2035-P: Treatment with a Dual Amylin and Calcitonin Receptor Agonist Improves Metabolic Health in a Rat Model of Elderly Menopausal Women

Abstract

Menopause is often characterized by detrimental metabolic changes, such as obesity, impaired glucose tolerance, insulin resistance and bone loss, often requiring treatment. KBP is a Dual Amylin and Calcitonin Receptor Agonist with promising effects on body weight and glucose control in rats. The objective of this study was to investigate the in vivo effect of KBP on the metabolic health in a model driven by unhealthy diet, age and menopause. Female Sprague Dawley rats were fed a high-fat diet (HFD) for 3 months before initiation of the study. At 6 months of age the rats were randomized into 4 groups (n=12) and subjected to ovariectomy surgery and subcutaneous injections of KBP; (1) HFD-Sham, (2) HFD-OVX + 10 µg/kg once/day, (3) HFD-OVX 5 µg/kg twice/day, (4) HFD-OVX + 30 µg/day 17a-ethynylestradiol (EE2). Body weight, food intake, oral glucose tolerance tests (OGTTs), subcutaneous fat and visceral fat and CTX-II were assessed during the 6 month study. HFD-OVX rats showed a significant and continuous increase in body weight throughout the study (10-13% weight increase compared to HFD alone, p<0.01). In HFD-OVX rats, KBP, independent of dosing frequency, caused an immediate decrease in both food intake and body weight within days and while food intake gradually returned to vehicle level over the first eight weeks, the weight loss remained until termination (P < 0.001). KBP increased glucose tolerance of HFD-OVX rats, significantly more than EE2. Furthermore, treatment with KBP reduced the weight of visceral and subcutaneous fat tissues. The cartilage degradation biomarker, CTX-II, was suppressed by both KBP groups. The data presented here clearly indicate a positive effect of KBP on metabolic health, with respect to weight loss, increased glucose tolerance and reduced weight of adipose tissues, as well as joint health, and may therefore represent a possible treatment opportunity for obese menopausal women. Disclosure A. Katri: Employee; Self; Nordic Bioscience. M.A. Karsdal: Employee; Self; Nordic Bioscience. K. Henriksen: Employee; Self; Nordic Bioscience. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Nordic Bioscience. Other Relationship; Self; Nordic Bioscience.