Endocrine Abstracts

Insulin-like growth factor binding protein-2 (IGFBP2) has been demonstrated to be a key mediator of the peripheral actions of leptin, and its deficiency is associated with impaired metabolic function. The metabolic activity of IGFBP2 can be localized to a unique heparin-binding domain (HBD-1) within its structure. AZP-3404 is a 9-amino acid analog of the IGFBP2 HBD-1 that has been demonstrated to increase glucose uptake by differentiated mouse myotubes in vitro, and to increase glucose disposal in leptin-deficient, and consequently IGFBP2-deficient, ob/ob mice. In the present study, we examined whether AZP-3404 could improve metabolic regulation in the db/db mouse which, as a result of a mutation in the leptin receptor, is leptin-resistant and consequently has elevated leptin levels but is IGFBP2-deficient. Nine-week old male db/db mice were treated with either vehicle or AZP-3404 at doses of 1, 3 or 6 mg/kg, sc, bid (n = 10/group). After 8 weeks of treatment, the impact on glucose disposal was assessed by administering an intraperitoneal glucose tolerance test (IPGTT; 1g glucose/kg, ip), following an overnight fast. All three doses of AZP-3404 produced similar increases in glucose disposal (AUC glucose decreased by 18.8, 21.4 and 23.1% with 1, 3 and 6 mg/kg AZP-3404, respectively) vs vehicle controls. Correspondingly, 4-hour fasted plasma insulin was decreased by 54, 48 and 52%, and the HOMA measure of insulin resistance was decreased by 55, 52 and 67%, following treatment with 1, 3 and 6 mg/kg AZP-3404, respectively, as compared with vehicle-treated mice. Over the 8 weeks of treatment, mice receiving vehicle gained an average 8.2 + 1.6 grams of body weight. Mice treated with AZP-3404 displayed a progressive decrease in body weight gain that began after 2 weeks and that continued through the 8 weeks of treatment, ultimately resulting in less than 50% of the weight gain observed in the vehicle-treated mice, and without an apparent change in food intake. Postmortem examination by micro-computerized tomography (µCT) imaging revealed decreases in both total and visceral fat mass that mirrored the AZP-3404-induced decrease in body weight gain, without effect on lean mass. These results, demonstrating both improved glucose metabolism and decreased body weight gain in the leptin-resistant, IGFBP2-deficient, db/db mouse, further confirms the ability of AZP-3404 to reproduce the metabolic activity of IGFBP2, as well as its potential benefit as a novel therapy for disease states characterized by insulin resistance and/or obesity.