The calcitonin receptor plays a major role in glucose regulation as a function of dual amylin and calcitonin receptor agonist therapy.

Amylin treatment improves body weight and glucose control, though limited by a short action and need for high doses. DACRAs are dual amylin and calcitonin receptor agonists with beneficial effects beyond those of amylin. However, to which extent the additional benefits reside in their higher potency or their targeting of the calcitonin receptor remains unclear. Here we deconstruct the receptors involved in the effects of a DACRA, KBP-088, by comparing it to rat amylin (rAMY), rat calcitonin (rCT) and their combination in obese HFD and diabetic ZDF rats. HFD fed Sprague Dawley rats and ZDF rats were treated for four weeks with KBP-088 (5 mug/kg/day), rAMY (300 mug/kg/day), rCT, (300 mug/kg/day) and the combination of rAMY and rCT (300+300 mug/kg/day) using infusion pumps. Body weight, food intake, fasting glycemia, HbA1c levels and glucose tolerance were assessed. In obese HFD fed rats, KBP-088, rAMY and the combination of rAMY and rCT significantly reduced body weight and improved glucose tolerance, while rCT alone had no effect. In diabetic ZDF rats, rCT was efficient in lowering fasting glycemia similar to rAMY, while dual activation by KBP-088 and the combination of rAMY and rCT were superior to activating either receptor alone. In conclusion, calcitonin therapy regulates fasting blood glucose in a diabetic rat model, thereby underscoring the importance of calcitonin receptor activation, as well as the known role of amylin receptor agonism in the potent metabolic benefits of this group of peptides. SIGNIFICANCE STATEMENT: We deconstruct the receptors activated by dual amylin and calcitonin receptor agonist (DACRA) therapy to elucidate through which receptor the beneficial metabolic effects of the DACRAs are mediated. We show that calcitonin receptor activation is important for blood glucose regulation in diabetes. This is in addition to the known metabolic beneficial role of amylin receptor activation. These data help in understanding the potent metabolic benefits of the DACRAs and underline the potential of DACRAs as treatment for diabetes and obesity.