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|78.4 - Summer 2005|
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Mitochondrial Dysfunction and Type-2 Diabetes
By Andrew Chang
Many factors can lead to type-2 diabetes through insulin resistance or ß-cell dysfunction. (Credit: sciencemag.org)
Insulin resistance and pancreatic ß-cell dysfunction are the two prominent causes of adult-onset, or type-2, diabetes. In his new hypothesis, Gerald I. Shulman, professor of medicine and cellular and molecular physiology, proposes that both of these complications have roots in mitochondrial defects. Known as the “power plants of the cell,” mitochondria are responsible for the oxidation of fats and the synthesis of ATP, the chemical fuel of the cell.
One path by which mitochondrial dysfunction can lead to diabetes is insulin resistance, characterized by a weakened ability to respond to insulin and to process glucose. Shulman traces this loss of function to the buildup of triglyceride fats inside liver and skeletal muscle cells, two key insulin-responsive sites responsible for maintaining normal glucose homeostasis.
To study skeletal muscle tissue and liver cells of both genetically modified mice and human diabetes patients, Shulman used a new MRS (magnetic resonance spectroscopy) imaging technique. The procedure uses non-ionizing radiation to monitor and image the internal function of living cells without harming them. Images showed that fatty acids prevent the intake of glucose through normal insulin signaling. Since previous studies have demonstrated that depressed rates of fat breakdown in mitochondria can lead to insulin resistance, Shulman concluded that defective mitochondria are responsible for fat buildup.
In pancreatic ß-cells with normal mitochondrial function, excess glucose stimulates the release of insulin to induce glucose uptake and storage by muscle and liver cells. Because intracellular ATP levels reflect a cell’s energy demands, high levels of ATP allow the cell to “sense” excess glucose. When the body cannot make enough pancreatic ß-cells or when the ß-cells can no longer respond properly to glucose levels, type-2 diabetes results. Thus, by disrupting pancreatic ß-cell function and glucose processing, mitochondrial problems can lead to type-2 diabetes. Since mitochondria with defective DNA cannot perform their job of producing ATP, ß-cells that contain these organelles are no longer stimulated to release insulin. In many cases, however, insulin-resistant individuals do not develop diabetes because their ß-cells adapt to meet the body’s demand for insulin by undergoing hypertrophy and hyperplasia.
How do mitochondria become defective? Shulman’s research suggests two possible mechanisms that lead to mitochondrial dysfunction. In the first mechanism, elderly individuals can gradually lose mitochondrial function due to accumulation of DNA defects commonly associated with the aging process. This condition is much more prevalent than we may think. Shulman states, “By age sixty-five, forty percent of us have type-2 diabetes or impaired glucose tolerance.”
Although most cases of adult-onset diabetes are found in people who are overweight, many insulin-resistant individuals are relatively young and lean. The development of type-2 diabetes in these individuals can be attributed to DNA impairments inherited from parents. Why would such unfavorable DNA be passed on to offspring? Shulman theorizes that this condition represents “thrifty genes.” Insulin-resistant individuals are more efficient at processing glucose and need less energy; therefore, they have fewer mitochondria in their cells. This phenomenon offers them an advantage during times of famine.
Having laid the basic foundation for understanding the relationship between mitochondrial dysfunction and type-2 diabetes, Shulman’s research has vast potential in developing treatments for this disease, from methods that prevent the import of fats into cells to proteins that increase mitochondrial oxidation of fats.Reference
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