Diabetes and Obesity: Identification of a "Master Regulator" Offers Hopes for More Effective Treatments

Diabetes and obesity are major leading causes of death and disability across the world, together afflicting over 450 million individuals. These diseases are similar in that both are characterized by disruptions of nutrient balance within the body: diabetes results in elevated sugar levels in the blood, while obesity leads to an accumulation of fat in body tissues.

Due to their important health and economic consequences, the development of novel therapeutics to better treat and manage these diseases is critical. In a recent study at Massachusetts General Hospital, researchers uncovered the critical role of a protein called SIRT6 in controlling blood sugar levels and fat metabolism. They believe that this protein may pave the way for more effective treatments for diabetes and obesity.

SIRT6, referred to as a "master regulator" by the authors, plays an important role in cell metabolism. It triggers a switch between different catabolic processes, chemical reactions our body uses to generate energy. Through these chemical reactions, our body converts the food we eat into the energy necessary for everything that we do. The body prefers to use a pathway known as aerobic respiration, which, as opposed to anaerobic respiration, generates energy in the presence of oxygen. This form of metabolism is extremely efficient and generates a large amount of energy per molecule of sugar we consume. However, under circumstances when the amount of oxygen present is unable to meet our body's energy needs, such as during exercise, anaerobic metabolism is utilized instead. This is a far less efficient pathway, and many more molecules of sugar must be broken down to achieve the same energy levels obtained from aerobic respiration.

In this study led by Dr. Raul Mostoslavsky, the role of the SIRT6 protein was made clear by examining the effects of its absence in mice. Compared to mice that had SIRT6, those that lacked this protein had lower sugar levels in their blood and were burning a larger amount of their fat reserves. This suggests that they were utilizing an anaerobic pathway and, thus, needed more sugar and fat stores to meet their energy needs. The study confirmed this hypothesis by showing that mice without SIRT6 had higher levels of proteins necessary for anaerobic energy production. The study also revealed that these mice also had lower levels of proteins needed for aerobic metabolism.

Though the study elucidated possible functions of the SIRT6 protein, much still remains unknown about this molecule. "We need to identify the factors that interact with SIRT6 and determine how it is regulated; investigate whether it acts as a tumor suppressor and how it might help lower glucose levels in diabetes; and determine its target organs in living animals, all of which we are investigating," says Dr. Mostoslavsky.

The findings from this study, however, do suggest that SIRT6 could be a potential drug target for novel obesity and diabetes treatments. Since the absence of SIRT6 leads to greater utilization of glucose and, consequently, lower blood glucose levels, drugs that reduce its levels may help diabetes patients manage their elevated blood sugar content. In addition, new SIRT6-based treatments may help obese individuals burn off greater amounts of accumulated fats, as was observed in the SIRT6-deficient mice.

References:

1) Zhong, et al. 2010. "The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α". Cell 140(2): 280-293.

2) CDC Diabetes and Obesity Data and Statistics

3) Massachusetts General Hospital News Release. "Understanding mechanism underlying SIRT6 activity may help treat diabetes, cancer" January 2010. http://www.massgeneral.org/about/pressrelease.aspx?id=1196

Author: Eanas Aboobaker

Reviewed by: Jessica Kloss, Natasha Hochlowski, and Yangguang Ou

JYI has received funding support from several sources, including the Burroughs Wellcome Fund, the National Science Foundation, and Duke University.
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