Dual amylin and calcitonin receptor agonist treatment improves insulin sensitivity and increases muscle-specific glucose uptake independent of weight loss.

Dual amylin and calcitonin receptor agonists (DACRAs) are known to induce significant weight loss as well as improve glucose tolerance, glucose control, and insulin action in rats. However, to what extent DACRAs affect insulin sensitivity beyond that induced by weight loss and if DACRAs affect glucose turnover including tissue-specific glucose uptake is still unknown. Hyperinsulinemic glucose clamp studies were carried out in pre-diabetic ZDSD and diabetic ZDF rats treated with either the DACRA KBP or the long-acting DACRA KBP-A for 12 days. The glucose rate of disappearance was assessed using 3-3H glucose and tissue-specific glucose uptake was evaluated using 14C-2-deoxy-D-glucose (14C-2DG). In diabetic ZDF rats, KBP treatment significantly reduced fasting blood glucose and improved insulin sensitivity independent of weight loss. Furthermore, KBP increased the rate of glucose clearance, likely by increasing glucose storage, but without altering the endogenous glucose production. This was confirmed in pre-diabetic ZDSD rats. Direct assessment of tissue-specific glucose uptake showed, that both KBP and KBP-A significantly increased glucose uptake in muscles. In summary, KBP treatment significantly improved insulin sensitivity in diabetic rats and markedly increased glucose uptake in muscles. Importantly, in addition to their well-established weight loss potential, the KBPs have an insulin-sensitizing effect independent of weight loss, highlighting DACRAs as promising agents for the treatment of type 2 diabetes and obesity.

Improved metabolic efficacy of a dual amylin and calcitonin receptor agonist when combined with semaglutide or empagliflozin.

Pharmacotherapies for obesity and type 2 diabetes (T2D) are thought to bridge the gap between lifestyle modification and the weight loss obtained with bariatric surgery. Although the effect of monotherapies, namely amylin and glucagon-like peptide-1 receptor (GLP-1R) agonists, has shown great potential, combination therapy is now becoming a strategy to optimize efficacy for weight management while minimizing adverse effects. This study investigated a dual amylin and calcitonin receptor agonist (DACRA); KBP-066A in combination with the GLP-1R agonist semaglutide or the sodium-glucose co transporter-2 inhibitor (SGLT2i) empagliflozin for anti-obesity and anti-diabetic treatment. The effect of KBP-066A, semaglutide, and empagliflozin alone and in combination was studied with respect to their impact on body weight, food intake, and glucose metabolism in high-fat diet (HFD) and Zucker diabetic fatty (fa/fa) (ZDF) rats. Treatment with KBP-066A and semaglutide lowered body weight by 13% and 9.7%. In contrast, a combination of both KBP-066A + semaglutide reduced body weight by 21% in HFD rats demonstrating superiority compared to monotherapies alone. A combination of KBP-066A with semaglutide or empagliflozin significantly lowered fasting blood glucose, and HbA1C (%) levels in ZDF rats. The complementary action by KBP-066A to GLP-1R agonist and SGLT2i on BW, food intake and glucose control endorsed the potential of DACRAs as an add-on therapy to therapeutic options for T2D and obesity.