An alternative spliced variant of circulating soluble tumor necrosis factor-α receptor-2 is paradoxically associated with insulin action

Objective: Serum concentrations of soluble tumor necrosis factor-α (TNF-α) receptor 2 (sTNFR2) are associated with insulin resistance. In a recent study, we provided evidence for the existence of a biologically active form of sTNFR2 produced by alternative splicing (DS-TNFR2). We aimed to evaluate whether this circulating DS-TNFR2 is associated with insulin action in humans. Design and methods: Real time PCR (light cycler technology) evaluated DS-TNFR2 expression in monocytes. DS-TNFR2 was measured using a monoclonal antibody against an epitope present in TNFR2 (first 14 residues of the juxtamembrane region) but predicted to be absent in soluble proteolytic cleavage-produced TNFR2. Insulin sensitivity was measured using euglycemic hyperinsulinemic clamp (n = 76) and homeostatic model of assessment (HOMA) value in a replication study of 223 subjects. Results: Real time PCR confirmed gene expression of DS-TNFR2 in monocytes from healthy subjects. A significant and positive association was found between serum DS-TNFR2 concentration and insulin sensitivity (P = 0.032, n = 76). This association was most significant in subjects with normal glucose tolerance (r = 0.44, P = 0.002). The subjects in whom DS-TNFR2 was detectable were more insulin sensitive than those with undetectable DS-TNFR2 (42.12±22.08 vs 31.71± 16.95 μmol × kg−1 × min−1, P = 0.039). DS-TNFR2 was inversely associated with body mass index, waist-to-hip ratio, systolic and diastolic blood pressure, fasting serum glucose, serum triglycerides and serum uric acid concentration and with the HOMA value (P = 0.03) in the replication study. Circulating DS-TNFR2 declined with increased number of components of the metabolic syndrome. Conclusion: Native sTNFR2 and DS-TNFR2 show opposite associations with insulin action. DS-TNFR2 might play a role as a counterpart of the proinflammatory environment associated with insulin resistance.