Imidazoline Compounds Protect Against Interleukin 1 –Induced -Cell Apoptosis

Imidazoline compounds have been considered for the treatment of type 2 diabetes. We have now investigated the effects of imidazolines on interleukin (IL)-1 –induced -cell apoptosis and the signal transduction pathways involved. Inhibition of Ca influx into -cells by D-600, a blocker of voltage-gated L-type Ca channels, suppressed IL-1 –induced apoptosis. Our data show that calcineurin, Ca/calmodulin-dependent serine/threonine protein phosphatase 2B, is responsible for the effect of Ca on -cell apoptosis. We also demonstrate that IL-1 – mediated apoptosis correlates with expression of inducible nitric oxide synthase (iNOS) and the increase in intracellular production of nitric oxide. An inhibitor of cGMP-dependent protein kinase (PKG), KT5823, suppressed IL-1 –induced apoptosis, suggesting the involvement of a PKG-dependent pathway in the apoptotic process. One of the major findings in this study is that imidazoline compounds RX871024 and efaroxan, suggested as prototypes of a new generation of drugs against type 2 diabetes, can protect against IL-1 –induced apoptosis in pancreatic -cells, possibly by their inhibition of the expression of iNOS, a key element in the IL-1 – induced apoptotic pathway in pancreatic -cells. These data suggest that imidazoline compounds should be explored as a potential therapeutic agent for the treatment of both type 1 and type 2 diabetes. Diabetes 50 (Suppl. 1):S70–S76, 2001