Targeted Pharmacological Therapy Restores Beta-Cell Function For Diabetes Remission

Dedifferentiation of insulin-secreting beta cells in the islets of Langerhans has been proposed to be a major mechanism of beta-cell dysfunction. Whether dedifferentiated beta cells can be targeted by pharmacological intervention for diabetes remission, and ways in which this could be accomplished, are unknown as yet. Here we report the use of streptozotocin-induced diabetes to study beta-cell dedifferentiation in mice. Single-cell RNA sequencing (scRNA-seq) of islets identified markers and pathways associated with beta-cell dedifferentiation and dysfunction. Single and combinatorial pharmacology further show that insulin treatment triggers insulin receptor pathway activation in beta cells and restores maturation and function for diabetes remission. Additional beta-cell selective delivery of oestrogen by Glucagon-like peptide-1 (GLP-1-oestrogen conjugate) decreases daily insulin requirements by 60%, triggers oestrogen-specific activation of the endoplasmic-reticulum-associated protein degradation system, and further increases beta-cell survival and regeneration. GLP-1-oestrogen also protects human beta cells against cytokineinduced dysfunction. This study not only describes mechanisms of beta-cell dedifferentiation and regeneration, but also reveals pharmacological entry points to target dedifferentiated beta cells for diabetes remission.