Induction of β-cell neogenesis for future management of diabetes

For almost a century we have been able to control diabetes with insulin injections, yet we still have no cure. One possible way to cure diabetes is by increasing the number of insulin-producing b-cells in the pancreas.

Here, we will use a novel drug-discovery approach in transgenic zebrafish to identify small molecules that can induce b-cell neogenesis from progenitors residing in the pancreatic duct—and transition to mouse, pig, and human analyses to determine whether the hits’ effects are conserved across species.

In addition to our whole-organism screen, we will follow up on a previous hit that promotes b-cell neogenesis as we now know it affects the translation-initiation complex on the mRNA cap, i.e., we will examine whether it induces a translatome that stimulates b-cell differentiation.

We will test the effect of the hits on b-cell neogenesis in mice and in neonatal pig islets, as indicated by an increase in number of b-cells lining the duct, co-expression of insulin and ductal markers, or lineage-tracing.

Further, we will determine whether the hits induce b-cell neogenesis also in organoids derived from human pancreatic duct, and delineate their mechanisms by defining differentiation trajectories and cellular states with single-cell RNA-seq.

By coupling whole-organism screens with mechanistic studies and validation across species, we will identify small molecules and pathways that can induce b-cell neogenesis and could thus form the basis of a cure for diabetes.