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
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Contact: Christina Roache
croache@hsph.harvard.edu
617-432-6052
Harvard School of Public Health
24-Aug-2006