One of the causes of diabetes could be the dedifferentiation of insulin-producing beta cells in the Langerhans' islets of the pancreas, i.e. the loss of cell identity. If and how dedifferentiated beta cells can be targeted by pharmacological intervention for beta cell regeneration is unknown. DZD-Researchers at Helmholtz Zentrum München demonstrated in collaboration with Novo Nordisk for the first time that a targeted combinatorial drug treatment is able to restore beta cell function, achieve beta cell redifferentiation and therefore potentially open new ways for diabetes remission.
To investigate whether dedifferentiated beta cells can be targeted pharmacologically to restore beta cell function, the researchers used streptozotocin-induced diabetes in mice. Using single cell RNA sequencing the researchers could show that after streptozotocin treatment, the surviving beta cells dedifferentiate into a dysfunctional state. The team then tested treatments for their potential to restore beta cell function. The researchers showed that a stable Glucagon-like peptide-1 (GLP-1)/estrogen conjugate (provided by Novo Nordisk) enables targeted and selective delivery of the nuclear hormone cargo to beta cells. The combination of GLP-1/estrogen and a long acting insulin was superior to mono-treatments to both normalize glycemia, glucose tolerance, to increase pancreatic insulin content and to increase the number of beta cells.
This study not only describes the mechanisms of beta cell dedifferentiation and regeneration, , but also reveals pharmacological entry points to target dedifferentiated dedifferentiated beta cells for diabetes remission.
This study brought together scientists from Helmholtz Zentrum München (Helmholtz Diabetes Center and Institute for Computational Biology), the German Center for Diabetes Research (DZD), Technical University Munich (TUM) as well as InSphero AG and Novo Nordisk with the aim to explore the potential therapeutic benefits of GLP1/estrogen treatment in an animal models and in human cells in vitro.
* Streptozotocin is a chemical compound that has a specific toxic effect on insulin-producing beta cells.
Sachs, S. et al, 2020: Targeted pharmacological therapy restores β-cell function for diabetes remission. Nature Metabolism, DOI: 10.1038/s42255-020-0171-3.