Mutant Mice With Calcium-Sensing Receptor Activation Have Hyperglycemia That Is Rectified by Calcilytic Therapy

摘要

The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor that plays a pivotal role in extracellular calcium homeostasis. The CaSR is also highly expressed in pancreatic islet alpha- and beta-cells that secrete glucagon and insulin, respectively. To determine whether the CaSR may influence systemic glucose homeostasis, we characterized a mouse model with a germline gain-offunction CaSR mutation, Leu723Gln, referred to as Nuclear flecks (Nuf). Heterozygous-(Casr(Nuf/+)) and homozygous-affected (Casr(Nuf/Nuf)) mice were shown to have hypocalcemia in association with impaired glucose tolerance and insulin secretion. Oral administration of a CaSR antagonist compound, known as a calcilytic, rectified the glucose intolerance and hypoinsulinemia of Casr(Nuf/+) mice and ameliorated glucose intolerance in Casr(Nuf/Nuf) mice. Ex vivo studies showed Casr(Nuf/+) and Casr(Nuf/Nuf) mice to have reduced pancreatic islet mass and beta-cell proliferation. Electrophysiological analysis of isolated Casr(Nuf/Nuf) islets showed CaSR activation to increase the basal electrical activity of beta-cells independently of effects on the activity of the adenosine triphosphate (ATP)-sensitive K+ (K-ATP) channel. Casr(Nuf/Nuf) mice also had impaired glucose-mediated suppression of glucagon secretion, whichwas associated with increased numbers of alpha-cells and a higher alpha-cell proliferation rate. Moreover, Casr(Nuf/Nuf) islet electrophysiology demonstrated an impairment of alpha-cell membrane depolarization in association with attenuated alpha-cell basal K-ATP channel activity. These studies indicate that the CaSR activation impairs glucose tolerance by a combination of alpha- and beta-cell defects and also influences pancreatic islet mass. Moreover, our findings highlight a potential application of targeted CaSR compounds formodulating glucose metabolism.