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)

Bibtex

@phdthesis{f6f3ad73b08e4048a6feb48fc976cb25,
title = "New aspects of voltage-gated calcium channel regulation in pancreatic beta-cells - Relevance for insulin release and type 2 diabetes",
abstract = "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.",
keywords = "voltage-gated calcium channels, L-type, insulin secretion, type 2 diabetes",
author = "Thomas Reinbothe",
note = "Defence details Date: 2011-09-30 Time: 09:00 Place: Sk{\aa}ne University Hospital Malm{\"o}, Entrance 72, CRC aula External reviewer(s) Name: Drews, Gisela Title: Prof. Affiliation: University of T{\"u}bingen ---",
year = "2011",
language = "English",
isbn = "978-91-86871-36-9",
series = "Lund University Faculty of Medicine Doctoral Dissertation Series ",
publisher = "Department of Clinical Sciences, Lund University",
school = "Department of Clinical Sciences, Malm{\"o}",

}