Summary The aim of our study was to clarify the association between glycated haemoglobin (HbA 1c ) and postoperative outcomes in people without an existing diagnosis of diabetes. Half a million adults were recruited into the UK Biobank prospective cohort study between March 2006 and October 2010. We divided participants into three groups: no diagnosis of diabetes and HbA 1c < 42 mmol.mol −1 ; no diagnosis of diabetes and elevated HbA 1c (≥ 42 mmol.mol −1 with no upper limit); and prevalent diabetes (regardless of HbA 1c concentration) at recruitment. We followed up participants by linkage with routinely collected hospital data to determine any surgical procedures undertaken after recruitment and the associated postoperative outcomes. Our main outcome measure was a composite primary outcome of 30‐day major postoperative complications and 90‐day all‐cause mortality. We used logistic regression to estimate the odds of the primary outcome by group. We limited analyses to those who underwent surgery within one year of recruitment (n = 26,653). In a combined effects logistic regression model, participants not known to have diabetes with HbA 1c ≥ 42 mmol.mol −1 had increased odds of the primary outcome (OR [95% CI] 1.43 [1.02–2.02]; p = 0.04), when compared with those without diabetes and HbA 1c < 42 mmol.mol −1 . This effect was attenuated and no longer statistically significant in a direct effects model with adjustment for hyperglycaemia‐related comorbidity (OR [95% CI] 1.37 [0.97–1.93]; p = 0.07). Elevated pre‐operative HbA 1c in people without diabetes may be associated with an increased risk of complications, but the association is likely confounded by end‐organ comorbidity. In contrast to previous evidence, our findings suggest that to prevent adverse postoperative outcomes, optimisation of pre‐existing morbidity should take precedence over reducing HbA 1c in people without diabetes.

TRAF2 is a signal transducing adaptor molecule which binds to the CD40 cytoplasmic domain. We have found that it is phosphorylated, predominantly on serine residues, when transiently overexpressed in 293 cells. The phosphorylation appears to be related to the signaling events that are activated by TRAF2 under these circumstances, since two nonfunctional mutants were found to be phosphorylated significantly less than the wild-type protein. Furthermore, the phosphorylation status of TRAF2 had significant effects on the ability of the protein to bind to CD40, as evidenced by our observations that the CD40 cytoplasmic domain interacted preferentially with underphosphorylated TRAF2 and that phosphatase treatment significantly enhanced the binding of TRAF2 to CD40. We conclude from these studies that the phosphorylation of TRAF2 is likely to play an important role in regulating signaling by virtue of its ability to influence the CD40–TRAF2 interaction.

TNF receptor-associated factor 2 (TRAF2) is a signal-transducing protein associated with the CD40 cytoplasmic domain. It has been hypothesized that during signal transduction, TRAF2 must be released from CD40 in order for it to interact with downstream signaling molecules. We found that CD40 and TRAF2 were constitutively associated with each other in a human B cell line. Following stimulation with an anti-CD40 Ab, a decrease in the amount of CD40-associated TRAF2 was observed that could not be explained by a change in total level of either of the proteins. These results, as well as similar findings obtained with 293 cells overexpressing CD40 and TRAF2, suggested that CD40-mediated signals inhibited the CD40-TRAF2 interaction. We then conducted binding studies using CD40 cytoplasmic domain fusion proteins and TRAF2 derived from either control or CD40-stimulated cell lines. These in vitro studies also indicated that the binding of TRAF2 to the CD40 cytoplasmic domain was inhibited by CD40 stimulation. The results of these experiments, as well as differences between the in vitro and in vivo findings, indicated that multiple mechanisms were involved in the inhibition of the CD40-TRAF2 interaction by CD40 signals. Possible mechanisms of inhibition are discussed based on mapping of the TRAF2 binding site on the CD40 cytoplasmic domain.