Wang Ningning, Li Junhui, Tian Erjun, Li Shutong, Liu Shuai, Cao Fei, Kong Junfeng, Yue Baohong
Department of Laboratory Medicine, The First People's Hospital of Pingdingshan, Pingdingshan, Henan, China.
Department of Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
PLoS One. 2025 Mar 19;20(3):e0316049. doi: 10.1371/journal.pone.0316049. eCollection 2025.
The presence of hypertension and various acute or chronic complications may affect the renin-angiotensin-aldosterone system (RAAS) in patients with type 2 diabetes mellitus (T2DM), which plays a crucial role in the regulation of glucose metabolism. However, the quantitative distribution of the RAAS components in relation to the progression of T2DM and the treatment of hyperglycemia and hypertension, as well as their association with different stages of complications and glucose metabolism, has not been well studied.
We enrolled a total of 151 patients with T2DM and essential hypertension, 40 patients with T2DM and normotension, and 46 healthy controls in the study. They were categorized into subgroups based on criteria for diabetic complications. Statistical analyses, including Spearman rank correlation and multiple linear regression, were conducted to assess the relationship between RAAS components and glucose metabolism indexes such as HbA1c, FBG, CP, HOMA-β, HOMA-IR, and UACR.
The results revealed significant differences in AII, ALD, REN, and ARR levels across various complication subgroups. Notably, the concentrations of ALD and REN exhibited a consistent trend, while ARR showed an opposite trend to the REN concentration. More than 60% of hypertensive patients were treated with ACEI/ARBs and calcium channel blockers, while 29.8% of the patients were prescribed β-blockers, resulting in decreased REN and increased ARR levels. All T2DM patients received antidiabetic treatment, among which 95 (49.7%) took SGLT-2is, 40 (20.9%) took GLP-1RAs injection and 55(28.8%) took DPP-4is. The subsequent analysis revealed that SGLT-2is, GLP-1RAs, DPP-4is and other glucose-lowering agents had no statistically significant effect on the RAAS system (p > 0.05). The correlation matrix analysis indicated positive associations between ALD, REN, CP, and HOMA-IR. Furthermore, the REN levels were negatively correlated with UACR in the hypertensive group and positively correlated with HbA1c and FBG levels in the normotensive group. Multiple linear regression analysis demonstrated that ALD levels increased with higher levels of CP and HOMA-IR, independently of the RAAS system, anti-RAAS treatment and antidiabetic therapy. REN levels decreased with increasing UACR and β-blocker usage in the hypertensive group, while they increased with higher levels of HbA1c, FBG, and HOMA-IR in the normotensive group, independently of the RAAS system and antidiabetic therapy.
The activation status of the RAAS system varied among T2DM patients with different complications, highlighting the need for clinical differentiation. ALD was positively associated with insulin resistance and glucose metabolism impairment, while REN exhibited negative correlations with urinary microalbumin and β-blocker usage, and positive correlations with hyperglycemia and insulin resistance. Blocking the RAAS system holds promise for improving insulin sensitivity and β-cell function, and potentially reversing abnormal glucose tolerance or ameliorating glucose metabolism disorders.
高血压以及各种急慢性并发症的存在可能会影响2型糖尿病（T2DM）患者的肾素-血管紧张素-醛固酮系统（RAAS），该系统在葡萄糖代谢调节中起关键作用。然而，RAAS各组分相对于T2DM进展、高血糖和高血压治疗的定量分布，以及它们与并发症不同阶段和葡萄糖代谢的关联，尚未得到充分研究。
我们共纳入了151例T2DM合并原发性高血压患者、40例T2DM合并血压正常患者以及46例健康对照者进行研究。根据糖尿病并发症标准将他们分为亚组。进行了包括Spearman等级相关分析和多元线性回归分析在内的统计分析，以评估RAAS各组分与糖化血红蛋白（HbA1c）、空腹血糖（FBG）、C肽（CP）、胰岛素抵抗指数（HOMA-IR）、胰岛素分泌指数（HOMA-β）和尿白蛋白肌酐比值（UACR）等葡萄糖代谢指标之间的关系。
结果显示，各并发症亚组之间的血管紧张素II（AII）、醛固酮（ALD）、肾素（REN）和醛固酮肾素比值（ARR）水平存在显著差异。值得注意的是，ALD和REN的浓度呈现一致趋势，而ARR与REN浓度呈现相反趋势。超过60%的高血压患者接受了血管紧张素转换酶抑制剂/血管紧张素受体阻滞剂（ACEI/ARBs）和钙通道阻滞剂治疗，而29.8%的患者使用了β受体阻滞剂，导致REN水平降低，ARR水平升高。所有T2DM患者均接受了抗糖尿病治疗，其中95例（49.7%）服用钠-葡萄糖协同转运蛋白2抑制剂（SGLT-2is），40例（20.9%）接受胰高血糖素样肽-1受体激动剂（GLP-1RAs）注射治疗，55例（28.8%）服用二肽基肽酶-4抑制剂（DPP-4is）。随后的分析表明，SGLT-2is、GLP-1RAs、DPP-4is和其他降糖药物对RAAS系统无统计学显著影响（p>0.05）。相关矩阵分析表明，ALD、REN、CP和HOMA-IR之间呈正相关。此外，高血压组中REN水平与UACR呈负相关，血压正常组中REN水平与HbA1c和FBG水平呈正相关。多元线性回归分析表明，独立于RAAS系统、抗RAAS治疗和抗糖尿病治疗，ALD水平随CP和HOMA-IR水平升高而升高。高血压组中REN水平随UACR升高和β受体阻滞剂使用而降低，而血压正常组中REN水平随HbA1c、FBG和HOMA-IR水平升高而升高，独立于RAAS系统和抗糖尿病治疗。
RAAS系统的激活状态在不同并发症的T2DM患者中有所不同，凸显了临床鉴别诊断的必要性。ALD与胰岛素抵抗和葡萄糖代谢受损呈正相关，而REN与尿微量白蛋白和β受体阻滞剂使用呈负相关，与高血糖和胰岛素抵抗呈正相关。阻断RAAS系统有望改善胰岛素敏感性和β细胞功能，并可能逆转异常糖耐量或改善葡萄糖代谢紊乱。
