Abstract

BackgroundTwo previous studies concluded that proenkephalin A (PENK-A) had predictive capabilities for stroke severity, recurrent myocardial infarction, heart failure and mortality in patients with stroke and myocardial infarction.ObjectivesThis study aimed to investigate the value of PENK-A as a biomarker for predicting mortality in patients with type 2 diabetes mellitus.MethodsPatients with type 2 diabetes mellitus were included from the prospective observational ZODIAC (Zwolle Outpatient Diabetes project Integrating Available Care) study. The present analysis incorporated two ZODIAC cohorts (1998 and 2001). Since blood was drawn for 1204 out of 1688 patients (71%), and information on relevant confounders was missing in 47 patients, the final sample comprised 1157 patients. Cox proportional hazard models were used for evaluating the relationship between PENK-A and (cardiovascular) mortality. Risk prediction capabilities were assessed with Harrell’s C statistics and the integrated discrimination improvement (IDI).ResultsAfter a follow-up period of 14 years, 525 (45%) out of 1157 patients had died, of which 224 (43%) were attributable to cardiovascular factors. Higher Log PENK-A levels were not independently associated with increased (cardiovascular) mortality. Patients with PENK-A values in the highest tertile had a 49% (95%CI 1%-121%) higher risk of cardiovascular mortality compared to patients in the reference category (lowest tertile). C-values were not different after removing PENK-A from the Cox models and there were no significant differences in IDI values.ConclusionsThe associations between PENK-A and mortality were strongly attenuated after accounting for all traditional risk factors. Furthermore, PENK-A did not seem to have additional value beyond conventional risk factors when predicting all-cause and cardiovascular mortality.

Highlights

  • Values in the highest tertile had a 49% (95%confidence interval (CI) 1%-121%) higher risk of cardiovascular mortality compared to patients in the reference category

  • C-values were not different after removing proenkephalin A (PENK-A) from the Cox models and there were no significant differences in integrated discrimination improvement (IDI) values

  • The associations between PENK-A and mortality were strongly attenuated after accounting for all traditional risk factors

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Summary

Introduction

The opioid peptide enkephalin is found in brain and endocrine tissues and has effects on neuroendocrine and nociceptive responses [1][2]. Enkephalin expression in the hypothalamus is stimulated in response to fat consumption and is thought to inhibit nociceptive responses in the spinal cord [3][4]. Enkephalins are expressed by pancreatic islets cells [5], and have an inhibitory effect on the insulin response through inhibiting glucose absorption [6]. Two previous studies showed that PENK-A levels had prognostic capabilities in patients with stroke and myocardial infarction [9][10]. Serum levels of PENK-A were related to stroke severity, recurrent myocardial infarction, heart failure and mortality [9][10]. Two previous studies concluded that proenkephalin A (PENK-A) had predictive capabilities for stroke severity, recurrent myocardial infarction, heart failure and mortality in patients with stroke and myocardial infarction

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