Widespread disease diabetes: Why do beta cells refuse to release insulin?

One in eleven adults worldwide suffers from diabetes, and the number of diabetes patients is rising rapidly. Diabetes is worldwide one of the most widespread diseases. In the most common form of diabetes, type 2 diabetes, the body cells react increasingly insensitively to the hormone insulin, which is produced by beta cells in the pancreas and is intended to promote the absorption of sugar from the blood into the cells. Due to the increasing insulin resistance of the cells, patients suffer from an increased blood sugar level with far-reaching consequences. After many years of illness, insulin production dries up and patients with type 2 diabetes have to inject insulin.

What causes the lack of insulin production in people with type 2 diabetes? Researchers from Paul Langerhans Institute of the Helmholtz Zentrum München at the University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden together with colleagues from Imperial College London and other research institutes from the UK, Canada and Italy have observed amazing cell interactions: The beta cells of the pancreas work as highly-connected clusters, known as islets, and their responses to rising blood glucose levels are coordinated by small teams of “leader cells”. To show that, the research teams developed an innovative imaging technique which allowed them to observe beta cells’ hierarchical relationship in live animals including in zebrafish and mouse.

"In these model organisms we saw that when blood glucose levels increased, the response of beta cells originated from temporally defined leader cells. When we selectively deleted the leader cells, the level of coordination in subsequent responses to glucose was disrupted," explains PhD student Luis Delgadillo Silva, one of the two lead authors of the study.

Mathematical analysis revealed that the leader cells have a controlling role over the islet. In addition, the researchers were able to show that some beta cells contained a unique molecular signature, which would allow them to be more metabolically active and perhaps more glucose-sensitive.

Based on these findings, the scientists will now investigate whether the leader cells are defined from birth or exchange identity with non-leader cells over time. They also want to investigate if these cells are more vulnerable to damage as diabetes develops and, crucially, whether new leaders can be induced by genetic or pharmacological reprogramming of non-leader cells.

“To understand better the role of “leader cells” in islet function, we have established a set of new tools in zebrafish, which will help us to activate or silence beta cells by shining light on them, as well as to track individual cells over time. Using these tools, we will be able to ask precisely how many cells are controlled by a leader cell and what genes determine the identity of a leader cell”, explains Luis Delgadillo Silva.

The Scientists just published their results in the renowned scientific journal Nature Metabolism, and are featured on the cover of the journal. Their study received funding from TUD/CRTD, the German Research Foundation, the Free State of Saxony, the German Center for Diabetes Research and the European Foundation for the Study of Diabetes.

Publication:
Leader β-cells coordinate Ca2+ dynamics across pancreatic islets in vivo. Salem V, Delgadillo Silva L, Suba K, Georgiadou E, Gharavy SNM, Akhtar N, Martin-Alonso A, Gaboriau DCA, Rothery SM, Stylianides T, Carrat G, Pullen TJ, Pal Singh S, Hodson DJ, Leclerc I, Shapiro AMJ, Marchetti P, Briant LJB, Distaso W, Ninov N & Rutter GA. Nature Metabolism. volume 1, pages615–629 (2019)

https://www.nature.com/articles/s42255-019-0075-2

Further information:
Dr. Nikolay Ninov
Tel: +49 (0) 351 463 82104
Email: nikolay.ninov@tu-dresden.de
Webpage: https://tu-dresden.de/med/mf/plid/forschung/Ninov