IN VITRO AND IN VIVO STUDIES OF APOLIPOPROTEIN CIII IN DIABETES

Apolipoprotein CIII (apoCIII) is an important regulator of lipid metabolism and it is also known to have pro-inflammatory properties. From the point of view of diabetes it is interesting that both insulin deficiency and insulin resistance increase the expression of the apoCIII gene. ApoCIII needs to be kept within a physiological window and this explains the different responses in islets from neonatal and adult rats exposed to the apolipoprotein. In the former the addition of apoCIII had an anti-inflammatory and protective role, while in the latter adult tissue the effects were negative. This is due to the fact that neonatal rats have subphysiological levels of apoCIII and supplement of the apolipoprotein lifts up the concentration to the optimal range, where it is protective, in contrast to adult islets where the addition results in levels outside the protective range and here apoCIII is pro-inflammatory and apoptotic. A previous study has demonstrated that lowering apoCIII with antisense oligonucleotides during a period of the pre-diabetic phase in BB rats, an animal model for type-1 diabetes (T1D), prolongs the time to onset of disease. In the same animal model treatment with polyphenol-containing red wines and fenofibrate, both PPARα agonists reported to lower apoCIII, were tested. However, these substances did not have any effect on apoCIII and consequently not on the debut of diabetes in BB rats. ApoCIII is also increased in type-2 diabetes (T2D) and the apolipoprotein is produced within the pancreatic islets. It increases in parallel with the development of insulin resistance and it deteriorates islet function. Impeding the increase maintains a normal islet function. Furthermore, HFD-induced obesity, insulin resistance and T2D can be prevented, and more interestingly reversed, by decreasing apoCIII, despite continuation on HFD. In conclusion, apoCIII is an important diabetogenic factor and the aim for the future is to find safe ways to lower the apolipoprotein in individuals at risk of developing obesity, insulin resistance and diabetes. LIST OF SCIENTIFIC PAPERS I. Karin Åvall, Per-Olof Berggren, Lisa Juntti-Berggren. The yin and yang of apolipoprotein CIII. Diabetes Metab. 2017 May 8. pii: S1262-3636(17)30064-2. doi: 10.1016/j.diabet. 2017.03. 009. II. Karin Åvall, Per-Olof Berggren, Lisa Juntti-Berggren. Neither polyphenol-rich red wine, alcohol nor fenofibrate affect the onset of type 1 diabetes mellitus in the BB-rat. Manuscript III. Karin Åvall * , Yusuf Ali * , Ingo B Leibiger, Barbara Leibiger, Tilo Moede, Meike Paschen, Andrea Dicker, Elisabetta Daré, Martin Köhler, Erwin Ilegems, Midhat H Abdulreda, Mark Graham, Roseanne M Crooke, Vanessa S Tay, Essam Refai, Stefan K Nilsson, Stefan Jacob, Lars Selander, PerOlof Berggren, Lisa Juntti-Berggren. Apolipoprotein CIII links islet insulin resistance to β-cell failure in diabetes. Proc Natl Acad Sci U S A. 2015 May 19;112(20):E2611-9. doi: 10.1073/pnas.1423849112. IV. Karin Åvall * , Ismael Valladolid Acebes * , Galyna Bryzgalova, Marie Björnholm, Anna Krook, Cheng Xu, Sergiu-Bogdan Catrina, Kerstin Brismar, Mark Graham, Roseanne M Crooke, Fredrik Landfors, Stefan K Nilsson, PerOlof Berggren, Lisa Juntti-Berggren. Lowering apolipoprotein CIII prevents diet-induced diabesity. Manuscript * These authors contributed equally PUBLICATIONS NOT INCLUDED IN THE THESIS Nancy Dekki Shalaly, Massimiliano Ria, Ulrika Johansson, Karin Åvall, Per-Olof Berggren, My Hedhammar. Silk matrices promote formation of insulin-secreting islet-like clusters. Biomaterials. 2016 Jun;90:50-61. doi: 10.1016/j Ulrika Johansson, Massimiliano Ria * , Karin Åvall * , Nancy Dekki Shalaly, Sergei V Zaitsev, Per-Olof Berggren, My Hedhammar. Pancreatic Islet Survival and Engraftment Is Promoted by Culture on Functionalized Spider Silk Matrices. PLoS One. 2015 Jun 19;10(6):e0130169 doi: 10.1371/journal.pone. 0130169. * These authors contributed equally TABLE OF CONTENTS