Abstract
Previously, compound 19e, a novel heteroaryl-containing benzamide derivative, was identified as a potent glucokinase activator (GKA) and showed a glucose-lowering effect in diabetic mice. In this study, the anti-apoptotic actions of 19e were evaluated in INS-1 pancreatic beta-cells co-treated with TNF-α and IL-1β to induce cell death. Compound 19e protected INS-1 cells from cytokine-induced cell death, and the effect was similar to treatment with another GKA or exendin-4. Compound 19e reduced annexin-V stained cells and the expression of cleaved caspase-3 and poly (ADP-ribose) polymerase protein, as well as upregulated the expression of B-cell lymphoma-2 protein. Compound 19e inhibited apoptotic signaling via induction of the ATP content, and the effect was correlated with the downregulation of nuclear factor-κB p65 and inducible nitric oxide synthase. Further, 19e increased NAD-dependent protein deacetylase sirtuin-1 (SIRT1) deacetylase activity, and the anti-apoptotic effect of 19e was attenuated by SIRT1 inhibitor or SIRT1 siRNA treatment. Our results demonstrate that the novel GKA, 19e, prevents cytokine-induced beta-cell apoptosis via SIRT1 activation and has potential as a therapeutic drug for the preservation of pancreatic beta-cells.
Highlights
Type 2 diabetes mellitus affected over 300 million people worldwide in 2013, and the prevalence of diabetes has increased noticeably over the past 50 years with a concomitant increase in the rates of obesity (Shaw et al, 2010)
As compound 19e treatment reduced cytokine-induced betacell death, we investigated whether compound 19e could protect beta-cells against apoptosis induced by the cytokine mixture and the effect was compared to treatment with PSN-GK1 or exendin-4 (Ferdaoussi et al, 2008; Oh et al, 2014)
Resveratrol, a SIRT1 activator, exhibits protective actions against cytokine-induced betacell dysfunction by activating nicotinamide-dependent protein deacetylase SIRT1 (Lee et al, 2009). These results suggest that compound 19e enhanced SIRT1 activity and inhibited cytokine-induced nuclear factor-κB (NF-κB) signaling pathways in INS-1 cells
Summary
Type 2 diabetes mellitus affected over 300 million people worldwide in 2013, and the prevalence of diabetes has increased noticeably over the past 50 years with a concomitant increase in the rates of obesity (Shaw et al, 2010). Diabetes is characterized by hyperglycemia, and insulin released by pancreatic beta-cells is the key hormone responsible for glucose homeostasis. In type 2 diabetes, beta-cells are damaged and become dysfunctional because of the persistently high levels of glucose, lipid, and inflammatory mediators released from the adipose tissues (Kahn et al, 2006). Various anti-diabetic drugs targeting pancreatic beta-cells such as sulfonylureas, thiazolidinediones, incretin mimetics [glucagon-like peptide-1 (GLP-1) analogs] and G-protein coupled receptor 40 (GPR40) agonists have been developed (Stein et al, 2013). Rosiglitazone, a thiazolidinedione, protects against palmitate-induced cell death in beta-cell lines (Wu et al, 2013); exenatide, a GLP-1 receptor agonist, increases beta-cell proliferation and Compound 19e Protects Beta-Cell Apoptosis reduces beta-cell apoptosis in vivo (Vilsboll, 2009); and CNX011-67, a GPR40 agonist, increases insulin secretion and reduces beta-cell apoptosis in the Zucker Diabetic Fatty rat, a diabetic animal model (Gowda et al, 2013)
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