Glucocorticoids stimulate while IGF-1 protects against apoptosis of insulin secreting cells. The present study examined effects of IGF-1 on glucocorticoid-induced cell death. INS-1 cells have been cultured under standard culture conditions. Cell growth was evaluated by BrdU staining, apoptosis by the number of DAPI-stained condensed nuclei, TUNEL assay and caspase-3 activity. IGF-1 (10 ng/ml) increased the amount of BrdU labelling, an effect which was counteracted by the PI3 kinase inhibitor LY294002 (10 mM) and inhibited by dexamethasone (dexa, 100 nM). Surprisingly, LY294002 enhanced the IGF-1-mediated protection against dexa-induced apoptosis. MAP kinase inhibition by PD98059 (10 mM) and SB203580 (10 mM), in contrast, counteracted the protective effect of IGF-1. While IGF-1 increased tyrosine-phosphorylation of IRS-2, dexa reduced it. AKT/PKB was dephosphorylated by dexa and further by the PI3kinase inhibitor LY294002. The anti-apoptotic protein Bcl-2 was decreased by dexa, an effect which was not antagonized by IGF-1 and remained significant also in the presence of the above inhibitors. These data suggest that IGF-1 stimulates proliferation via PI3 kinase and AKT/PKB but protects against dexa-induced cell death via a MAP kinase- dependent, PKB- and PI3 kinase-independent mechanism.