Does receptor balance matter? – Comparing the efficacies of the dual amylin and calcitonin receptor agonists cagrilintide and KBP-336 on metabolic parameters in preclinical models

Are insulin sensitizers the new strategy to treat Type 1 diabetes? A long‐acting dual amylin and calcitonin receptor agonist improves insulin‐mediated glycaemic control and controls body weight

“…KBP-336 reduced fasting blood glucose levels, similarly to lean controls, when combined with either dose of Humulin. These data indicate that KBP-336 improves insulin sensitivity and thereby lowers insulin requirements, which is in line with recent studies showing that DACRAs improved insulin sensitivity in T2D rats during a hyperinsulimic glucose clamp (Larsen et al, 2022;Larsen, Melander, et al, 2023).…”

“…In the present study, all treatments resulted in decreased circulating glucagon levels, similar to lean controls. Along with the previously demonstrated improvement in glycaemic control and delay in gastric emptying by DACRAs (Andreassen et al, 2021;Larsen et al, 2022), it is possible that KBP-336 with Humulin postponed the release of nutrients that stimulate glucagon production, leading to the lower glucagon levels observed. Moreover, amylin can act directly on pancreatic alpha-cells and thereby inhibit glucagon secretion (Scherbaum, 2009;Young, 2005).…”

“…diabetes (Larsen et al, 2022;Larsen, Melander, et al, 2023). Moreover, treatment with the DACRA, salmon calcitonin, was proposed to enhance the function of pancreatic beta-cells and increase beta-cell area in Zucker diabetic fatty (ZDF) rats (Feigh et al, 2012).…”

“…Another interesting group of molecules in this regard are the long‐acting dual amylin and calcitonin receptor agonists (DACRAs), which are novel candidates for the treatment of both obesity and T2D. Preclinical studies have shown that DACRA treatment can induce substantial weight loss and improve glucose control through weight‐dependent and independent mechanisms (Andreassen et al, 2021; Larsen et al, 2022; Sonne et al, 2022). The effects of DACRAs are, in part, mediated through the amylin receptor, which drives the reduction on food intake, delays gastric emptying, and inhibits inappropriate secretion of glucagon (Andreassen, Hjuler, et al, 2014; Feigh et al, 2012; Hjuler et al, 2015).…”

“…The effects of DACRAs are, in part, mediated through the amylin receptor, which drives the reduction on food intake, delays gastric emptying, and inhibits inappropriate secretion of glucagon (Andreassen, Hjuler, et al, 2014; Feigh et al, 2012; Hjuler et al, 2015). Recently, treatment with DACRAs was shown to enhance insulin sensitivity and increase tissue specific glucose uptake in rat models of both prediabetes and diabetes (Larsen et al, 2022; Larsen, Melander, et al, 2023). Moreover, treatment with the DACRA, salmon calcitonin, was proposed to enhance the function of pancreatic beta‐cells and increase beta‐cell area in Zucker diabetic fatty (ZDF) rats (Feigh et al, 2012).…”