Phosphatase inhibitors induce defective hormone secretion in insulin-secreting cells and entry into apoptosis

A long-term (greater than or equal to 24 h) exposure of insulin-secreting H IT T15 cells to the phosphatase inhibitor, okadaic acid (OA), at concentrat ions inhibiting serine/threonine phosphatases 1 (PP1) and 2A (PP2A) reduced proliferation and insulin secretion. The reduced proliferation was related to the induction of apoptosis as evidenced by morphological criteria and t he occurrence of internucleosomal DMA fragmentation after 15 h in 50 nM OA. The compromised insulin secretion was not simply a consequence of a lowere d hormone content and cell growth, but comprised also a complete suppressio n of secretion stimulated by K+ depolarisation and forskolin. K+ depolarisa tion of HIT cells cultured for 24 h in 50 nM OA resulted in a nearly unimpa ired influx of Ca2+, but did not induce secretion. These observations sugge st that the secretory defect may be localised distal to Ca2+ influx in stim ulus secretion coupling of insulin-secreting cells.