A) Ins-GLuc MIN6 β cells respond as expected to the diazoxide paradigm; 200 µM diazoxide (Dz) (basal), Dz + 35 mM KCl (triggering), and Dz + 35 mM KCl + 20mM glucose (amplifying). Data are representative of an entire 96-well plate with 32 replicates for each condition and a Z-score >0.5. B) Mock screen of 24 h DMSO treatment of 384 well plates of Ins-GLuc MIN6 cells followed by the GLuc assay modified for high throughput screening. Data are the average of 3 mock plates ± SE for each column of the 384 well plate. C,D) Ins-GLuc MIN6 cells were treated overnight with the entire UTSW marine natural product library (~6400 fractions), DMSO (1%), or thapsigargin (1µM) (in red) and the next day cells were subjected to stimulation under Dz/KCl/glucose conditions for 1 h before assaying luciferase activity. Two-point normalized values were used to calculate the RZ score for suppressors of secretion (B) and RZ-score calculated from single-point normalized values were used for potentiators (C). Fractions with RZ scores > 3 or < -3 were flagged as hits.