The key metabolic hormone, leptin, acts in part through the liver to regulate glucose homeostasis, as well as the maturation of both adipocytes and osteoblasts. These actions have been demonstrated to be mediated by insulin-like growth factor binding protein 2 (IGFBP-2), independent of its ability to bind IGF1. The effects of IGFBP-2 on adipocyte and osteoblast maturation can be localized to a short peptide sequence within the unique heparin binding domain (HBD-1) of IGFBP-2. AZP-3404 is a 9-amino acid peptide analog derived from the HBD-1 of IGFBP-2 that reproduces the activity of IGFBP-2 on adipocyte and osteoblast maturation. The present study examines whether AZP-3404 can likewise reproduce the ability of leptin/IGFBP-2 to restore glucose homeostasis in the leptin-deficient ob/ob mouse. Carotid artery glucose levels were continuously monitored in unanesthetized, unrestrained, male B6.Cg-Lepob/J mice fitted with wireless HD-XG telemetric devices (Data Sciences International). The mice were randomly assigned to groups (n=8) that received either AZP-3404 or vehicle, b.i.d., for four weeks. By day 27 of treatment, AZP-3404, administered at either 1 or 3 mg/kg, reduced the average daily glucose concentration by 64±29 and 100±16 mg/dl, respectively, from the pretreatment mean level of 507±102 mg/dl. Glucose levels in the vehicle-treated mice slightly increased by 14±29 mg/dl. To assess the efficiency of glucose disposal, an intraperitoneal glucose tolerance test (IPGTT: 1 g glucose/kg) was administered on days 7, 14, 21 and 28 of treatment, following a 24-hour fast. After 28 days of treatment with either 1 or 3 mg/kg AZP-3404, fasting glucose was reduced by 8 and 20%, respectively, as compared with fasted levels on day 7. The IPGTTs demonstrated that AZP-3404 progressively and dose-dependently improved glucose disposal in the severely insulin-resistant ob/ob mice, reducing post-challenge glucose levels by 40% after treating with 3 mg/kg AZP-3404 for 4 weeks. In addition, we have demonstrated that AZP-3404, both alone and in an additive manner with insulin, increases glucose uptake by mouse C2C12 differentiated myotubes through activation of AMP-activated protein kinase (AMPK), suggesting that at least a portion of the observed effect of AZP-3404 in the ob/ob mouse may be by promoting glucose uptake by muscle. These results demonstrate that AZP-3404 is able to reproduce the ability of IGFBP-2 to restore glucose homeostasis in the ob/ob mouse and support the development of AZP-3404 as a novel therapy for syndromes of severe insulin resistance.
18 May 2019 - 21 May 2019