Joslin Center report

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Joslin Researchers: New Target for Treatment of Type 2 Diabetes and

Prediabetes Identified

30-Aug-2011

Researchers at the Joslin Diabetes Center have shown that an enzyme found in

the mitochondria of cells is decreased in the skeletal muscle of those with

diabetes, a finding that could lead to the development of drugs to boost the

activity of this enzyme in an effort to fight the disease.

A paper in published online today in the Proceedings of the National Academy

of Sciences, showed that the enzyme, Sirt3, is decreased in the skeletal

muscle of humans and animals with diabetes by at least half, compared to

those without diabetes and that this may contribute to development of

insulin resistance, one of the earliest manifestations of the disease. Sirt3

is found in the mitochondria, the power producers of cells that convert

energy into usable forms.

" Ours is perhaps the first study to understand what is going wrong in the

mitochondria of those with diabetes, " said senior author C. Kahn,

M.D., Head of the Joslin Section on Integrative Physiology and Metabolism

and the 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. "

Dr. Kahn said the study sought to look at how decreased Sirt3 levels might

affect the metabolism of cells, particularly how it could affect insulin

action in cells. " We know that one of the hallmarks of early diabetes is

insulin resistance in muscle, but we didn't know what caused it, " he said.

He said the study showed that when Sirt3 levels are low, as they are in the

case of diabetes, the mitochondria of the cells are not as efficient in

energy metabolism as they should be.

When the mitochondria become inefficient, they generate what are known as

reactive oxygen species (ROS), chemically reactive molecules containing

oxygen, which create insulin resistance in the muscles, he said.

" This is the first time this has been shown, " Dr. Kahn said.

The goal for the future will be to find ways to restore levels of Sirt3 or

increase the activity of the existing Sirt3, perhaps with a drug, in a bid

to improve insulin resistance in the muscle and improve muscle metabolism,

he said.

" It is a new target, " he said.

Dr. Kahn noted that this study is one of the first demonstrations of a

single defect that could affect mitochondrial metabolism and insulin

signaling in the muscle.

" In further studies we will try to understand what proteins Sirt3 acts on, "

he said.

He noted that one of the earliest hallmarks of diabetes is insulin

resistance in the skeletal muscle. As a result, a drug to boost Sirt3 levels

could be useful in the treatment of prediabetes or in those newly diagnosed

with the disease, he said.

" Agents which increase Sirt3 activity could, therefore, potentially reverse

at least some of the adverse effects of type 2 diabetes, " the paper

concludes.

Co-authors included Enxuan Jing, lead author, as well as Brice Emanuelli,

Jeremie Boucher and Lee, all of Joslin; D. Hirschey and

M. Verdin, both of Gladstone Institute of Virology and Immunology and the

University of California, San Francisco; and Lombard, formerly of the

Department of Genetics at Harvard Medical School and currently at the

Department of Pathology and Institute of Gerontology at the University of

Michigan.

Dr. Verdin noted that by " uncovering the multi-faceted role of SIRT3, we are

laying important groundwork to better combat this widespread disease at the

cellular level. "

The study was supported by research grants to Kahn and Verdin as well as a

grant from the Ellison Foundation and the K. Iacocca Professorship. The

study also received support from the Joslin DERC cores laboratories.

Source: Joslin Diabetes Center