可溶性神经纤毛蛋白-1 对 2 型糖尿病低血糖的反应：在 SARS-CoV-2 感染中是增加风险还是保护？
Soluble Neuropilin-1 Response to Hypoglycemia in Type 2 Diabetes: Increased Risk or Protection in SARS-CoV-2 Infection?
机构信息
Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.
Academic Endocrinology, Diabetes and Metabolism, Hull York Medical School, Hull, United Kingdom.
出版信息
Front Endocrinol (Lausanne). 2021 Jun 23;12:665134. doi: 10.3389/fendo.2021.665134. eCollection 2021.
INTRODUCTION
Neuropilin-1(NRP1) is a cofactor that enhances SARS-CoV-2 coronavirus cell infectivity when co-expressed with angiotensin-converting enzyme 2(ACE2). The Renin-Angiotensin System (RAS) is activated in type 2 diabetes (T2D); therefore, the aim of this study was to determine if hypoglycaemia-induced stress in T2D would potentiate serum NRP1(sNRP1) levels, reflecting an increased risk for SARS-CoV-2 infection.
METHODS
A case-control study of aged-matched T2D (n = 23) and control (n = 23) subjects who underwent a hyperinsulinemic clamp over 1-hour to hypoglycemia(<40mg/dl) with subsequent timecourse of 4-hours and 24-hours. Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement determined RAS-related proteins: renin (REN), angiotensinogen (AGT), ACE2, soluble NRP1(sNRP1), NRP1 ligands (Vascular endothelial growth factor, VEGF and Class 3 Semaphorins, SEM3A) and NRP1 proteolytic enzyme (A Disintegrin and Metalloproteinase 9, ADAM9).
RESULTS
Baseline RAS overactivity was present with REN elevated and AGT decreased in T2D (p<0.05); ACE2 was unchanged. Baseline sNRP1, VEGF and ADAM9 did not differ between T2D and controls and remained unchanged in response to hypoglycaemia. However, 4-hours post-hypoglycemia, sNRP1, VEGF and ADAM9 were elevated in T2D(p<0.05). SEMA3A was not different at baseline; at hypoglycemia, SEMA3A decreased in controls only. Post-hypoglycemia, SEMA3A levels were higher in T2D versus controls. sNRP1 did not correlate with ACE2, REN or AGT. T2D subjects stratified according to ACE inhibitor (ACEi) therapies showed no difference in sNRP1 levels at either glucose normalization or hypoglycaemia.
CONCLUSION
Hypoglycemia potentiated both plasma sNRP1 level elevation and its ligands VEGF and SEMA3A, likely through an ADAM9-mediated mechanism that was not associated with RAS overactivity or ACEi therapy; however, whether this is protective or promotes increased risk for SARS-CoV-2 infection in T2D is unclear.
CLINICAL TRIAL REGISTRATION
https://clinicaltrials.gov, identifier NCT03102801.
简介
神经纤毛蛋白-1（NRP1）是一种辅助因子，当与血管紧张素转换酶 2（ACE2）共表达时，可增强 SARS-CoV-2 冠状病毒的细胞感染力。肾素-血管紧张素系统（RAS）在 2 型糖尿病（T2D）中被激活；因此，本研究的目的是确定 T2D 中的低血糖诱导应激是否会增强血清 NRP1（sNRP1）水平，反映出 SARS-CoV-2 感染的风险增加。
方法
对年龄匹配的 T2D（n=23）和对照组（n=23）受试者进行了一项病例对照研究，他们在 1 小时内接受了胰岛素强化治疗以达到低血糖（<40mg/dl），随后进行了 4 小时和 24 小时的时间过程。使用缓慢释放率修饰适体（SOMA）扫描血浆蛋白测量法测定了 RAS 相关蛋白：肾素（REN）、血管紧张素原（AGT）、ACE2、可溶性 NRP1（sNRP1）、NRP1 配体（血管内皮生长因子，VEGF 和 3 类信号素，SEM3A）和 NRP1 蛋白水解酶（解整合素和金属蛋白酶 9，ADAM9）。
结果
T2D 患者存在基线 RAS 过度活跃，表现为 REN 升高和 AGT 降低（p<0.05）；ACE2 没有变化。T2D 和对照组之间的基线 sNRP1、VEGF 和 ADAM9 没有差异，并且对低血糖反应没有变化。然而，低血糖后 4 小时，T2D 患者的 sNRP1、VEGF 和 ADAM9 升高（p<0.05）。基线时 SEMA3A 没有差异；在低血糖时，仅对照组的 SEMA3A 下降。低血糖后，T2D 患者的 SEMA3A 水平高于对照组。sNRP1 与 ACE2、REN 或 AGT 不相关。根据 ACE 抑制剂（ACEi）治疗对 T2D 患者进行分层，在血糖正常化或低血糖时，sNRP1 水平没有差异。
结论
低血糖增强了血浆 sNRP1 水平的升高及其配体 VEGF 和 SEMA3A，可能通过 ADAM9 介导的机制，与 RAS 过度活跃或 ACEi 治疗无关；然而，这是否具有保护作用或是否会增加 T2D 患者 SARS-CoV-2 感染的风险尚不清楚。
临床试验注册
https://clinicaltrials.gov，标识符 NCT03102801。
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