Imidazoline compounds have been considered for the treatment of type 2 diabetes. We have now investigated the effects of imidazolines on interleukin (IL)-1β-induced β-cell apoptosis and the signal transduction pathways involved. Inhibition of Ca2+ influx into β-cells by D-600, a blocker of voltage-gated L-type Ca2+ channels, suppressed IL-1β-induced apoptosis. Our data show that calcineurin, Ca2+/calmodulin-dependent serine/threonine protein phosphatase 2B, is responsible for the effect of Ca2+ on β-cell apoptosis. We also demonstrate that IL-1β-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-1β-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-1β-induced apoptosis in pancreatic β-cells, possibly by their inhibition of the expression of iNOS, a key element in the IL-1β-induced apoptotic pathway in pancreatic β-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.
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism