A research team at the Joslin Diabetes Center has discovered that an enzyme located in cell mitochondria is less common in the skeletal muscle of diabetes. The discovery could pave the way for the development of medications that increase the enzyme’s activity and contribute to the body’s defense against diabetes.

The enzyme is called SIRT3 and, according to a paper published in the Proceedings of the National Academy of Sciences, its appearance is decreased in the skeletal muscles of both humans and animals with diabetes by at least 50%. This lack of SIRT3 may contribute to the organism’s development of insulin resistance — a precursor symptom of diabetes. SIRT3 is found in the mitochondria of animal cells, which are the cell powerhouses that create the cell’s energy from raw materials.

“Ours is perhaps the first study to understand what is going wrong in the mitochondria of those with diabetes,” said C. Ronald Kahn, M.D., Head of the Joslin Section on Integrative Physiology and Metabolism and the Mary K. Iacocca Professor of Medicine at Harvard Medical School. “Many studies have shown that the mitochondria don’t work well in those with diabetes. This points to a cause of why they don’t work well.”

According to Dr. Kahn, the study aimed at analyzing the effect that lower levels of SIRT3 could have on cell metabolism and insulin action in particular. “We know that one of the hallmarks of early diabetes is insulin resistance in muscle, but we didn’t know what caused it,” said Kahn. The study revealed that lower SIRT3 levels are connected with reduced efficiency in energy metabolism in mitochondria. Diabetes is commonly linked with such lower SIRT3 activity.

One of the side effects of inefficient mitochondria activation is that they produced reactive oxygen species, or ROS — chemically-reactive molecules that contain oxygen and work to inhibit insulin resistance in the muscles. “This is the first time this has been shown,” said Dr. Kahn.

Now that the phenomenon has been identified, researchers will be setting their sights on a new goal: increasing the levels of SIRT3 or the activity of the remaining SIRT3 in an attempt to bring insulin resistance in the muscles back to normal level and to regulate muscle metabolism. “It is a new target,” said Dr. Kahn.

He noted that the study is one of the first to show that one defect could have a negative impact on mitochondrial metabolism and insulin signaling in muscle tissue. “In further studies we will try to understand what proteins Sirt3 acts on,” he said.

According to Dr. Kahn, one of the first symptoms of diabetes is insulin resistance in the skeletal muscle of the patient. Thus, drugs that boost SIRT3 activity levels could prove to be useful in the treatment of both prediabetes and newly-diagnosed diabetics.

“Agents which increase Sirt3 activity could, therefore, potentially reverse at least some of the adverse effects of type 2 diabetes” according to the research paper.

Co-authors of the study include Enxuan Jing, who worked as lead author, and Brice Emanuelli, Jeremie Boucher and Kevin Lee, all part of the team at Joslin Diabetes Center; Matthew D. Hirschey and Eric M. Verdin, from the Gladstone Institute of Virology and Immunology and the University of California in San Francisco; and David Lombard, with the Department of Pathology and Institute of Gerontology at the University of Michigan.

Dr. Verdin with the Gladstone Institute stated that by “uncovering the multi-faceted role of SIRT3, we are laying important groundwork to better combat this widespread disease at the cellular level.”