Loss of α2δ-1 Calcium Channel Subunit Function Increases the Susceptibility for Diabetes
| Autor: | Erik Renström, Arnold Schwartz, Petronel Tuluc, Jörg Striessnig, Bernhard E. Flucher, Gerald J. Obermair, Mathias Drach, Helene Hofer, Sylvia M. Flucher, Vincenzo Mastrolia |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Blood Glucose
Male 0301 basic medicine Gene isoform medicine.medical_specialty Patch-Clamp Techniques Endocrinology Diabetes and Metabolism Protein subunit medicine.medical_treatment Biology Article Islets of Langerhans Mice 03 medical and health sciences Diabetes mellitus genetics Sex Factors 0302 clinical medicine Insulin-Secreting Cells Internal medicine Diabetes mellitus Insulin Secretion Diabetes Mellitus Internal Medicine medicine Animals Insulin Genetic Predisposition to Disease Patch clamp Mice Knockout Calcium channel Pancreatic islets medicine.disease Immunohistochemistry 030104 developmental biology Endocrinology medicine.anatomical_structure Disease Progression Female Calcium Channels 030217 neurology & neurosurgery |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | Reduced pancreatic β-cell function or mass is the critical problem in developing diabetes. Insulin release from β-cells depends on Ca(2+) influx through high voltage– gated Ca(2+) channels (HVCCs). Ca(2+) influx also regulates insulin synthesis and insulin granule priming and contributes to β-cell electrical activity. The HVCCs are multisubunit protein complexes composed of a pore-forming α1 and auxiliary β and α(2)δ subunits. α(2)δ is a key regulator of membrane incorporation and function of HVCCs. Here we show that genetic deletion of α(2)δ-1, the dominant α(2)δ subunit in pancreatic islets, results in glucose intolerance and diabetes without affecting insulin sensitivity. Lack of the α(2)δ-1 subunit reduces the Ca(2+) currents through all HVCC isoforms expressed in β-cells equally in male and female mice. The reduced Ca(2+) influx alters the kinetics and amplitude of the global Ca(2+) response to glucose in pancreatic islets and significantly reduces insulin release in both sexes. The progression of diabetes in males is aggravated by a selective loss of β-cell mass, while a stronger basal insulin release alleviates the diabetes symptoms in most α(2)δ-1(−/−) female mice. Together, these findings demonstrate that the loss of the Ca(2+) channel α(2)δ-1 subunit function increases the susceptibility for developing diabetes in a sex-dependent manner. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|