High Plasma Levels of Gremlin-1 and Macrophage Migration Inhibitory Factor, but Not Their Ratio, Indicate an Increased Risk for Acute Coronary Syndrome in Patients With Type 2 Diabetes Mellitus

Clin Cardiol. 2016 Apr;39(4):201-6. doi: 10.1002/clc.22509.


Background: Chronic inflammation promotes atherosclerosis and is a prognostic factor in coronary artery disease (CAD). Patients with type 2 diabetes mellitus (DM2) are at risk for progressive atherosclerosis. Macrophage migration inhibitory factor (MIF) is a key player in atherosclerosis, mediating pro-inflammatory responses. Its endogenous antagonist Gremlin-1 inhibits foam-cell formation and atheroprogression by binding MIF, neutralizing its proatherosclerotic functions.

Hypothesis: Plasma levels of MIF and Gremlin-1 correlate with the stability of CAD in patients with DM2.

Method: We assessed plasma levels of Gremlin-1 and MIF in 198 nondiabetic and 88 diabetic patients with symptomatic CAD using enzyme-linked immunosorbent assays.

Results: Plasma levels of Gremlin-1 were higher DM2 patients (278.8 ± 16.6 vs 224.7 ± 6.7 ng/mL; P = 0.001). MIF levels were elevated but not significantly increased in DM2 (P = 0.098). Interestingly, we found that Gremlin-1 plasma levels were significantly higher in diabetic patients with stable angina pectoris (SAP; n = 53) or acute coronary syndrome (ACS; n = 35) compared with nondiabetic patients with SAP (P = 0.008 and P = 0.011, respectively). MIF levels were significantly higher in diabetic patients with ACS compared with SAP (P < 0.001). Although the single plasma parameters showed an association with DM2 and CAD status, we could not confirm that the Gremlin-1/MIF ratio is significantly different in patients stratified by DM2 and CAD (P = 0.072). Hence, Gremlin-1/MIF ratio was significantly lower in patients with ACS compared with SAP (1.1 ± 0.1 vs 4.4 ± 1.1; P = 0.003).

Conclusions: Diabetic patients with ACS show increased levels of Gremlin-1 and MIF, leading to unfavorable Gremlin-1/MIF ratios. However, DM2 alone is not associated with low Gremlin-1/MIF ratios.

Publication types

  • Observational Study

MeSH terms

  • Acute Coronary Syndrome / diagnosis
  • Acute Coronary Syndrome / etiology*
  • Aged
  • Aged, 80 and over
  • Biomarkers / blood
  • Case-Control Studies
  • Cross-Sectional Studies
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / diagnosis
  • Female
  • Germany
  • Humans
  • Intercellular Signaling Peptides and Proteins / blood*
  • Intramolecular Oxidoreductases / blood*
  • Macrophage Migration-Inhibitory Factors / blood*
  • Male
  • Middle Aged
  • Pilot Projects
  • Predictive Value of Tests
  • Prognosis
  • Registries
  • Risk Assessment
  • Risk Factors
  • Up-Regulation


  • Biomarkers
  • GREM1 protein, human
  • Intercellular Signaling Peptides and Proteins
  • Macrophage Migration-Inhibitory Factors
  • Intramolecular Oxidoreductases
  • MIF protein, human