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

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.