Targeting the voltage-gated calcium channels as treatment for type 2 diabetes
Author
Summary, in English
The first study identified a mechanism, by which β-cells regulate surface expression of L-type Ca2+ channels in response to glucose and activation of channels. Stimulation of clonal, insulin-secreting cells caused evacuation of L-type channels from the plasma membrane to the cytosol. This effect was reversible after cessation of the stimulation and was mediated by eIF3e, the novel regulatory protein of Ca2+ channels. Ablation of eIF3e abolished channel internalization, thereby rendered cells prone to Ca2+ overload.
The second study showed that in β-cells from T2D human donors the number of L-type channels at the plasma membrane is elevated and that internalization mechanism is not functional. These two abnormalities cause cells susceptible to toxicity of glucose due to Ca2+ overload mediated by L-type Ca2+ channels entrapped in the plasma membrane.
The third study delineated mechanism, through which Ca2+ overload contributes to the loss of β-cell mass observed in T2D in the presence of elevated levels of glucose and free fatty acids, the characteristic milieu for this disease. Overly active L-type Ca2+ channels activated Nur77 and Nor-1 proteins, which inhibited autophagy, the crucial process rescuing cells from cytotoxic stresses exerted by glucose and free fatty acids.
Taken together, this thesis shows that L-type Ca2+ channels determine vitality of β-cells and that deregulation of expression of these channels occurs in T2D contributing to progression of the disease.
Publishing year
2015
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2015:97
Document type
Dissertation
Publisher
Islet patophysiology, Clinical Sciences, Malmö
Topic
- Cell and Molecular Biology
Keywords
- autophagy
- apoptosis
- calcium channels
- Type 2 Diabetes
Status
Published
Research group
- Diabetes - Islet Patophysiology
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-7619-176-7
Defence date
1 October 2015
Defence time
09:00
Defence place
Lilla Aulan, MFC, Jan Waldenströms gata 1, Skånes universitetssjukhus i Malmö.
Opponent
- Anders Tengholm (Professor)