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

Summary

A long-term (>24 h) exposure of insulin-secreting HIT T15 cells to the phosphatase inhibitor, okadaic acid (OA), at concentrations 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 the occurrence of internucleosomal DNA fragmentation after 15 h in 50 nM OA. The compromised insulin secretion was not simply a consequence of a lowered hormone content and cell growth, but comprised also a complete suppression of secretion stimulated by K⁺ depolarisation and forskolin. K⁺ depolarisation of HIT cells cultured for 24 h in 50 nM OA resulted in a nearly unimpaired influx of Ca²⁺, but did not induce secretion. These observations suggest that the secretory defect may be localised distal to Ca²⁺ influx in stimulus secretion coupling of insulin-secreting cells.

Key words

Ser/thr phosphatase inhibitors - okadaic acid - calyculin A - apoptosis - insulin secretion