Mutant Mice With Calcium-Sensing Receptor Activation Have Hyperglycemia That Is Rectified by Calcilytic Therapy
| Autor: | Babinsky, Valerie N, Hannan, Fadil M, Ramracheya, Reshma D, Zhang, Quan, Nesbit, M Andrew, Hugill, Alison, Bentley, Liz, Hough, Tertius A, Joynson, Elizabeth, Stewart, Michelle, Aggarwal, Abhishek, Prinz-Wohlgenannt, Maximilian, Gorvin, Caroline M, Kallay, Enikö, Wells, Sara, Cox, Roger D, Richards, Duncan, Rorsman, Patrik, Thakker, Rajesh V |
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| Rok vydání: | 2017 |
| Předmět: |
Mice
Knockout endocrine system Diabetes Pancreatic and Gastrointestinal Hormones Phenylpropionates Receptors G-Protein-Coupled Islets of Langerhans Mice HEK293 Cells Hyperglycemia Glucose Intolerance Indans Mutation Body Composition Animals Humans Calcium Receptors Calcium-Sensing Research Articles Cell Proliferation |
| Zdroj: | Endocrinology |
| ISSN: | 0013-7227 |
| DOI: | 10.1210/en.2017-00111 |
| Popis: | 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- (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 β-cell proliferation. Electrophysiological analysis of isolated CasrNuf/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+ (KATP) channel. CasrNuf/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, CasrNuf/Nuf islet electrophysiology demonstrated an impairment of α-cell membrane depolarization in association with attenuated α-cell basal KATP 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. Mice with a germline gain-of-function CaSR mutation have hypoinsulinemia, hyperglucagonemia, reduced pancreatic islet mass, and impaired glucose tolerance, which is rectifiable by calcilytic therapy. |
| Databáze: | OpenAIRE |
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