Visualising replication and neogenesis of rodent and human pancreatic islets
Final Report Abstract
The here described Emmy Noether Project “Visualizing replication and neogenesis of rodent and human pancreatic islets” had the objective to shed new light on islet cell regeneration by studying the involved processes under in vivo conditions. For this purpose a novel imaging approach, the anterior chamber of the eye platform, was established and combined with different mouse models to study islet cell physiology longitudinally at a cellular level. During the initial phase of the project we successfully set up the necessary techniques. We improved the original method by various means, enabling us to address additional biological questions and facilitating the quantitative analysis of long-term imaging studies. Subsequently, we established protocols to combine physiological mouse models of islet physiology and pathophysiology and transgenic fluorescent reporter mice with this platform. Our results revealed new aspects on the kinetics, contribution and mechanisms of islet compensation and failure. We could show that functional beta cell plasticity, regulated by blood glucose levels and immune cell infiltration plays a major role during onset of T1D and for its remission after anti-CD3 treatment. Interestingly, even though mouse islets demonstrate a substantial increase in beta cell mass in response to hyperglycemia after treatment, restoration of glucose tolerance depends on functional recovery of beta cells during prolonged normoglycemia. Conversely, under identical conditions human islets exhibit functional plasticity, while islet mass shows no regenerative potential. Furthermore, we assessed for the first time beta cell function and islet mass adaptation simultaneously in a model of type 2 diabetes pathogenesis, from normal glucose tolerance, through compensation of insulin resistance to pre-diabetes. Our study provides first in vivo evidence that beta cell function predominates islet mass adaptation during compensation of insulin resistance and progression to pre-diabetes. We demonstrate that this functional capacity of beta cells to compensate for higher insulin demand relies on the amplification of insulin secretion by Epac-dependent mechanisms. However, after prolonged diet-induced insulin resistance decreased intracellular Calcium activity and insufficient amplification facilitate the onset of pre-diabetes. In contrast, islet mass is not decreased at pre-diabetes onset, but is still increasing, revealing a prevalent role of beta cell function in T2D pathogenesis. In summary, these findings demonstrate that beta cell function has a predominant role in the pathogenesis of diabetes, often outweighing the effect of changes in islet cell mass. This concept applies in particular to the development of T2D, but interestingly also to distinct stages of T1D pathogenesis and has strong implications for diabetes therapies.
Publications
- (2011). Donor islet endothelial cells in pancreatic islet revascularization. Diabetes, 60, 2571-2577
Nyqvist, D., Speier, S., Rodriguez-Diaz, R., Molano, R.D., Lipovsek, S., Rupnik, M., Dicker, A., Ilegems, E., Zahr-Akrawi, E., Molina, J., Lopez-Cabeza, M., Villate, S., Abdulreda, M.H., Ricordi, C., Caicedo, A., Pileggi, A., and Berggren, P.O.
- (2011). Experimental approaches for high-resolution in vivo imaging of islet of Langerhans biology. Current Diabetes Reports, 11, 420-425
Speier, S.
- (2012). Noninvasive in vivo model demonstrating the effects of autonomic innervation on pancreatic islet function. PNAS, 109, 21456-21461
Rodriguez-Diaz, R., Speier, S., Molano, R.D., Formoso, A., Gans, I., Abdulreda, M.H., Cabrera, O., Molina, J., Fachado, A., Ricordi, C., Leibiger, I., Pileggi, A., Berggren, P.O., and Caicedo, A.
- (2013). Age-dependent labeling and imaging of insulin secretory granules. Diabetes, 62, 3687-3696
Ivanova, A., Kalaidzidis, Y., Dirkx, R., Sarov, M., Gerlach, M., Schroth-Diez, B., Muller, A., Liu, Y., Andree, C., Mulligan, B., Munster, C., Kurth, T., Bickle, M., Speier, S., Anastassiadis, K., and Solimena, M.
(See online at https://doi.org/10.2337/db12-1819) - (2013). Mouse pancreas tissue slice culture facilitates long-term studies of exocrine and endocrine cell physiology in situ. PloS one, 8, e78706
Marciniak, A., Selck, C., Friedrich, B., and Speier, S.
(See online at https://doi.org/10.1371/journal.pone.0078706) - (2014). Mesenchymal stromal cells improve transplanted islet survival and islet function in a syngeneic mouse model. Diabetologia, 57, 522-531
Borg, D.J., Weigelt, M., Wilhelm, C., Gerlach, M., Bickle, M., Speier, S., Bonifacio, E., and Hommel, A.
(See online at https://doi.org/10.1007/s00125-013-3109-4) - (2014). Using pancreas tissue slices for in situ studies of islet of Langerhans and acinar cell biology. Nature Protocols 9, 2809-2822
Marciniak, A., Cohrs, C.M., Tsata, V., Chouinard, J.A., Selck, C., Stertmann, J., Reichelt, S., Rose, T., Ehehalt, F., Weitz, J., Solimena, M., Slak Rupnik, M., and Speier, S.
(See online at https://doi.org/10.1038/nprot.2014.195) - (2015). Distinct roles of beta-cell mass and function during type 1 diabetes onset and remission. Diabetes, 64, 2148-2160
Chmelova, H., Cohrs, C.M., Chouinard, J.A., Petzold, C., Kuhn, M., Chen, C., Roeder, I., Kretschmer, K., and Speier, S.
(See online at https://doi.org/10.2337/db14-1055) - (2016). Alterations in beta cell calcium dynamics and efficacy outweigh islet mass adaptation in compensation of insulin resistance and prediabetes onset. Diabetes [Epub Ahead of Print]
Chen, C., Chmelova, H., Cohrs, C.M., Chouinard, J.A., Jahn, S.R., Stertmann, J., Uphues, I., and Speier, S.
(See online at https://doi.org/10.2337/db15-1718) - (2016). Identification of proliferative and mature β-cells in the islet of Langerhans. Nature, 535, pages 430–434 (21 July 2016)
Bader, E., Migliorini, A., Gegg, M., Moruzzi, N., Gerdes, J., Roscioni, S.S., 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
(See online at https://doi.org/10.1038/nature18624) - (2016). The biomechanical properties of an epithelial tissue determine the location of its vasculature. Nat Commun, 7, Article number: 13560
Kragl, M., Schubert, R., Karsjens, H., Otter, S., Bartosinska, E., Chen, C., Eberhard, D., Jeruschke, K., Weiss, J., Alsteens, D., Kuss, O., Speier, S., Müller, D.J., and Lammert, E.
(See online at https://doi.org/10.1038/ncomms13560) - Vessel Network Architecture of Adult Human Islets Promotes Distinct Cell-Cell Interactions In Situ and Is Altered After Transplantation. Endocrinology, Volume 158, Issue 5, 1 May 2017, Pages 1373–1385
Cohrs, C.M., Chen, C., Jahn, S.R., Stertmann, J., Chmelova, H., Weitz, J., Bähr, A., Klymiuk, N., Steffen, A., Ludwig, B., Kamvissi, V., Wolf, E., Bornstein, S. R., Solimena, M., and Speier, S.
(See online at https://doi.org/10.1210/en.2016-1184)
