Boston, MA – Treatment of obese and diabetic mice with compounds that act as chemical chaperones called PBA and TUDCA restored healthy glucose levels and normal insulin action — and reduced the presence of fatty liver disease — according to a study published in the August 25 issue of Science. The work was conducted by a team of 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.

Gökhan 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/press11202002b.html. ER stress appears to trigger abnormal JNK activity, which is often seen in obesity and type 2 diabetes.

In the new Science paper, Hotamisligil; lead author Umut Özcan, a postdoctoral fellow; and their co-authors first identified compounds that alleviate ER stress in cellular models and demonstrated how two of these chemicals — PBA (4-phenyl butyric acid) and TUDCA (taurine-conjugated derivative) — reduced ER stress, prevented JNK activation, and restored normal glucose homeostasis in type 2 diabetic mice.

The researchers used the ob/ob murine model, where mice are both severely obese and insulin resistant. Oral administration of PBA (1 g per kg of body weight) was given to seven- to eight-week-old male ob/ob mice and to leaner, wild-type mice for 20 days. PBA reduced blood glucose levels in the ob/ob mice to those of their wild-type counterparts within four days; the levels were maintained for up to three weeks and were not associated with changes in body weight. PBA treatment also improved glucose tolerance in ob/ob mice, reduced the indicators of ER stress, and prevented JNK activation and suppression of insulin action in peripheral tissues.