Elevated Markers of Death Receptor-Activated Apoptosis are Associated with Increased Risk for Development of Diabetes and Cardiovascular Disease

Article history: Received 25 July 2017 Received in revised form 17 November 2017 Accepted 23 November 2017 Available online 24 November 2017 Background:An increased rate of cell death by apoptosis has been implicated in both diabetes and atherosclerosis. Apoptosis can be induced through activation of the death receptors TNF receptor 1 (TNFR-1), TRAIL receptor 2 (TRAILR-2) and Fas. Soluble forms of these receptors are found in plasma. The objective of this study was to determine if soluble death receptors are markers of receptor-activated apoptosis and predict risk for development of diabetes and cardiovascular events. Methods: Fas ligandwas used to induce apoptosis in peripheral blood mononuclear cells and INS-1 pancreatic βcells and release of TNFR-1, TRAILR-2 and Fasmeasured by ELISA. Proximity Extension Assaywas used to analyze plasma levels of TNFR-1, TRAILR-2 and Fas in baseline samples of 4742 subjects in the Malmö Diet and Cancer Study and related to development of diabetes and cardiovascular events during 19.2 years of follow-up. Results: Activation of apoptosis by Fas ligand was associated with release of soluble Fas, TNFR-1 and TRAILR-2 in both cell types. Circulating levels of all three receptors were higher in subjects with diabetes and correlatedwith markers of impaired glucosemetabolism in non-diabetic subjects. Among the latter, those in the highest tertile of soluble Fas, TNFR-1 and TRAILR-2 had increased risk for development of diabetes and cardiovascular events. These associations became weaker when adjusting for cardiovascular risk factors in Cox regression models, but remained significant for TRAILR-2 with incident diabetes, cardiovascular mortality, myocardial infarction and ischemic stroke, and for TNFR-1 with myocardial infarction. Conclusion: The present study demonstrates an association between several cardiovascular risk factors and elevated levels of circulating markers of apoptotic cell death. It also shows that subjects with high levels of these biomarkers have increased risk of diabetes and CVD. This implies that soluble death receptors aremarkers of β-cell and vascular injury and potentially could be used as surrogate markers of therapeutic efficiency in risk factor interventions.