The Role of Nitric Oxide, Lipocalin-2, and Proinflammatory Cytokines on Proteinuria and Insulin Resistance in Type 2 Diabetes Mellitus Subgroups.

BACKGROUND: Nitric oxide (NO) is a bioactive signaling molecule that mediates various physiological and biological processes. Type 2 diabetes mellitus (T2DM) can be categorized into several subgroups according to fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) levels. Few studies have closely examined the effect of NO and lipocalin-2 on albuminuria and insulin resistance in T2DM subgroups. This study investigated the role of NO, lipocalin-2, and proinflammatory cytokines on the development of proteinuria and insulin resistance in patients with T2DM subgroups. METHODS: A total of 256 subjects, including 191 patients with T2DM and 65 non-diabetic healthy individuals, were evaluated. NO metabolites (NOx), lipocalin-2, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels were measured. Patients with T2DM were classified into three subgroups: patients with FPG-defined diabetes (PG-DM), those with HbA1c-defined diabetes (HA-DM), and those who met the criteria for both FPG and HbA1c (PG/HA-DM). The albumin-to-creatinine ratio (ACR) and the homeostasis model assessment of β-cell function (HOMA-B) and insulin resistance (HOMA-IR) were calculated. RESULTS: NOx, lipocalin-2, and TNF-α levels were significantly higher in patients with T2DM than in healthy individuals. Patients with PG/HA-DM had significantly higher NOx levels than those with PG-DM or HA-DM. Of the patients with high NOx levels, patients with lipocalin-2 elevation exhibited higher ACR and HOMA-IR than those without lipocalin-2 elevation. NOx was positively correlated with lipocalin-2, ACR, HOMA-IR, and TNF-α but not with HOMA-B and IL-6. The upper quartile of NOx levels led to a 1.2-fold increase in the risk of albuminuria (odds ratio: 1.215; 95% CI: 1.012-2.418; p < 0.001). CONCLUSION: NO plays a crucial role in proteinuria and insulin resistance by collaborating with lipocalin-2 and TNF-α, showing significantly higher levels in patients with PG/HA-DM than in those with PG-DM or HA-DM.