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.
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.


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


METHODS
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.
Department of Cardiology and Circulatory Diseases, Internal Medicine Clinic III, Eberhard Karls University Tübingen, Tübingen, Germany.|La Jolla Institute for Allergy and Immunology, La Jolla, California.
Karin A L
KA
Müller
Department of Cardiology and Circulatory Diseases, Internal Medicine Clinic III, Eberhard Karls University Tübingen, Tübingen, Germany.
Dominik
D
Rath
Department of Cardiology and Circulatory Diseases, Internal Medicine Clinic III, Eberhard Karls University Tübingen, Tübingen, Germany.
Martina
M
Schmid
Department of Cardiology and Circulatory Diseases, Internal Medicine Clinic III, Eberhard Karls University Tübingen, Tübingen, Germany.
Heiko
H
Schoenleber
Department of Cardiology and Circulatory Diseases, Internal Medicine Clinic III, Eberhard Karls University Tübingen, Tübingen, Germany.
Meinrad
M
Gawaz
Department of Cardiology and Circulatory Diseases, Internal Medicine Clinic III, Eberhard Karls University Tübingen, Tübingen, Germany.
Tobias
T
Geisler
Department of Cardiology and Circulatory Diseases, Internal Medicine Clinic III, Eberhard Karls University Tübingen, Tübingen, Germany.
Iris I
II
Müller
D054058:Acute Coronary Syndrome / Q000175:diagnosis / Q000209:etiology*; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000150:complications / Q000175:diagnosis; D005260:Female; D005858:Germany; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood*; D019746:Intramolecular Oxidoreductases / Q000097:blood*; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011237:Predictive Value of Tests; D011379:Prognosis; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D015854:Up-Regulation
D015415:Biomarkers; C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human