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Findings Point to Novel Therapeutic Drug Target for Type 2 Diabetes
Researchers at the Pennington Biomedical Research Center, in results published in Nature Medicine, have discovered the mechanism that leads to an inflammatory response in obesity. This is an important finding because inflammation compromises insulin sensitivity, a key trigger leading to type 2 diabetes. Inflammation can also increase the risk of cancers, heart disease and dementia in obese individuals.
Lead investigator Vishwa Deep Dixit, D.V.M., Ph.D. and his colleagues at the Pennington Biomedical Research Center identified that “NLRP3 inflammasome complex”-- a “molecular machine” within specialized immune cells senses the obesity-related danger signals such as toxic lipids--triggers chronic inflammation. The new findings show that by blocking the activity of this “NLRP3 inflammasome-complex” in obesity, the run-away inflammation and abnormal immune cell activation can be reduced, leading to improved insulin action in obese individuals.
“Based on these findings, it is possible that future drugs could be developed to block the activation of the ‘inflammasome complex’, improving the current treatment strategies for type 2 diabetic patients,” said Dr. Dixit. However, he cautions further research is needed before these new findings can be translated to safe medications.
For many years scientists have known that the human immune system is activated by external, foreign pathogens. This immune response, including inflammation, is a helpful mechanism which allows humans to respond to infections and heal wounds. Once the infection or injury is healed, the immune system is deactivated and inflammation subsides. In obesity, there is no overt infection, however immune cells are activated. What causes the immune system to be activated and why does that increase the risk of type-2 diabetes? What fuels inflammation in obesity? Answers to these puzzling questions have thus far been elusive to scientists.
This study shows that the ‘inflammasome complex’ is like molecular ‘glue’ which is assembled when immune cells come across specific danger signals like toxic lipids that are overproduced during obesity. “Once this ‘inflammasome complex’, which contains three unique proteins, combines in tissues during obesity, it causes the cytokines like Interleukin-1B and Interleukin-18 to be activated and cause inflammation,” said Dr. Dixit.
Pennington Executive Director Steven Heymsfield, M.D. recognized the significant work and said, “This is another step for the Pennington Center as we work to improve the understanding of the basis for obesity-associated inflammation. Our goal is to enhance the knowledge base for development of new diagnostic, preventive, and treatment approaches.”
While these basic science discoveries await further study and the possibility of future drug development, Dr. Dixit and his colleagues found that losing weight through exercise and calorie restriction is an effective means of blocking the activation of the “inflammasome complex”, thereby improving type 2 diabetes in obese individuals.
The findings, published in the January 9, 2011, advanced online edition of Nature Medicine, was co-authored by Bolormaa Vandanmagsar, Ph.D. Nature Medicine isa biomedical research journal devoted to publishing the latest and most exciting advances in biomedical research for scientists and physicians in the biomedical fields of immunology, cancer biology, neuroscience, gene therapy, and cardiovascular research.
In addition to Dixit and Vandanmagsar, the other study authors include: Yun-Hee Youm, Ph.D.; Anthony Ravussin, B.S.; Jose E. Galgani, Ph.D; Krisztian Stadler, Ph.D; Randall L. Mynatt, Ph.D.; Eric Ravussin, Ph.D.; and Jacqueline M. Stephens, Ph.D.
The research was funded by the National Institutes of Health, the Coypu Foundation and the Pennington Biomedical Research Foundation. <
The Pennington Biomedical Research Center is at the forefront of medical discovery as it relates to understanding the triggers of obesity, diabetes, cardiovascular disease, cancer and dementia. It is a campus of Louisiana State University and conducts basic, clinical and population research. The research enterprise at Pennington Biomedical includes approximately 80 faculty and more than 25 post-doctoral fellows who comprise a network of 44 laboratories supported by lab technicians, nurses, dietitians, and support personnel, and 13 highly specialized core service facilities. Pennington Biomedical’s more than 500 employees perform research activities in state-of-the-art facilities on the 222-acre campus located in Baton Rouge, Louisiana.