Yale Bulletin and Calendar

February 20, 2004|Volume 32, Number 19

Study of muscles yields clues
about genetic causes of diabetes

Researchers at Yale have found that decreased activity in muscle mitochondria, the powerhouses of the cell, may be a major factor in the development of type 2 diabetes in young, lean offspring of parents with the disease.

They demonstrated a potential mechanism for the accumulation of fat in muscle cells of young, lean, insulin-resistant children of parents with type 2 diabetes by comparing them with insulin-sensitive control subjects matched for age, weight, height and activity.

"There is a strong relationship between lipid content in the muscle and insulin resistance in skeletal muscle," says principal investigator Dr. Gerald I. Shulman, professor of internal medicine and cellular & molecular physiology at the School of Medicine. "Insulin resistance is the best predictor for whether someone will eventually develop type 2 diabetes."

Using proton magnetic resonance spectroscopy (MRS), a safe, non-invasive method that does not involve any ionizing radiation, researchers found that insulin resistance in muscle of the diabetic offspring was accompanied by an increase in muscle cell lipid content.

Shulman, an investigator at the Howard Hughes Medical Institute, and his group set out to distinguish whether the increase in muscle cell triglycerides was the result of increased delivery of fatty acids to muscle cells from the fat stored in "fat cells" (adipocytes), or the result of a decreased rate of fat oxidation by the mitochondria in the muscle cells. They measured rates of fatty acid release from adipocytes and found no differences between the two groups. In contrast, using phosphorus MRS they found a 30% reduction in the rate of mitochondrial energy production in the muscle of insulin resistant subjects compared to the control group.

"These data support the hypothesis that insulin resistance in young, lean, healthy insulin-resistant offspring of patients with type 2 diabetes may be due to an inherited defect that causes decreased mitochondrial activity and predisposes them to accumulate fat inside their muscle cells and develop insulin resistance," says Shulman.

Shulman and his team are now investigating whether the decrease is due to a reduced number of mitochondria and/or reduced mitochondrial function and whether these abnormalities can be reversed with exercise training.

"These results support the hypothesis that nuclear encoded genes that regulate mitochondrial biogenesis may be an important genetic cause of type 2 diabetes and that mitochondrial biogenesis represents a novel therapeutic target for treatment and possible prevention of type 2 diabetes," says Shulman.

Other authors on the study include Dr. Kitt Falk Petersen, assistant professor of internal medicine, Sylvie Dufour, Douglas Befroy and Rina Garcia.

-- By Karen Peart

T H I SW E E K ' SS T O R I E S

Report decries illegal logging in Indonesia

Yale and unions launch 'historic' new partnership'

Journalist describes adventures at 'tip of the spear' of the Iraq invasion

Yale climbers find serenity in high places

Yale College term bill to rise by 5% next year

Researchers report promising results in study . . .

Study of muscles yields clues about genetic causes of diabetes

Works pay tribute to 'lost culture' of Native Americans

Wasserman to women science students: 'Become a consumer of jobs'

Biostatistician elected fellow of statistical association

Yale Books in Brief

Campus Notes