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Cited by 40Pancreatic function and diabetesIon channel regulation and functionDiabetes and associated disorders

Loss of α2δ-1 Calcium Channel Subunit Function Increases the Susceptibility for Diabetes

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Mastrolia, Vincenzo, Flucher, Sylvia M., Obermair, Gerald J., Drach, Mathias, Hofer, Helene, Renström, Erik, Schwartz, Arnold, Striessnig, Jörg +2 more·2017·Diabetes
DOI 10.2337/db16-0336PMC PMC7360433
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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 α1 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 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.

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  • Ablation of α2δ in β-cells is associated with a 50% reduction in Ca2+ current amplitude and a strong reduction of insulin secretion.

    “Ablation of α2δ in β-cells is associated with a 50% reduction in Ca2+ current amplitude and a strong reduction of insulin secretion (434), suggesting its role in β-cells may be similar to that in neurons.”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [434]

    The Results section on Ca2+ influx in pancreatic β-cells reports an approximately 70% reduction in mean maximal Ca2+ current density after α2δ-1 knockout, not 50%. The Results section on insulin release reports substantial reductions in both phases of secretion in isolated islets, supporting that part of the claim. No page numbers are available in our copy. (LLM, conf=0.90)

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Authors
Mastrolia, V., Flucher, S. M., Obermair, G. J., Drach, M., Hofer, H., Renström, E., Schwartz, A., Striessnig, J., Flucher, B. E., & Tuluc, P.
Affiliations
  • Innsbruck Medical University (AT)
  • Lund University (SE)
  • University of Cincinnati (US)
  • Universität Innsbruck (AT)
Corresponding author
  • Flucher, Bernhard E.
  • Tuluc, Petronel
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2017-01-23
Volume
66
Issue
4
Pages
897-907
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db16-0336
PMC
PMC7360433
OpenAlex
W2580796570
Cited by
40
References
7
Citations by year
2026: 6 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 2 · 2021: 8 · 2020: 3 · 2019: 4 · 2018: 3 · 2017: 2
FWCI
3.36
Type
journal article
Language
en
Open access
Licence
www.diabetesjournals.org/content/license (vor, 57 d)
Locations
  • Diabetes (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • Austrian Science Fund (P23479, F4406, F4415)
  • University of Innsbruck (P7400-027-011, P7400-027-012)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords
α2δ-1 subunit, pancreatic beta cells, diabetes susceptibility, impaired glucose tolerance, insulin secretion, calcium influx, sex differences, beta-cell mass, insulin sensitivity, pancreatic islets, gene deletion
MeSH terms
Insulin Secretion, Animals, Blood Glucose, Diabetes Mellitus, Female, Immunohistochemistry, Insulin, Islets of Langerhans, Male, Sex Factors, Calcium Channels, Mice, Knockout, Patch-Clamp Techniques, Disease Progression, Genetic Predisposition to Disease, Insulin-Secreting Cells, Mice

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