The dual amylin- and calcitonin-receptor agonist KBP-042 increases insulin sensitivity and induces weight loss in rats with obesity

Abstract

Objective: In this study, KBP-042, a dual amylin- and calcitonin-receptor agonist, was investigated as a treatment of obesity and insulin resistance in five different doses (0.625 µg/kg–10 µg/kg) compared with saline-treated and pair-fed controls. Methods: Rats with obesity received daily s.c. administrations for 56 days, and glucose tolerance was assessed after one acute injection, 3 weeks of treatment, and again after 7 weeks of treatment. To assess the effect on insulin sensitivity, rats received 5 µg/kg KBP-042 for 21 days before hyperinsulinemic–euglycemic clamp. Results: KBP-042 induced a sustained weight loss of up to 20% without any significant weight reduction in the pair-fed groups. Decreases in adipose tissues and lipid deposition in the liver were observed, while plasma adiponectin was increased and plasma leptin levels were decreased. Acute administration of KBP-042 led to impaired glucose tolerance and increased plasma lactate, while this diabetogenic effect was reversed by chronic treatment. Finally, assessment of insulin sensitivity using the hyperinsulinemic–euglycemic clamp showed that KBP-042 increased the glucose infusion rate. Conclusions: The study indicates that KBP-042 combines two highly relevant features, namely weight loss and insulin sensitivity, and is thus an excellent candidate for chronic treatment of obesity and insulin resistance.