Changes in Urinary NGAL, FN, and LN Excretion in Type 2 Diabetic Patients Following Anti-Diabetic Therapy with Metformin

Background: Excessive accumulation of glomerular extracellular matrix (ECM) is a key factor in the development and progression of diabetic nephropathy (DN). As kidney dysfunction has been reported in normoalbuminuric patients, identifying novel diagnostic and prognostic markers is essential for the prevention and treatment of DN. Methods: Urinary excretion of neutrophil gelatinase-associated lipocalin (NGAL) and ECM-related glycoproteins, i.e., fibronectin (FN) and laminin (LN), was measured in obese patients with newly diagnosed type 2 diabetes mellitus (T2DM) before and after 6 months of metformin therapy. Results: Baseline NGAL (1.27 (0.80-2.36) ng/mg Cr), FN (11.19 (5.31-21.56) ng/mg Cr) and LN (123.17 (54.56-419.28) pg/mg Cr) levels did not significantly differ between T2DM patients and controls (1.95 (1.09-2.97) ng/mg Cr, 11.94 (7.78-18.01) ng/mg Cr and 157.85 (83.75-326.40) pg/mg Cr, respectively). In multivariate regression analysis, the body mass index was identified as the only significant predictor influencing urinary NGAL and FN levels at baseline, with beta = 0.249, p = 0.005 and beta = 1.068, p = 0.010, respectively. Metformin treatment significantly increased urinary levels of both ECM proteins, i.e., FN (18.48 (11.64-32.46) ng/mg Cr) and LN (179.51 (106.22-414.68) pg/mg Cr), without any effect on NGAL levels (1.44 (0.81-2.72) ng/mg Cr). FN and LN were positively associated with NGAL both before (r = 0.709 and r = 0.646, both p < 0.001, respectively) and after (r = 0.594 and r = 0.479, both p < 0.001, respectively) therapy. No correlations were found between NGAL, FN, LN, and albuminuria. However, NGAL was positively correlated with the albumin/creatinine ratio (ACR) both before (r = 0.323, p < 0.05) and after (r = 0.287, p < 0.05) therapy, and negatively with estimated glomerular filtration rate (eGFR) in pre-treatment diabetics (r = -0.290, p < 0.05). FN and LN were also correlated with ACR (r = 0.384, p < 0.01 and r = 0.470, p < 0.001), although the association for LN was limited to untreated patients (r = 0.422, p < 0.01). Conclusions: Our results suggest that metformin has a beneficial effect on ECM turnover with a significant increase in urinary excretion of non-collagenous markers of glomerular injury, i.e., FN and LN. Additionally, ECM-related markers may serve as useful tools for monitoring early renal injury in obese diabetic patients.