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Strategies to increase β-cell mass expansion

Student thesis: Doctoral ThesisDoctor of Philosophy

Aim: Failure of the functional β-cell mass to adapt to compensate for peripheral insulin resistance leads to the development of type 2 diabetes and gestational diabetes. The overall aim of this thesis was to study mechanisms regulating β-cell mass expansion, using pregnancy in mice as an experimental model in which the β-cell mass increases during gestation and returns to normal levels post-partum. The mechanisms underlying this adaptation are not well understood, although placental signals are thought to be involved. The first objective of the project was to analyse changes in the β-cell mass during pregnancy, and post-partum. The second objective was to quantify the expression of islet β-cell G protein-coupled receptors (GPCRs) and their placental ligands to identify novel placental signals potentially involved in β-cell adaptation to pregnancy. The third objective was to examine the effects of one of the novel placental signals, R-spondin 4 (RSPO4), on β-cell function.
Methods: β-cell proliferation was quantified using immunohistochemical staining of pancreatic sections labelled with 5-bromo-2'-deoxyuridine (BrdU), a thymidine analogue. β-cell identity was confirmed by co-immunostaining for insulin and quantified by morphometric analysis. Islet GPCR and placental ligand mRNAs were quantified using a non-biased quantitative real time PCR (qRT-PCR) array approach. The effects of RSPO4 on insulin secretion, β-cell proliferation and survival were evaluated using radioimmunoassay, BrdU incorporation and caspase 3/7 apoptosis assays, respectively.
Results: Mouse β-cells proliferated during pregnancy, peaking around gestational day 12, are the newly-formed β-cells which were not selectively lost post-partum. Placental expression of GPCR ligands was upregulated on day 12, and islet GPCR expression was differentially regulated during pregnancy. One candidate placental GPCR ligand, RSPO4, had pro-proliferative and insulinotropic effects in β-cells, consistent with an adaptive function during pregnancy. Conclusion: The placenta synthesizes many GPCR ligands, such as RSPO4, which have the potential to influence β-cell function during pregnancy, and which may have therapeutic potential in treating diabetes.
Original languageEnglish
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Award date2017

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