Abstract 467: The ApoA-1 Mimetic Peptide D-4F Shows Antidiabetic Efficacy In db/db Mice Only After Intraperitoneal Administration

Objective: The apoA-I mimetic peptide L-4F has previously been shown to have antidiabetic efficacy in ob/ob mice. In this study we tested the antidiabetic potential of the D-4F peptide. Methods: We dosed 6 weeks old male db/db mice once daily with 4.5 μmol/kg D-4F either given by the ip. or the sc. route. Blood glucose (BG) and body weight (BW) were monitored twice weekly, 24 h food intake was measured daily and HbA1c was measured once weekly. After 5 weeks the mice were sacrificed and blood was collected for D-4F concentration measurements. Abdominal and subcutaneous tissues were harvested for histology. Results: Blood glucose, HbA1c and food intake were all significantly reduced in the group dosed with D-4F by the ip route as compared to the vehicle dosed group. In contrast, there was no effect of D-4F when given by the sc. route. This was despite similar and high plasma concentration of D-4F (Table 1). Macroscopially, chronic adhesive peritonitis was evident in the ip dosed group and histological evaluation of the peritoneal tissue covering abdominal fat confirmed this finding. In the group dosed sc, chronic inflammation was also observed at the injection site, both histologically and by macroscopic evaluation. Conclusion: Ip dosing of D-4F gave rise to chronic peritonitis, which could have caused the reduced food intake and consequently the reduction in blood glucose and HbA1c. This effect was not observed when D-4F was injected sc, despite the local tissue reaction in subcutis. Therefore, we speculate that the antidiabetic effect of D-4F observed after ip administration is an artefact due to abdominal inflammation and reduced food intake. Table 1. Means±SEM § Vehicle ip from a separate study; * p