Impact of Hyperlipidemia on Endothelial Dysfunction and Arginine Metabolism in Diabetic Patients: Implications for Nitric Oxide Dysregulation and Increased Cardiovascular Risk

BACKGROUND. Type 2 Diabetes Mellitus (T2DM) is a primary public health concern globally, characterized by chronic hyperglycemia, insulin resistance, impaired beta-cell function. Endothelial dysfunction is a hallmark of diabetes and is exacerbated by hyperlipidemia.

AIM. This study investigates the impact of hyperlipidemia on nitric oxide synthesis, arginine metabolism, and vascular health markers in T2DM.

MATERIALS AND METHODS. A total of 120 participants were included in this cross-sectional, comparative study. Serum methylarginine derivatives (Asymmetric dimethyl arginine (ADMA), Symmetric dimethyl arginine (SDMA), L-N Mono-methylarginine (L-NMMA) and related metabolites (arginine, homoarginine, citrulline, ornithine) levels were measured in three groups: diabetes with hyperlipidemia (DM-HL), diabetes with normolipidemia (DM-NL), and healthy controls (HC) using API SCIEX 3200 LC-MS/MS methods. Statistical comparisons between groups were performed using IBM SPSS 26.0 to assess the influence of hyperlipidemia on these markers.

RESULTS. ADMA and SDMA levels were significantly elevated in DM-HL group compared to DM-NL and HC (p=0.001, p=0.000 respectively), indicating increased endothelial dysfunction and potential dyslipidemia-induced renal or vascular impairment. Reduced arginine and homoarginine levels in diabetic groups suggest impaired nitric oxide synthesis and altered urea cycle function (p=0.013, p=0.000 respectively). Notably, the DM-HL group exhibited significantly higher L-NMMA levels (p=0.001). It disrupted metabolic ratios (e.g., SDMA/ADMA, arginine/ADMA, and homoarginine/ADMA), reflecting enhanced nitric oxide inhibition and reduced bioavailability. Hyperlipidemia significantly exacerbated these disruptions, as evidenced by altered citrulline/arginine and citrulline/ADMA ratios, underscoring its additive impact on endothelial dysfunction.

CONCLUSIONS. Hyperlipidemia amplifies the adverse effects of diabetes on endothelial function by exacerbating nitric oxide inhibition, oxidative stress, and arginine metabolism dysregulation. Key biomarkers and metabolic ratios, particularly ADMA and SDMA-related indices, provide valuable insights into cardiovascular risk in this population. Therapeutic strategies targeting lipid management, arginine supplementation, and ADMA reduction could improve vascular health and mitigate cardiovascular complications in DM-HL.

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