MON-481 MA-[D-Leu-4]-OB3, a Small Molecule Synthetic Peptide Leptin Mimetic, Enhances the Effects of Insulin on Glycemic Control and Cognitive Function in Streptozotocin-Induced Hyperglycemic Swiss Webster Mice

Glucose dysregulation and disruption of insulin signaling in the brain have been suggested as a possible etiology of Alzheimer’s Disease. In the present study, we show that oral delivery of MA-[D-Leu-4]-OB3 to young male Swiss Webster (SW) mice rendered hyperglycemic by intraperitoneal injection of streptozotocin (STZ), prevented insulin-induced increase in body weight gain and enhanced the effects of insulin alone on fasting blood glucose to levels approaching those of normal SW mice of the same age and sex. Novel object testing indicated that insulin treatment improved working memory in STZ-induced hyperglycemic mice, and that MA-[D-Leu-4]-OB3 given in combination with insulin significantly accelerated the time course of this improvement. Although positive results in an animal model may not be recapitulated in human pathology, our data suggest that MA-[D-Leu-4]-OB3, when added to an insulin regimen, may have application to the treatment of Alzheimer’s Disease by improving insulin sensitivity and glycemic control, thus slowing or preventing the progression of memory disruption associated with this disease.