Navas-Acien reported having no relevant financial relationships.

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape Medical News and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom(the memoir of two brave Afghan sisters who told her their story).