New aspects of voltage-gated calcium channel regulation in pancreatic beta-cells - Relevance for insulin release and type 2 diabetes

Research output: ThesisDoctoral Thesis (compilation)


Voltage-gated Ca2+ channels are essential transducers of cellular signals in many electrically excitable cells. In the pancreatic beta-cell they mediate controlled Ca2+ influx, which is the final trigger for Ca2+ dependent release (exocytosis) of the blood glucose lowering hormone insulin. Several subtypes of voltage-gated Ca2+ channels are known and the L-type has been found to be the main contributor to electrical Ca2+ currents in beta-cells. However, which L-type isoform is operative in human beta-cells and how the L-type channels may be regulated in health and disease are two questions that remain unanswered and formed the basis for this thesis.
The first study identified the redox protein glutaredoxin-1 to localize to rat beta-cell membranes and to be indispensable for glucose induced insulin release. In addition, its substrate NADPH reduces L-type channel activity while at the same time it is increasing the rate of insulin release. We suggest this to happen by a redox dependent mechanism that makes the exocytotic machinery more Ca2+ sensitive, thereby increasing its efficiency to release insulin.
In the second study we found that glucose stimulation of an insulin secreting cell line induces the internalization of the L-type channel isoform Cav1.2. This process is dependent on the eukaryotic translation initiation factor 3 subunit e (eIF3e). Impairment of this mechanism by suppressing the expression of eIF3e in human islets results in increased intracellular Ca2+ levels and augmented rates of apoptosis, two phenomena of great importance in the pathogenesis of beta-cell destruction in diabetes.
The third study revealed that the L-type Ca2+ channel isoform Cav1.3 is the major isoform in enriched human beta-cells and that islets of type 2 diabetes patients express reduced levels of Cav1.3 mRNA than controls. We also identified a single nucleotide polymorphism (SNP) that diminishes Cav1.3 expression and insulin release and 2 SNPs that increase the risk for type 2 diabetes. Investigating glucose dependent effects on Cav1.3 expression demonstrates that the beta-cell responds to increased glucose levels with a raise in Cav1.3 expression, which in turn is necessary for insulin release but also lifts the intracellular Ca2+ concentration to in the long run putatively cytotoxic levels.
In the last part of this thesis we gathered genetic, molecular and functional data about the two main L-type Ca2+ channel isoforms Cav1.2 and Cav1.3 in order to identify significant differences that may allow for development of currently unavailable isoform specific drugs. A review of the literature revealed that there are indeed discrete dissimilarities that could form the basis for such venture.
In conclusion this thesis not only supports the notion of L-type Ca2+ channels being essential for beta-cell function but also reveals new aspects that help to understand their regulation in health and disease with the prospect of this being of relevance for future scientific work.


  • Thomas Reinbothe
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Clinical Medicine


  • voltage-gated calcium channels, L-type, insulin secretion, type 2 diabetes
Original languageEnglish
Awarding Institution
Supervisors/Assistant supervisor
Award date2011 Sep 30
  • Department of Clinical Sciences, Lund University
Print ISBNs978-91-86871-36-9
Publication statusPublished - 2011
Publication categoryResearch

Bibliographic note

Defence details Date: 2011-09-30 Time: 09:00 Place: Skåne University Hospital Malmö, Entrance 72, CRC aula External reviewer(s) Name: Drews, Gisela Title: Prof. Affiliation: University of Tübingen ---

Related research output

Pawel Buda, Thomas Reinbothe, Vini Nagaraj, Taman Mahdi, Cheng Luan, Yunzhao Tang, Annika Axelsson, Daiqing Li, Anders Rosengren, Erik Renström & Enming Zhang, 2013, In: PLoS ONE. 8, 5, e64462.

Research output: Contribution to journalArticle

Thomas Reinbothe, Sami Alkayyali, Emma Ahlqvist, Tiinamaija Tuomi, Bo Isomaa, Valeriya Lyssenko & Erik Renström, 2013, In: Diabetologia. 56, 2, p. 340-349

Research output: Contribution to journalArticle

Annalisa Zuccotti, Stefano Clementi, Thomas Reinbothe, Angelo Torrente, David Vandael & Antonella Pirone, 2011, In: Trends in Pharmacological Sciences. 32, 6, p. 366-375

Research output: Contribution to journalReview article

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