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Two Chemical Compounds Restore Healthy Glucose Levels In Obese Mice

Chemical compounds called PBA and TUDCA were found to restore healthy glucose levels and normal insulin action in obese and diabetic mice, according to new research.// The study is published in the August 25 issue of Science and was conducted by researchers from the Harvard School of Public Health (HSPH).

Type 2 diabetes - 90 to 95 percent of all diabetes cases - affects an estimated 18 million people in the United States, and causes some 200,000 deaths a year. Obesity is closely associated with insulin resistance and is one of the leading risk factors for type 2 diabetes. The molecular mechanisms that link these two metabolic diseases remain under investigation, and current therapeutic options are limited.

G?khan S. Hotamisligil, chair of the HSPH Department of Genetics and Complex Diseases, is the senior author of the Science paper. In 2004, he led a team that identified a major molecular pathway that causes diabetes. A cornerstone of that discovery was a hypothesis that the key to the obesity-diabetes connection might be found in the endoplasmic reticulum, or ER - a system of folded membranes and tubules in the cytoplasm of cells where proteins and lipids are manufactured, processed, and shipped around the cell. When unusual demands - such as excess fat - are put on the ER's capacity, the organelle starts failing, and the cell enters an emergency mode, emitting stress signals. The condition is called ER stress. Cellular inflammation, insulin resistance and diabetes result. (http://www.hsph.harvard.edu/press/releases
/press10142004.htm).

Hotamisligil's team also previously identified the JNK gene as a key component linking inflammation to metabolic signaling and as a gene that interferes with insulin sensitivity.
(http://www.hsph.harvard.edu
/press/releases/press
11202002b.html.
ER stress appears to trigger abnormal JNK activity, which is often seen in obesity and type 2 diabetes.

In the new Scien
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