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冠状病毒感染中的内分泌与代谢变化

  Type 2 diabetes mellitus(T2DM)seems to be a risk factor for acquiring the new coronavirus infection.Indeed,T2DM and hypertension have been identified as the most common comorbidities for other coronavirus infections,such as severe acute respiratory syndrome(SARS)and Middle East respiratory syndrome(MERS-CoV)1.According to several reports,including those from the Centers for Disease Control and Prevention(CDC),patients with T2DM and the metabolic syndrome might have up to ten-times greater risk of death when they contract COVID-19(CDC coronavirus reports).Although T2DM and the metabolic syndrome increase the risk of more severe symptoms and mortality in many infectious diseases,there are some additional specific mechanistic aspects in coronavirus infections that require separate consideration,which will have clinical consequences for improved management of patients who are severely affected.

  2型糖尿病(T2DM)似乎是获得新冠状病毒感染的危险因素,事实上,T2DM和高血压已被确定为其他冠状病毒感染最常见的合并症,如严重急性呼吸综合征(SARS)和中东呼吸综合征(MERS-CoV)1来自疾病控制和预防中心(CDC)的患者、2型糖尿病患者和代谢综合征患者在感染COVID-19时死亡的风险可能高出10倍(CDC冠状病毒报告),尽管在许多传染病中,2型糖尿病和代谢综合征增加了更严重症状的风险和死亡率,冠状病毒感染还有一些特殊的机制方面需要单独考虑,这将对改善严重感染患者的治疗产生临床后果。

  Hyperglycaemia and a diagnosis of T2DM are independent predictors of mortality and morbidity in patients with SARS1.This finding could be due to these patients having a state of metabolic inflammation that predisposes them to an enhanced release of cytokines.For COVID-19,a cytokine storm(that is,greatly elevated levels of inflammatory cytokines)has been implicated in the multi-organ failure in patients with severe disease.

  高血糖症和T2DM是SARS患者死亡率和发病率的独立危险因素1。这可能是是由于患者处于代谢炎症期,从而加强了细胞因子释放。对于COVID-19,重症患者多器官功能衰竭与细胞细胞因子风暴(即炎性细胞因子大量释放)密切相关3。

  Metabolic inflammation will also compromise the immune system,reducing the body's ability to tackle the infection,impairing the healing process and prolonging the recovery.An animal model demonstrated that comorbid T2DM results in immune dysregulation and enhances disease severity following MERS-CoV infection2.In this work,diabetic mice expressing the human DPP4(resulting in MERS-CoV susceptibility)exhibited an altered profile of cytokines,with increased expression of IL-17αfollowing infection.These data support the hypothesis that the combination of coronavirus infection and T2DM triggers a dysregulated immune response,resulting in a more aggravated and prolonged lung pathology2.

  炎症反应会损伤免疫系统,诱发机体抗感染反应,损伤修复过程以及延长恢复期。动物模型显示合并T2DM会导致免疫紊乱并加重MERS-CoV感染后的严重程度2。表达人DPP4(导致MERS-CoV易感性)的糖尿病小鼠模型显示细胞因子水平发生改变,并且感染后IL-17α表达增加。这些数据证实了以下假设:同时患有冠状病毒感染和T2DM会引发免疫调节异常,导致肺部病变加重和延长2。

  A direct endocrine link

  内分泌因素

  The coronavirus SARS-CoV-2(which causes COVID-19)enters human cells via the envelope spike glycoprotein,which is also responsible for host-to-host transmission4.This glycoprotein,which is found on the surface of the virus,binds to the ectoenzyme angiotensin-converting enzyme 2(ACE2;located on human cells)to gain entry into the cell.In addition,the cellular serine protease TMPRSS2 is required to prime viral entry via ACE24.

  冠状病毒SARS-CoV-2(COVID-19病原体)通过包膜上的钉状糖蛋白进入人体细胞,导致宿主之间的传播4。这种位于病毒表面的糖蛋白,与胞外血管紧张素酶2(ACE2;人细胞体内)相结合来进入细胞内。此外,病毒通过ACE2进入过程需要细胞丝氨酸蛋白酶TMPRSS24。

  In the respiratory system,ACE2 has the function of degrading angiotensin II into angiotensin 1–7 and acts as a key regulatory point for the angiotensin system.When ACE1 activity is increased and ACE2 inhibited,intact angiotensin II acts via the angiotensin 1 receptor(AT1R)or AT2R to exert pro-inflammatory responses and stimulate aldosterone secretion;these effects not only increase blood pressure and potentially cause hypokalaemia,but will also increase vascular permeability locally,increasing the risk of respiratory distress syndrome.By contrast,angiotensin 1–7 acts on the Mas receptor pathway,which leads to anti-inflammatory and anti-fibrotic responses that would be favourable to the recovery of patients with COVID-195.It could be postulated that individuals with more severe COVID-19 have an imbalance in the activation of these pathways,with an increase in the activation of AT1R and AT2R,which could be the case in T2DM,hypertension and insulin-resistant states.
纽约时报中英文网 www.qqenglish.com


  在呼吸系统中,ACE2将血管紧张素II降解为血管紧张素1-7,并作为血管紧张素系统中的关键调节因子。当ACE1活性增加,ACE2下降时,完整的血管紧张素II通过血管紧张素1受体(AT1R)或AT2R启动促炎症应答,促进醛固酮分泌;其后果是不仅增加血压,并可导致低钾血症,还会提高局部血管通透性,增加患呼吸窘迫综合征的风险。相比之下,血管紧张素1-7作用于Mas受体通路,产生抗炎症作用和抗纤维化作用,有利于COVID-19患者的康复5。由此可以推论出在重症COVID-19患者中,这些通路的激活过程处于失衡状态,AT1R和AT2R激活水平增高,这可能也是产生T2DM,高血压和胰岛素抵抗的原因。

  A direct metabolic link

  代谢因素

  In addition to a link between coronavirus infection and hypertension,there seems to be a direct link to T2DM.In the pancreas,binding of the SARS coronavirus(SARS-CoV,which causes SARS)to its receptor,ACE2,damages islets and reduces insulin release6.In one study,patients with SARS who had no history of T2DM and received no steroid treatment were compared with their healthy siblings during a 3-year follow-up period.More than 50%of the patients in the study became diabetic during hospitalization for the SARS-CoV infection.After 3 years of recovery from the viral infection,only 5%of patients remained diabetic6.As the human endocrine pancreas expresses ACE2,the coronavirus might enter islets and cause acuteβ-cell dysfunction,leading to acute hyperglycaemia and transient T2DM6.More importantly,evidence in diabetic mice demonstrated that ACE2 activity levels were enhanced in the pancreas7.This finding suggests that patients with T2DM might be particularly vulnerable to a coronavirus infection.Likewise,T2DM induces expression of angiotensin-converting enzymes in other tissues,including lung,liver and heart7,which explains why T2DM can contribute mechanistically to multi-organ failure in SARS-CoV infections.

  冠状病毒感染除了与高血压密切相关,也似乎与T2DM有直接的关联。在胰腺中,SARS冠状病毒(SARS-CoV;SARS病原体)与ACE2受体结合,损伤胰岛并减少了胰岛素释放6。在一项研究中,将无T2DM病史,未接受类固醇激素治疗的SARS患者与其健康亲属进行了为期3年的随访。超过50%的病人在SARS-CoV感染住院治疗期间患上了糖尿病。但感染痊愈后的3年,仅仅5%的患者仍有糖尿病6。由于人体内分泌胰腺表达ACE2,冠状病毒可能进入胰岛造成急性β细胞功能紊乱,导致急性高血糖症和暂时性T2DM6。更重要的是,糖尿病模型小鼠显示胰腺中ACE2激活水平增高7。其结果暗示T2DM患者可能在冠状病毒感染中有更高的易感性。同样的,T2DM诱导其他组织中的血管紧张素转换酶表达,包括肺、肝和心脏组织,这也解释了为何T2DM可能在代谢方面造成SARS-CoV感染后的多器官衰竭。
纽约时报中英文网 www.qqenglish.com


  Immediate clinical consequences

  即时临床效果

  Based on the data discussed here,it is evident that optimal metabolic control of T2DM and associated metabolic parameters in patients with COVID-19 is mandatory.This is not only relevant because of the obvious danger and increased risk of complications for patients with T2DM and a severe infectious disease,but also because this approach might help the treatment of all patients with COVID-19.

  以上数据表明,很明显,对COVID-19患者结合相关参数,进行合适的T2DM代谢管理是必须的。不仅仅是由于T2DM患者患重症的危险性和并发症风险都显著增高,而且这些方法可能会有助于COVID-19患者的治疗。

  Antidiabetic medications,such as GLP1 agonists,that improve the metabolic function and induce the activity of the protective ACE2 and Mas receptor pathways might have the advantage of ameliorating glucose metabolism and blood pressure,and also preventing coronaviruses from entering cells as a result of competitive binding to ACE2.This effect might help to protect and restore pulmonary function5.Likewise,early treatment with angiotensin II receptor blockers(such as losartan or telmisartan)or,more directly,recombinant ACE2,might be useful to enhance the ACE2 and Mas system in preference to the pathways mediated by angiotensin receptors.This approach would enable the combination of an antidiabetic,anti-inflammatory and antiviral effect.

  抗糖尿病药物,例如GLP1激动剂能提高代谢功能和引起ACE2保护活性增强,激活Mas受体通路。这对改善糖代谢和血压有积极作用,也同时作为ACE2竞争性结合剂,阻止冠状病毒进入细胞。这可能会有助于保护和恢复肺功能5。同样,早期血管紧张素受体II拮抗剂(例如氯沙坦和替米沙坦)治疗,或直接使用重组ACE2,这或许能加强ACE2和Mas系统,而不是血管紧张素受体介导的通路。这种方式能同时实现抗糖尿病、抗炎和抗病毒作用。

  Finally,the synthetic protease inhibitor camustat,which blocks the serine protease TMPRSS2 required for ACE2-mediated coronavirus entry into the cells4,also reverses dyslipidaemia and hyperglycaemia8.The intriguing link between coronavirus infections and these endocrine and metabolic pathways will have an important effect on the general medical management of severe COVID-19.Glucocorticoids that have been helpful in the treatment of acute respiratory distress syndrome might not be indicated in patients with coronavirus infection.Glucocorticoids not only aggravate metabolic control,but also attenuate angiotensin 1–7 and Mas receptor expression9.Hence,they might have a limited role in the management of patients with COVID-19.By contrast,the anti-rheumatic drug hydroxychloroquine,which is now widely used in many centres around the world treating patients with COVID-19,has also attracted interest as a potential therapeutic intervention for patients with T2DM10.At this point,it is unclear whether hydroxychloroquine in addition to anti-inflammatory and antidiabetic drugs will also directly interfere with the coronavirus–ACE2 pathways.

  最后,合成蛋白酶抑制剂卡米斯塔(camustat)可以阻碍丝氨酸蛋白酶TMPRSS2,后者是ACE2介导的冠状病毒进入所必须4,同时它还可以调节血脂异常和高血糖症8。冠状病毒感染和内分泌,代谢通路之间的微妙联系对COVID-19重症患者的医疗管理有着重要的作用。糖皮质激素有助于急性呼吸窘迫综合征的治疗,但可能对冠状病毒感染的患者无显著作用。糖皮质激素不仅对代谢控制并无好处,也对血管紧张素1-7和Mas受体表达有负性作用。因此,在COVID-19病人管理中应该限制使用。相反,现在已被广泛使用于世界各地COVID-19病人治疗中的抗风湿药物羟氯喹,同样被看做是一种潜在的T2DM治疗干预药物10。这一点上,羟氯喹与抗炎和抗糖尿病药物合用是否也能直接干扰冠状病毒-ACE2通路,仍不得而知。

  In conclusion,COVID-19 is not primarily a metabolic disease,but metabolic control of glucose,lipid levels and blood pressure are key in these patients.This approach is important to address the well-established metabolic and cardiovascular complications of this primary comorbidity.Moreover,effective control of these metabolic parameters might represent a specific and mechanistic approach to prevent and ameliorate the acute effects of this virus by reducing the local inflammatory response and blocking its entry into cells.

  总的说来,虽然COVID-19不是一种直接的代谢疾病,但是糖代谢、脂代谢和血压控制是治疗的关键。此方式对稳定代谢水平和心血管并发症具有重要意义。此外,有效的代谢参数控制可能会成为一种特殊的方式,通过减少局部炎症应答和阻止病毒进入细胞,来改善急性病毒感染症状。
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