The imidazoline RX871024 induces death of proliferating insulin-secreting cells by activation of c-jun N-terminal kinase

Abstract

An insufficient number of insulin-producing beta-cells is a major cause of defective control of blood glucose in both type 1 and type 2 diabetes. The aim of this study was to clarify whether the insulinotropic imidazolines can affect the survival of highly proliferating insulin-secreting cells, here exemplified by the MIN6 cell line. Our data demonstrate that RX871024, but not efaroxan, triggered MIN6 cell death and potentiated death induced by a combination of the pro-inflammatory cytokines interleukin-1beta, interferon- gamma and tumor necrosis factor-alpha. These effects did not involve changes in nitric oxide production but correlated with stimulation of c-jun N-terminal kinase (JNK) activity and activation of caspases-1, -3, -8 and -9. Our results suggest that the imidazoline RX871024 causes death of highly proliferating insulin-secreting cells, putatively via augmentation of JNK activity, a finding that may impact on the possibility of using compounds of similar activity in the treatment of diabetes.

Suppressor of cytokine signaling-1 inhibits caspase activation and protects from cytokine-induced beta cell death

“…Following stimulation with the mixture of IL-1b, TNFa, and IFNc for 40 h, caspase-8 and caspase-9 activities were measured in cell lysates from B6 or SOCS-1-Tg B6 mouse islet cells. In contrast to previous reports using beta cell lines [17,18], we were unable to detect any caspase-8 activation in primary B6 islet cells stimulated with cytokines. However, caspase-9 was activated in islet cells from B6 mice stimulated with the cytokine mixture (Fig.…”

“…Our data support this view since activation of caspase-3 in B6 mouse islet cells is accompanied by an increase in cell death. Initiator caspase-8 and caspase-9 can activate the effector caspase-3 [44], and we and others demonstrated that cytokines activate caspase-8 in beta cell lines [17,18]. However, our observation that caspase-8 known to be induced after ligation of the TNF receptor [46] is not activated in primary mouse islet cells incubated with a combination of IL-1b, TNFa, and IFNc suggests that the mechanisms underlying cytokine-induced primary beta cell death may differ from those triggering cell death in beta cell lines.…”

“…Caspase-3 is an effector caspase that is activated by initiator caspases [16], such as caspase-8 and caspase-9. Caspase-8 is shown to be activated by TNFa in insulinproducing cell lines [17,18], and caspase-9 by the combination of IL-1b, IFNc, and TNFa in human pancreatic islets [19].…”

Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes

“…The imidazoline 1-phenyl-2-(imidazoline-2-yl)benzimidazole (RX871024) causes death of highly proliferating insulin-secreting cells, putatively via augmentation of Janus kinase activity (Zaitseva et al, 2008).…”

Docking and molecular dynamics studies on the interaction of four imidazoline derivatives with potassium ion channel (Kir6.2)

“…But not all imidazolines can be used to treat diabetes because of the b-cell toxicity. The toxicity is due to individual properties of the imidazolines and is different from the sequence of the K ATP channel-blocking and insulin-releasing effect; Efaroxan has no b-cell toxicity, Idazoxan is markedly b-cell toxic and RX871024 has a mediated toxicity [32,33]. The relationship of toxicity and the binding sites of imidazolines on Kir6.2 is still unclear and further studies are required.…”