An alternative spliced variant of circulating soluble tumor necrosis factor-alpha receptor-2 is paradoxically associated with insulin action.
OBJECTIVE
Serum concentrations of soluble tumor necrosis factor-alpha (TNF-alpha) 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.


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 micromol x kg(-1) x 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.


CONCLUSIONS
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.
Fernández-Real
José Manuel
JM
Section of Diabetes, Endocrinology and Nutrition, University Hospital of Girona Dr. Josep Trueta, Ctra. França s/n, 17007 Girona, Spain. uden.jmfernandezreal@htrueta.scs.es
Straczkowski
Marek
M
Lainez
Begoña
B
Chacón
Matilde R
MR
Kowalska
Irina
I
López-Bermejo
Abel
A
García-España
Antonio
A
Nikolajuk
Agnieszka
A
Kinalska
Ida
I
Ricart
Wifredo
W
D000328:Adult; D017398:Alternative Splicing; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D018149:Glucose Intolerance / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009000:Monocytes / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood* / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012995:Solubility
D007328:Insulin; D012333:RNA, Messenger; D047889:Receptors, Tumor Necrosis Factor, Type II