Exendin-4 decelerates food intake, weight gain, and fat deposition in Zucker rats

Exendin-4 is a 39 amino acid peptide produced in the salivary gland of the Gila monster lizard. It has a 53% amino acid homology to the incretin hormo ne glucagon-like peptide-1 (GLP-1). Exendin-4 induces insulin release throu gh activation of the GLP-1 receptor but is a much more patent insulinotropi c agent than GLP-1. Of critical importance for its potential use as a treat ment for diabetes is its much longer biological effect in vivo. Previous st udies involving once daily administration of exendin-4 over 13 weeks to db/ db mice demonstrated that it lowers hemoglobin A(1c) (HbA(1c)), a marker of mean blood glucose levels. Food consumption in the treated animals dropped over the first 4 days and then increased to a level comparable with that o f the untreated animals. In this study, we initially examined the effect of once daily injections (over 14 days) on the food consumption of Zucker fat ty rats. We observed an immediate reduction in food intake which then level ed off (after 5 days) to match that of the untreated animals. Subsequently we injected the same animals twice daily (treatment period of 56 days in to tal) and observed a sustained reduction in food intake and weight-gain. Thi s was matched by a reduction in the critical parameters of HbA(1c), fasting blood glucose and plasma insulin. MRI imaging of the abdominal regions of the animals showed that initially only the amount of fat deposited in the s c region was reduced after 4 weeks exendin-4 treatment. At the 8-week time point there was a corresponding decrease in the amount of visceral fat depo sition. The combination of appetite reduction, decreased fat deposition and an improvement in the parameters associated with glucose intolerance makes a case for the use of exendin-4 as a treatment for diabetes.