Chemical Compounds Restore Normal Glucose Levels And Insulin Action In Obese Mice

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.

Administration of TUDCA in a different set of ob/ob and wild-type mice normalized blood glucose levels within one week of treatment of the obese mice. TUDCA helped improve insulin response by reducing ER stress and suppressing JNK gene activation.

TUDCA and PBA treatment also appeared to interfere with the storage of fat in the liver, significantly reducing the presence of fatty liver disease -- a condition closely related to obesity and insulin resistance. One form of this disease — nonalcoholic steatohepatitis — is associated with inflammation and the creation of fibrous tissue, which can lead to cirrhosis.

PBA has been approved by the U.S. Food and Drug Administration for clinical use in urea-cycle disorders in humans. TUDCA has been used as a liver-protecting agent in human cholestatic liver diseases.

“Already used safely in people for some disorders, these compounds and others like them may warrant clinical investigation into their effects on type 2 diabetes in humans,” said Hotamisligil. “If these compounds work in humans as they do in experimental models, they could dramatically change the approaches to treat many components of metabolic syndrome.”

Researchers on this study are supported by grants from the National Institutes of Health, Japan Society for the Promotion of Science, and American Diabetes Association.