Insulin pathway component explains insulin resistance, age-associated metabolic syndrome

Metabolic syndrome, an aging-associated group of disorders that includes insulin resistance, heart disease and high lipid levels, may be treatable thanks to a newly discovered role for a regulatory gene, according to a team of scientists at the Burnham Institute for Medical Research.

In addition, the scientists found that this single gene may contribute to the body's responses to caloric restriction and may explain some aspects of the Atkins Diet.

The gene's new function was discovered in Drosophila fruit flies; previously it was associated solely with the control of growth. Until now, how the gene regulates insulin, as well as other symptoms of metabolic syndrome, was largely unknown. The study was conducted by Sean Oldham, Ph.D., assistant professor, and his colleagues at the Burnham and the National Institute on Alcoholism and Alcohol Abuse. Oldham's findings appear in the journal Cell Metabolism to be released on August 8th.

Using fruit flies bred with a newly created mutant form of the gene TOR (short for target of rapamycin), Oldham and his colleagues were able to determine how the TOR pathway interacted with other important regulators of insulin, glucose and lipid metabolism.

TOR is an ancient gene, found in nearly all animal and plant cells. The researchers discovered that their new mutant fly reduced TOR function, allowing them to observe what happens when TOR's influence is removed.

Reductions in TOR function lowered glucose and lipid levels in the body. They also blocked the function of another important insulin regulator, a factor called FOXO, which is known to be a critical mediator of insulin signals and therefore glucose and lipid metabolism. In addition, flies with the mutated form of TOR had longer life spans than control flies.

“It has been unclear how TOR signaling affects the insulin pathway,” said Oldham. “Our study adds another dimension to TOR's activity by revealing unexpected and novel levels of beneficial regulation of insulin metabolism, by reducing insulin resistance. This study provides the first details of how TOR may regulate energy homeostasis and responses to aging, in particular the coordination of weight reduction effects caused by caloric restriction and, in humans, it may explain the effects of the Atkins diet. It suggests that reducing TOR function could lead to a possible treatment for any or all symptoms of metabolic syndrome and insulin resistance.”

Oldham's group, in collaboration with Dr. Rolf Bodmer at Burnham, showed that reducing TOR function also blocks the age-dependent decline of heart function, providing a partial explanation for why excess calories from overeating can lead to resistance to insulin's ability to process sugars and may contribute to reduced heart function.

Dr. Oldham and his colleagues are continuing their search to understand how TOR mediates caloric restriction, aging and other effects on insulin signaling and metabolism. They want to understand TOR's role in the relationship between growth, metabolism and aging, both in healthy individuals and individuals with metabolic diseases. The researchers also are screening possible drugs that could treat metabolic syndrome by reducing TOR function.

“This study provides the first direct evidence that reducing TOR function could be clinically beneficial to counter insulin resistance, metabolic syndrome and diabetes,” said Oldham. “We believe further studies on fruit flies are invaluable to discovering more details about this pathway, and will give us indispensable insight into pathological aspects of aging and senescence.”