Figure 1.

Identification of small-molecule inducers of rat β-cell replication and their combinatorial use. (a) Summary of rat β-cell replication screening results. Compounds are clustered according to their annotated bioactivity. Supplemental Tables 1 and 2 list primary screening and confirmatory testing β-cell–replication results. (b) The β-cell replication–promoting profile of prioritized compounds. Data are presented as mean ± standard deviation (SD; n = 3 to 5 wells per treatment condition; results confirmed in n ≥ 3 independent experiments). (c) Representative images of rat islet cultures treated with vehicle (DMSO) or CC-401. (d) Representative images of compound-treated rat islet cultures. The percentage of replicating PDX1⁺ cells and compound treatments are indicated. (e) Rat islet β-cell replication indices Ki67 (blue) and PCNA (red). Compound concentrations were as indicated in (b) and was 1 μM for CHIR99021. Individual data points represent 2000 to 3000 β cells (n = 4 to 8 replicates per condition; mean ± SD shown). All compounds increased β-cell replication above DMSO (P < 0.01). All compound combinations increased β-cell replication above the relevant individual compound-treatment conditions (P < 0.01). (f) Rat islet β-cell replication index after compound treatment as indicated. Single compound treatment, CNS-1102 combinations, and BML-266 combinations are shown. All individual compound treatments increased replication (vs DMSO; P < 0.01); select combinations increased β-cell replication vs relevant individual compound-treated conditions. *P < 0.01. Individual data points represent 2000 to 3000 β cells (n = 4 to 8 replicates per condition; mean ± SD shown). Error bars represent the standard deviation of an experimental condition (n ≥ 3). cAMP, cyclic adenosine monophosphate; CAS#, Chemical Abstracts Service number; PDE, phosphodiesterase.