The role of metallothionein-3 in streptozotocin-induced beta-islet cell death and diabetes in mice

Metallothionein-3 (Mt3), a zinc (Zn)-regulatory protein mainly expressed in the central nervous system, may contribute to oxidative cell death. In the present study, we examined the possible role of Mt3 in streptozotocin (STZ)-induced islet cell death and consequent hyperglycemia. Quantitative real-time polymerase chain reaction (RT-PCR) confirmed that islet cells expressed Mt3 mRNA. In all cases, wildtype (WT) mice injected with STZ exhibited hyperglycemia 7-21 days later. In stark contrast, all Mt3-null mice remained normoglycemic following STZ injection. STZ treatment increased free Zn levels in islet cells and induced their death in WT mice, but failed to do so in Mt3-null mice. Consistent with this, cultured Mt3-null islet cells exhibited striking resistance to STZ toxicity. Notably, PDE3a (phosphodiesterase 3A) was downregulated in islets of Mt3-null mice compared to those of WT mice, and was not induced by STZ treatment. Moreover, the PDE3 inhibitor cilostazol reduced islet cell death, likely by increasing cAMP levels, further supporting a role for PDE3 in STZ-induced islet cell death. Collectively, these results demonstrate that Mt3 may act through PDE3a to play a key role in Zn dyshomeostasis and cell death in STZ-treated islets.