title: Loss of α2δ-1 Calcium Channel Subunit Function Increases the Susceptibility for Diabetes.
abstract: Reduced pancreatic β-cell function or mass is the critical problem in developing diabetes. Insulin release from β-cells depends on Ca2+influx through high voltage-gated Ca2+channels (HVCCs). Ca2+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 α1and auxiliary β and α2δ subunits. α2δ is a key regulator of membrane incorporation and function of HVCCs. Here we show that genetic deletion of α2δ-1, the dominant α2δ subunit in pancreatic islets, results in glucose intolerance and diabetes without affecting insulin sensitivity. Lack of the α2δ-1 subunit reduces the Ca2+currents through all HVCC isoforms expressed in β-cells equally in male and female mice. The reduced Ca2+influx alters the kinetics and amplitude of the global Ca2+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 α2δ-1-/-female mice. Together, these findings demonstrate that the loss of the Ca2+channel α2δ-1 subunit function increases the susceptibility for developing diabetes in a sex-dependent manner.
authors.affiliation: Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria.|Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mastrolia
authors.affiliation: Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Sylvia M
authors.initials: SM
authors.lastname: Flucher
authors.affiliation: Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Obermair
authors.affiliation: Department of General Pathology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Mathias
authors.initials: M
authors.lastname: Drach
authors.affiliation: Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Helene
authors.initials: H
authors.lastname: Hofer
authors.affiliation: Department of Clinical Sciences Malmö, Lund University, Lund, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Renström
authors.affiliation: College of Medicine, University of Cincinnati, Cincinnati, OH.
authors.forename: Arnold
authors.initials: A
authors.lastname: Schwartz
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria.
authors.forename: Jörg
authors.initials: J
authors.lastname: Striessnig
authors.affiliation: Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria petronel.tuluc@uibk.ac.at bernhard.e.flucher@i-med.ac.at.
authors.forename: Bernhard E
authors.initials: BE
authors.lastname: Flucher
authors.affiliation: Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria petronel.tuluc@uibk.ac.at bernhard.e.flucher@i-med.ac.at.|Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria.
authors.forename: Petronel
authors.initials: P
authors.lastname: Tuluc
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics*; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D012737:Sex Factors
chemical_list: D001786:Blood Glucose; C512066:CACNA2D1 protein, mouse; D015220:Calcium Channels; D007328:Insulin