Neutrophil gelatinase associated lipocalin (NGAL) is elevated in type 2 diabetics with carotid artery stenosis and reduced under metformin treatment

Abstract

BackgroundNeutrophil gelatinase-associated lipocalin (NGAL), an acute phase protein released by neutrophils, has been described as biomarker of inflammatory states. Type 2 diabetes mellitus (T2DM) is characterized by increased inflammation and an elevated risk for embolization of carotid artery stenosis (CAS). We aimed to explore the role of NGAL systemically and in plaques of diabetics undergoing carotid endarterectomy. Moreover, the potential anti-inflammatory effect of metformin on NGAL was addressed in diabetics.MethodsSerum NGAL and matrix metalloproteinase (MMP)-9/NGAL levels were measured in 136 patients (67 with T2DM vs. 69 non-diabetics) by specific ELISA. Endarterectomy samples were graded histologically according to the American Heart Association´s classification. NGAL mRNA expression was detected using RealTime-PCR in carotid endarterectomy specimens.ResultsSerum NGAL [median 107.4 ng/ml (quartiles: 75.2–145.0) vs. 64.4 (50.4 –81.3), p < 0.0001] and MMP-9/NGAL [41.5 ng/ml (20.8–63.9) vs. 27.6 (16.0–42.4), p = 0.017] were significantly elevated in diabetics compared to non-diabetics, as were leukocytes, neutrophils, C-reactive protein and fibrinogen (all p < 0.05). In patients with symptomatic and asymptomatic CAS diabetics had higher NGAL levels compared to non-diabetics [128.8 ng/ml (100.8–195.6) vs. 64.8 (48.9–82.2] and [101.6 ng/ml (70.1–125.3) vs. 63.8 (51.0–81.3), respectively, both p < 0.0001]. Presence of T2DM and type VI plaques (with surface defect, hemorrhage or thrombus) had a profound impact on NGAL levels (both p < 0.01) in multiple linear regression analysis. NGAL mRNA was detectable in 95% of analyzed carotid artery lesions of diabetics compared to 5% of non-diabetics (p < 0.0001). Accordingly, cerebral embolization was more frequent in diabetics (52.2% vs. 29%, p = 0.006). Metformin treatment was associated with decreased NGAL [60.7 ng/ml (51.9–69.2) vs. 121.7 (103.7–169.9), p < 0.0001] and MMP-9/NGAL [20.8 ng/ml (12.1–26.5) vs. 53.7 (27.4–73.4), p = 0.007] in diabetics and reduced leukocyte infiltration in carotid lesions of diabetics.ConclusionsHigher NGAL levels in serum and plaques are associated with T2DM in patients with CAS. Metformin significantly reduced the inflammatory burden including NGAL in diabetics. Early treatment of these patients may be recommended, as elevated NGAL levels were linked with vulnerable plaques prone for embolization.

Correlations between serum concentration of three bone-derived factors and obesity and visceral fat accumulation in a cohort of middle aged men and women

“…Similarly, Wang et al observed significantly higher circulating NGAL levels in obese people than non-obese people in a Hong Kong population. Moreover, elevated NGAL levels in serum and plaques were associated with type 2 diabetes mellitus in patients with carotid artery stenosis [ 23 ]. Based on these findings, circulating NGAL levels were associated with metabolic diseases, including obesity [ 24 – 26 ].…”

Metformin and Autoimmunity: A “New Deal” of an Old Drug

“…Also, metformin has been shown to reduce neutrophil count in young women with PCOS ( 108 ) and in girls born small for gestational age with exaggerated adrenarche and precocious pubarche ( 108 ), two conditions characterized by a pronounced systemic inflammatory state. Finally, in diabetic patients undergoing endarterectomy for carotid artery stenosis, Eilenberg et al ( 109 ) demonstrated that metformin treatment was associated with reduced expression of neutrophil gelatinase-associated lipocalin—a protein released by activated neutrophils and associated with atherosclerotic plaques vulnerability—thus contributing to lower cerebral embolization events.…”

Circulating Lipocalin-2 Levels Are Associated With Soluble Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Levels In Type 2 Diabetic Patients

“…Supporting this finding, Hemdahl AL et al [28] showed that LCN-2 expression was increased in atherosclerotic plaques. Eilenberg W et al [27] also showed that diabetics under metformin treatment had significantly lower LCN-2 levels compared to non-diabetics. We only found that LCN-2 levels were lower in diabetic patients with better glycemic control compared to those with worse glycemic control based on hba1c (hba1c ≤7% vs. >7%) (p = 0.045).…”