Mitochondria sheds light on diabetes



A new study by Yale researchers has found decreased mitochondrial activity in children of parents with type 2 diabetes, which may lead to the onset of the disease.

The research, which took place at the Howard Hughes Medical Institute in Chevy Chase, Md., involved the comparison of a sample of insulin-resistant children of diabetic parents against insulin-sensitive control subjects.

Mitochondria break down fatty acids and other substrates in a cell to form energy. Impaired mitochondrial function results in the buildup of fats and fatty acids in muscle cells, which previous studies have shown interferes with cellular functions that enable insulin to take effect.

Insulin promotes the absorption of the glucose from the blood into cells for storage and conversion to energy. Decreased sensitivity to insulin, called insulin resistance, is the best predictor of the later development of type 2 diabetes, in which cells do not respond to insulin and glucose collects in the blood while cells starve.

Using proton magnetic resonance spectroscopy (MRS), researchers found that insulin-resistant youths had increased muscle cell fat content. Researchers were able to rule out over-production by fat cells as the reason for the fat buildup.

“The idea is that the fat builds up in the muscle — is it increased delivery from the fat cell to the muscle cell, or the decreased ability of the muscle cell to oxidize the fat?” said Gerald I. Shulman, M.D., a professor of internal medicine at the Yale School of Medicine. “We looked at the rate of fat breakdown in the fat cell to its component fat acid and glycerol. We measured fat acid turnover — that gives us the rate of whole body [lipid breakdown],” Shulman said.

Shulman found that the results showed no difference in fat production between insulin-resistant and normal youths. Other tests also confirmed the normal function of fat cells.

Researchers then used other imaging technology to examine how well the mitochondria were breaking down fat, and found mitochondria in insulin-resistant children were producing 30 percent less energy than in normal cells.

This finding suggests children of diabetic parents most likely inherit an as-yet-unidentified gene that results in less effective mitochondrial function, leading to slower fat breakdown.

Researchers are currently studying muscle tissue to determine the exact nature of the mitochondrial dysfunction.

“We’re now doing muscle biopsy studies to determine whether the mitochondria are working properly — it could be that [insulin-resistant youths] have a normal number of mitochondria and they’re not working properly, or there could be — fewer mitochondria in [their] muscles,” Shulman said.

Researchers are also analyzing possible genes that might result in the mitochondrial defect.

This research could lead to possible therapies, including lifestyle changes like exercise or medicinal approaches. An enzyme, ATP kinase, has been associated with the synthesis of mitochondria, and could be a possible drug target to stimulate mitochondria production if the patient has too few of them.

“If it turns out to be a reduction in mitochondrial content, understanding the factors that regulate mitochondrial [formation] would be potential targets [for drugs],” Shulman said.

The most common type of diabetes, type 2 diabetes accounts for up to 95 percent of all diabetes cases, according to the National Institute of Health. The number of diabetes cases diagnosed yearly is rising in the U.S., and an increasing number of young people are diagnosed with type 2 diabetes, which is normally associated with older populations.

“Diabetes is reaching epidemic proportions in this country — it’s the leading cause of blindness, end-stage renal disease and non-traumatic loss of limbs,” Shulman said. “It’s costing the U.S. $100 billion dollars a year.”

Other researchers included Kitt Falk Petersen, M.D., assistant professor of internal medicine at Yale; Sylvie Dufour, research specialist at Howard Hughes Medical Institute; Douglas Befroy, Yale research scientist in internal medicine, and Rina Garcia.

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