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

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 α- and β-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-of-function 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 β-cell proliferation. Electrophysiological analysis of isolated Casr(Nuf/Nuf) islets showed CaSR activation to increase the basal electrical activity of β-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, which was associated with increased numbers of α-cells and a higher α-cell proliferation rate. Moreover, Casr(Nuf/Nuf) islet electrophysiology demonstrated an impairment of α-cell membrane depolarization in association with attenuated α-cell basal K(ATP) channel activity. These studies indicate that the CaSR activation impairs glucose tolerance by a combination of α- and β-cell defects and also influences pancreatic islet mass. Moreover, our findings highlight a potential application of targeted CaSR compounds for modulating glucose metabolism.