Circulating levels of TNF-related apoptosis inducing ligand (TRAIL)

In their interesting study published in this issue of Clinical Endocrinology, Xiang et al.[1]demonstrated that the circulating levels of TNF-related apoptosis inducing ligand (TRAIL) are significantly decreased in a cohort of 55 newly diagnosed type 2 diabetic (T2D) patients as compared to sex- and aged-matched normal controls, confirming and expanding the data reported in a previous study performed on a smaller group (n = 22) of T2D patients.[2] Of interest, another group of investigators has shown similar findings in an independent and larger cohort (n = 387) of paediatric patients with newly diagnosed with Type 1 diabetes (T1D).[3] In the study of Tornese et al.,[3] the lowest levels of TRAIL were observed in patients with ketoacidosis and those with higher insulin requirements. According to all these studies, both types of diabetes at diagnosis are characterized by low levels of circulating TRAIL, suggesting that metabolic compromise rather than immune-mediated mechanisms (characteristic of T1D but not of T2D) are responsible for the decrease in the circulating levels of TRAIL. The link between circulating levels of TRAIL and the metabolic situation is further suggested in the study of Xiang et al. by the fact that following 6 months therapy with insulin or metformin levels of circulating TRAIL increased significantly, although they still did not reach the values of the control group.[1] In addition, and perhaps more importantly, Xiang et al.[1] were able to demonstrate that circulating TRAIL levels showed a significant positive correlation with flow-mediated endothelium-dependent arterial dilation (FMD), an important clinical index of endothelial function. These findings are particularly relevant since endothelial dysfunction represents an early physiological event in atherosclerosis,[4] and thus the data of Xiang support the hypothesis that TRAIL might have a protective role in endothelial function, at least in the diabetic context. The current findings of Xiang et al.,[1] together with the previous works of Volpato et al. [5] and of Deftereos et al.,[6] strongly support experimental data obtained in animal models, showing that TRAIL is able to counteract the accelerated atherosclerosis observed in streptozotocin-treated apolipoprotein E−/− mice.[7, 8] Moreover, it was previously shown that recombinant TRAIL administration ameliorates the natural history of diabetes in streptozotocin-treated mice.[9] Finally, it has been shown that TRAIL −/− apolipoprotein E−/− mice on an high-fat diet gain more body weight and that they display higher fasting glucose and pro-inflammatory cytokines levels than apolipoprotein E−/− mice,[10] and that recombinant TRAIL delivery was able to reduce body weight, and lower fasting glucose and pro-inflammatory cytokine levels, overall ameliorating diabetes. In conclusion, this study of Xiang et al. [1] provides solid clinical support to the idea that there are significant changes in the circulating levels of TRAIL at the onset of T2D and in response to therapy. Future studies are needed to distinguish whether the decreased levels of circulating TRAIL in both types of diabetes represent simply a new biomarker of metabolic compromise, or whether such reduced levels might play a pathogenetic role in endothelial cell dysfuncion and the development of atherosclerosis