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Exendin-4 Decelerates Food Intake, Weight Gain, and Fat Deposition in Zucker Rats

Diabetes Section (M.E.D., J.A.B., J.M.E.), NMR Unit (M.S., R.G.S.S.), and Drug Design and Development Section (H.W.H., N.H.G.), Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224

Address all correspondence and requests for reprints to: Josephine M. Egan, M.D., Diabetes Section, no. 23, GRC/NIA/NIH, 5600 Nathan Shock Drive, Baltimore, Maryland 21224. E-mail: eganj{at}vax.grc.nia.nih.gov

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 hormone glucagon-like peptide-1 (GLP-1). Exendin-4 induces insulin release through activation of the GLP-1 receptor but is a much more potent insulinotropic agent than GLP-1. Of critical importance for its potential use as a treatment for diabetes is its much longer biological effect in vivo. Previous studies 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 of the untreated animals. In this study, we initially examined the effect of once daily injections (over 14 days) on the food consumption of Zucker fatty rats. We observed an immediate reduction in food intake which then leveled 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 total) and observed a sustained reduction in food intake and weight-gain. This 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 sc 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 deposition. 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.

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