Lee Tien F, Tommasi Sara, Bersten Andrew, Heilbronn Leonie K, Sotgia Salvatore, Zinellu Angelo, Carru Ciriaco, Mangoni Arduino A, Burt Morton G
College of Medicine and Public Health, Flinders University, Flinders Drive, Bedford Park, SA, 5042, Australia.
Southern Adelaide Diabetes and Endocrine Services, Flinders Medical Centre, Flinders Drive, Bedford Park, SA, 5042, Australia.
Diabetol Metab Syndr. 2023 Apr 1;15(1):68. doi: 10.1186/s13098-023-01035-8.
Changes in the arginine metabolites asymmetric dimethyl-L-arginine (ADMA) and L-homoarginine and acute blood glucose concentrations have been shown to cause endothelial dysfunction and be independently associated with mortality in Intensive Care Unit (ICU) patients. The aim of this study was to investigate whether hyperglycemia potentially modulates these arginine metabolite concentrations to provide a mechanism that may link hyperglycemia and mortality in this patient group.
A clinical and in vitro study were undertaken. Glucose, glycosylated hemoglobin-A1c (HbA1c) and the stress hyperglycemia ratio (SHR) (to quantify absolute, chronic and relative hyperglycemia respectively) were measured in 1155 acutely unwell adult patients admitted to a mixed medical-surgical ICU. SHR was calculated by dividing the admission glucose by the estimated average glucose over the last 3 months, which was derived from HbA1c. ADMA and L-homoarginine were measured in a plasma sample collected at admission to ICU by liquid chromatography tandem mass spectrometry. The activity of dimethylarginine-dimethylaminohydrolase 1 (DDAH1), the main enzyme regulating ADMA concentrations, was assessed at varying glucose concentrations in vitro by quantifying the conversion of ADMA to citrulline in HEK293 cells that overexpress DDAH1.
In the clinical study, plasma ADMA was not significantly associated with any measure of hyperglycemia. L-homoarginine was positively associated with glucose (β = 0.067, p = 0.018) and SHR (β = 0.107, p < 0.001) after correction for glomerular filtration rate. However, as L-homoarginine is a negative predictor of mortality, the direction of these associations are the opposite of those expected if hyperglycemia was affecting mortality via changes in L-homoarginine. In vitro DDAH1 activity was not significantly influenced by glucose concentrations (p = 0.506).
In critically ill patients the association between relative hyperglycemia and mortality is not mediated by changes in ADMA or L-homoarginine. Trial registration ANZCTR Trial ID ACTRN12615001164583.
精氨酸代谢产物不对称二甲基-L-精氨酸（ADMA）和L-高精氨酸的变化以及急性血糖浓度已被证明可导致内皮功能障碍，并与重症监护病房（ICU）患者的死亡率独立相关。本研究的目的是调查高血糖是否可能调节这些精氨酸代谢产物的浓度，以提供一种可能将高血糖与该患者群体死亡率联系起来的机制。
进行了一项临床和体外研究。对入住综合内科-外科ICU的1155例急性不适的成年患者测量了血糖、糖化血红蛋白A1c（HbA1c）和应激高血糖比率（SHR）（分别用于量化绝对、慢性和相对高血糖）。SHR通过将入院时的血糖除以根据HbA1c得出的过去3个月的估计平均血糖来计算。通过液相色谱串联质谱法在ICU入院时采集的血浆样本中测量ADMA和L-高精氨酸。通过在体外不同葡萄糖浓度下定量过表达二甲基精氨酸二甲胺水解酶1（DDAH1）的HEK293细胞中ADMA向瓜氨酸的转化，评估调节ADMA浓度的主要酶DDAH1的活性。
在临床研究中，血浆ADMA与任何高血糖指标均无显著相关性。在校正肾小球滤过率后，L-高精氨酸与血糖呈正相关（β = 0.067，p = 0.018），与SHR呈正相关（β = 0.107，p < 0.001）。然而，由于L-高精氨酸是死亡率的负预测因子，这些关联方向与高血糖通过L-高精氨酸变化影响死亡率时预期的方向相反。体外DDAH1活性不受葡萄糖浓度的显著影响（p = 0.506）。
在危重症患者中，相对高血糖与死亡率之间的关联并非由ADMA或L-高精氨酸的变化介导。试验注册澳大利亚和新西兰临床试验注册中心试验编号ACTRN12615001164583。
