| First Author | Babinsky VN | Year | 2017 |
| Journal | Endocrinology | Volume | 158 |
| Issue | 8 | Pages | 2486-2502 |
| PubMed ID | 28575322 | Mgi Jnum | J:247025 |
| Mgi Id | MGI:5917832 | Doi | 10.1210/en.2017-00111 |
| Citation | Babinsky VN, et al. (2017) Mutant Mice With Calcium-Sensing Receptor Activation Have Hyperglycemia That Is Rectified by Calcilytic Therapy. Endocrinology 158(8):2486-2502 |
| abstractText | 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-of-function CaSR mutation, Leu723Gln, referred to as Nuclear flecks (Nuf). Heterozygous- (CasrNuf/+) and homozygous-affected (CasrNuf/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 CasrNuf/+ mice and ameliorated glucose intolerance in CasrNuf/Nuf mice. Ex vivo studies showed CasrNuf/+ and CasrNuf/Nuf mice to have reduced pancreatic islet mass and beta-cell proliferation. Electrophysiological analysis of isolated CasrNuf/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+ (KATP) channel. CasrNuf/Nuf mice also had impaired glucose-mediated suppression of glucagon secretion, which was associated with increased numbers of alpha-cells and a higher alpha-cell proliferation rate. Moreover, CasrNuf/Nuf islet electrophysiology demonstrated an impairment of alpha-cell membrane depolarization in association with attenuated alpha-cell basal KATP 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 for modulating glucose metabolism. |
