The Calcitonin Receptor Plays a Major Role in Glucose Regulation as a Function of Dual Amylin and Calcitonin Receptor Agonist Therapy

Apr 23, 2020The Journal of pharmacology and experimental therapeutics

The Calcitonin Receptor's Key Role in Controlling Blood Sugar with Combined Amylin and Calcitonin Receptor Treatments

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Abstract

KBP-088 treatment resulted in significant reductions in body weight and improved glucose tolerance in obese rats.

KBP-088, a dual amylin and calcitonin receptor agonist, was compared to rat amylin and rat calcitonin in obesity and diabetes models.
In obese high-fat diet-fed rats, KBP-088 and rat amylin, alone or in combination with rat calcitonin, effectively reduced body weight.
Rat calcitonin alone did not affect body weight in obese rats.
In diabetic Zucker diabetic fatty rats, both KBP-088 and the combination of rat amylin and rat calcitonin significantly lowered fasting blood glucose levels.
Rat calcitonin demonstrated similar efficacy to rat amylin in reducing fasting glycemia in diabetic rats.
Calcitonin receptor activation is linked to blood glucose regulation, alongside the established role of amylin receptor activation.

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Amylin treatment improves body weight and glucose control, although it is limited by a short action and need for high doses. Dual amylin and calcitonin receptor agonists (DACRAs) are dual amylin and calcitonin receptor agonists with beneficial effects beyond those of amylin. However, to what 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 high-fat diet (HFD) and diabetic Zucker diabetic fatty (ZDF) rats. HFD-fed Sprague-Dawley rats and ZDF rats were treated for 4 weeks with KBP-088 (5 µg/kg per day), rAMY (300 µg/kg per day), rCT (300 µg/kg per day), and the combination of rAMY and rCT (300+300 µg/kg per day) using infusion pumps. Body weight, food intake, fasting glycemia, glycated hemoglobin type A1c 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, whereas rCT alone had no effect. In diabetic ZDF rats, rCT was efficient in lowering fasting glycemia similar to rAMY, whereas 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.

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The Calcitonin Receptor Plays a Major Role in Glucose Regulation as a Function of Dual Amylin and Calcitonin Receptor Agonist Therapy

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