In the Gerdes lab, we are interested in primary cilia, especially their role in energy metabolism. We have recently discovered that disrupting beta-cell cilia in mice leads to rapid and drastic glucose intolerance, defects in insulin secretion and, ultimately, in loss of beta-cells. In addition, we have evidence that cilia are playing a similar role in human beta-cells and that misregulation of ciliary genes is found in Type 2 diabetic patients. However, there is a striking difference between human and mouse beta-cells: While in mice almost all beta-cell are ciliated, in humans (and pigs) only a subset of beta-cells have primary cilia.
Beta-cell heterogeneity: Ciliated vs. non-ciliated beta-cells
What is the difference between ciliated and non-ciliated beta cells? And how does it relate to beta-cell function? Beta-cell heterogeneity could be linked to proliferative capacity, signalling pathway activity and several other factors. To better understand there differencens, we will design, clone and test reporter constructs that will enable us to distinguish between ciliated and non-ciliated beta-cells. Using these constructs, we will use single cell RNA seq and other cell-based techniques to determine the difference between these two cell populations. The work will predominantly be carried out in our lab at the Helmholtz Diabetes Center in Munich. In addition, we have a long-standing collaboration with the MacDonald lab at the Alberta Diabetes Initiative in Edmonton, Alberta, and part of the analysis of human beta-cells will be carried out there. In addition to human material, we will also use the reporter construct to generate a transgenic pig model to help in the analysis and to elucidate the mechanism.
Gerdes J, Christou-Safina S, Xiong Y, Moede T, Moruzzi N, Karlsson-Edlund P, Leibiger B, Leibiger I, Ostenson C, Beales P, Berggren P: Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of Type 2 Diabetes in rodents. Nature communications 2014;5:5308
Volta F, Gerdes JM: The role of primary cilia in obesity and diabetes. Ann N Y Acad Sci 2016;139:71-84
Bader E, Migliorini A, Gegg M, Moruzzi N, Gerdes J, Roscioni SS, Bakhti M, Brandl E, Irmler M, Beckers J, Aichler M, Feuchtinger A, Leitzinger C, Zischka H, Wang-Sattler R, Jastroch M, Tschöp M, Machicao F, Staiger H, Häring H-U, Chmelova H, Chouinard JA, Oskolkov N, Korsgren O, Speier S, Lickert H: Identification of proliferative and mature β-cells in the islets of Langerhans. Nature 2016;535:430-434
Gerdes JM, Davis EE, Katsanis N: The vertebrate primary cilium in development, homeostasis, and disease. Cell 2009;137:32-45