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Loss of a2d-1 calcium channel subunit function increases the susceptibility for diabetes

Mastrolia, Vincenzo; Flucher, Sylvia M.; Obermair, Gerald J.; Drach, Mathias; Hofer, Helene; Renström, Erik LU ; Schwartz, Arnold; Striessnig, Jörg; Flucher, Bernhard E. and Tuluc, Petronel (2017) In Diabetes 66(4). p.897-907
Abstract

Reduced pancreatic b-cell function or mass is the critical problem in developing diabetes. Insulin release from b-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 aremultisubunit protein complexes composed of a pore-forming a1 and 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 α 2δ subunit in pancreatic islets, results in glucose intolerance and diabetes without affecting insulin sensitivity. Lack of... (More)

Reduced pancreatic b-cell function or mass is the critical problem in developing diabetes. Insulin release from b-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 aremultisubunit protein complexes composed of a pore-forming a1 and 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 α 2δ subunit in pancreatic islets, results in glucose intolerance and diabetes without affecting insulin sensitivity. Lack of the α 2δ-1 subunit reduces the Ca2+ currents through all HVCC isoforms expressed in b-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 b-cell mass, while a stronger basal insulin release alleviates the diabetes symptoms in most α2δ -1 2/2 female mice. Together, these findings demonstrate that the loss of the Ca2+ channel α2β-1 subunit function increases the susceptibility for developing diabetes in a sex-dependent manner.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
66
issue
4
pages
11 pages
publisher
American Diabetes Association Inc.
external identifiers
  • scopus:85019633638
  • wos:000397114900014
ISSN
0012-1797
DOI
10.2337/db16-0336
language
English
LU publication?
yes
id
9d1b7bea-4e25-46b3-aac2-9edb6fdfdc84
date added to LUP
2017-07-03 17:56:48
date last changed
2018-01-07 12:10:23
@article{9d1b7bea-4e25-46b3-aac2-9edb6fdfdc84,
  abstract     = {<p>Reduced pancreatic b-cell function or mass is the critical problem in developing diabetes. Insulin release from b-cells depends on Ca<sup>2+</sup> influx through high voltage- gated Ca2+ channels (HVCCs). Ca<sup>2+</sup> influx also regulates insulin synthesis and insulin granule priming and contributes to β-cell electrical activity. The HVCCs aremultisubunit protein complexes composed of a pore-forming a<sup>1</sup> and auxiliary β and α<sup>2</sup>δ subunits. α2δ is a key regulator of membrane incorporation and function of HVCCs. Here we show that genetic deletion of α2δ<sup>-1</sup>, the dominant α <sup>2</sup>δ subunit in pancreatic islets, results in glucose intolerance and diabetes without affecting insulin sensitivity. Lack of the α 2δ<sup>-1</sup> subunit reduces the Ca<sup>2+</sup> currents through all HVCC isoforms expressed in b-cells equally in male and female mice. The reduced Ca<sup>2+</sup> influx alters the kinetics and amplitude of the global Ca<sup>2+</sup> 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 b-cell mass, while a stronger basal insulin release alleviates the diabetes symptoms in most α2δ <sup>-1</sup> <sup>2/2</sup> female mice. Together, these findings demonstrate that the loss of the Ca<sup>2+</sup> channel α<sub>2</sub>β<sup>-1</sup> subunit function increases the susceptibility for developing diabetes in a sex-dependent manner.</p>},
  author       = {Mastrolia, Vincenzo and Flucher, Sylvia M. and Obermair, Gerald J. and Drach, Mathias and Hofer, Helene and Renström, Erik and Schwartz, Arnold and Striessnig, Jörg and Flucher, Bernhard E. and Tuluc, Petronel},
  issn         = {0012-1797},
  language     = {eng},
  month        = {04},
  number       = {4},
  pages        = {897--907},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Loss of a2d-1 calcium channel subunit function increases the susceptibility for diabetes},
  url          = {http://dx.doi.org/10.2337/db16-0336},
  volume       = {66},
  year         = {2017},
}