Iron Overload Contributes to Risk for Type 2 Diabetes in Mice

Iron Overload Contributes to Risk for Type 2 Diabetes in Mice

Oct 25, 2010 9:28 AM

SALT LAKE CITY—Iron intake is critical to a healthy diet, but a new study by University of Utah medical researchers shows that excessive levels of that micronutrient contribute to the risk for developing a disease that has become epidemic worldwide – Type 2 diabetes.
Published in the journal Diabetes online on Sept. 28, 2010, the study answers a longstanding question about the role of iron in Type 2 diabetes by showing that iron overload caused mouse models to develop two hallmark characteristics of the disease – higher glucose production in the liver and metabolic inflexibility, a condition in which the body is less able to shift between breaking down fatty acids and glucose.

The work adds to a growing body of evidence that excess iron may confer diabetes risk, and was done in the laboratory of Donald A. McClain, M.D., Ph.D., professor of internal medicine and biochemistry, director of the U of U Center for Clinical and Translational Science, and senior author of the study. Postdoctoral researcher Jingyu Huang Ph.D., the first author, points out that the current studies, performed in mice, provide two possible reasons for the connection between iron and diabetes, but they are yet to be confirmed in humans.
Diabetes is a metabolic disease in which blood glucose levels rise above normal, sometimes resulting in life-threatening damage to the kidneys, eyes, nerves, blood vessels, and other tissues. There are two main types of diabetes: Type 1, in which the body cannot make insulin, a hormone normally produced in the pancreas to help metabolize glucose, and Type 2, the far more prevalent form of the disease, in which the body becomes resistant to insulin. It is Type 2 that has most convincingly been linked to excess iron.

For various reasons including higher rates of obesity and increased food intake, diabetes is increasing epidemically worldwide. According to the International Diabetes Federation, an estimated 285 million people had diabetes in 2009.  The World Health Organization projects 366 million people will have diabetes by 2030. The American Diabetes Association reported in 2009 that 23.6 million people had diabetes in the United States – 7.8 percent of the population – with many more unaware they are at high risk for the disease. Between 80 percent and 90 percent of all cases are Type 2 diabetes.

Among patients with Type 2 diabetes, approximately 30 percent have iron overload. A direct role of iron is suggested by the fact that hereditary hemochromatosis, a disease that interferes with the body’s ability to regulate iron levels, is strongly associated with diabetes. Although the association between iron overload and Type 2 diabetes long has been recognized, until this U of U study no one had shown that excessive iron levels directly cause changes in metabolism that contribute to the risk for developing the disease.
“We consume and lose iron every day,” Huang says. “Although 30 percent of Type 2 diabetics have an elevated iron level, we still know relatively little about the role of iron in the development of the disease.” Huang and McClain point out that they are not able from these studies to define an optimal level of iron, but they suggest that diets with too much red meat, for example, may carry risks other than that usually associated only with their fat content. They caution, however, that certain other individuals require iron supplements and that they should follow their doctors’ advice if they are using iron supplements.

To understand the role of iron, Huang, McClain, and their U of U colleagues studied glucose and fatty acid metabolism in mouse models of hemochromatosis. After establishing the link between iron overload and the increased production of liver glucose and metabolic inflexibility in the mice, Huang and colleagues investigated the mechanisms involved. They found the mice had lower glucose oxidation – the chemical process in which glucose is broken down to release energy into the body – and relatively higher fatty acid oxidation, indicating that the mice had trouble shifting between diets high in glucose and fat. This metabolic inflexibility leads to higher glucose production in the liver and is a hallmark of typical Type 2 diabetes, according to Huang.
“After the glucose is synthesized in the liver, it is released into the blood to increase the blood glucose level, which increases the risk for Type 2 diabetes,” he says. “Studying mice models is a good tool to learn how iron affects this disease, although we still need to prove the same connections exist in humans.”

The current study follows an earlier one in which McClain and colleagues showed that glucose tolerance is dramatically improved and diabetes symptoms significantly helped when diabetic mice are fed a low-iron diet or treated with iron chelator, a molecule that makes iron less toxic in the body. Studies to replicate these results in humans are under way at the U in Dr. McClain’s lab.
Along with Huang and McClain, the other U of U researchers involved in the study were: Deborah Jones, Bai Luo, Michael Sanderson, and Jamie Soto, from the Departments of Internal Medicine and Biochemistry at the University of Utah School of Medicine; E. Dale Abel, M.D., Ph.D., professor of internal medicine and chief of the Division of Endocrinology; and Robert Cooksey, Department of Internal Medicine and the George E. Wahlen Department of Veterans Affairs Medical Center in Salt Lake City.

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