Hyperglycemia and insulin resistance in COVID-19 versus non-COVID critical illness: Are they really different?,Critical Care

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Hyperglycemia and insulin resistance in COVID-19 versus non-COVID critical illness: Are they really different?
Critical Care ( IF 15.1 ) Pub Date : 2021-12-17 , DOI: 10.1186/s13054-021-03861-6
Lies Langouche ₁ , Greet Van den Berghe ₁ , Jan Gunst ₁

Affiliation

Hyperglycemia frequently develops in patients with severe COVID-19, regardless of preadmission diabetes status, as in non-COVID critically ill patients [1, 2]. In non-COVID patients, stress hyperglycemia has been attributed to insulin resistance due to elevated counterregulatory hormones, cytokines, and drugs including steroids, although beta-cell dysfunction through prolonged hyperglycemia, poor beta-cell reserve, hypoperfusion and inflammation may co-exist in some patients (Fig. 1) [3]. As in non-COVID patients, numerous observational studies have associated more severe hyperglycemia and increased glucose variability with poor outcome in COVID-19 patients [1, 2, 4, 5]. However, causality remains unclear, since insulin resistance and resultant hyperglycemia closely relate to illness severity [1, 6]. In this regard, a recent observational study also associated insulin treatment with increased mortality of COVID-19 [7]. Evidently, observational studies have an inherent risk of residual confounding, whereby the ideal glucose target can only be derived from adequately powered randomized controlled trials (RCTs).

Despite substantial similarities with non-COVID critical illness, some investigators have suggested that COVID-19 patients may be at increased risk of more severe hyperglycemia due to virus-mediated effects on beta-cell function and/or insulin sensitivity (Fig. 1) [8,9,10,11], which could predispose COVID-19 patients to diabetic emergencies. On the other hand, patients with severe COVID-19 more commonly have pre-existing diabetes and/or increased body-mass index as risk factors for insulin resistance, which is aggravated by routine steroid treatment [2, 12]. Clinical evidence confirming an increased incidence of diabetic emergencies related to COVID-19 surges is inconsistent, as are mechanistic studies on potential virus-induced alterations in glucose homeostasis [2, 8,9,10,11].

In a recent mechanistic study, Reiterer et al. reported that COVID-19-associated hyperglycemia may be driven through viral adipocyte infection, resulting in reduced release of adiponectin—a glucoregulatory hormone—, and secondary insulin resistance [11]. Indeed, in animal and in vitro studies, adipocytes could be infected by SARS-CoV-2, which was associated with decreased adiponectin expression. Moreover, in a relatively small human study (N = 101), patients with COVID-19-associated acute respiratory distress syndrome had lower circulating adiponectin and elevated C-peptide over glucose—potentially indicating insulin resistance and beta-cell reserve—as compared to intensive care patients without COVID-19, who were classified as having (predominantly) beta-cell failure as cause of hyperglycemia [11]. Yet, it remains unclear whether these findings reveal a specific pathophysiological response to SARS-CoV-2, since low adiponectin concentrations have been reported in non-COVID critical illness as well [13]. Moreover, numerous potential confounders warrant caution. First, patients were not matched for baseline characteristics, with more diabetics in the non-COVID cohort and—presumably—a higher illness severity in the COVID-19 cohort, in view of the higher peak glucose concentrations observed in these patients. Hence, baseline imbalance could explain the claimed differences in insulin resistance versus beta-cell failure between cohorts. Second, circulating glucose, C-peptide and adiponectin are affected by nutrition and insulin treatment [14, 15], which was not reported, respectively differed between the groups, and time of blood sampling was not standardized. Finally, the used definitions of insulin resistance and beta-cell failure are contentious. Insulin resistance was defined as the absence of beta-cell failure, although both conditions may co-exist. Moreover, the cutoff of C-peptide over glucose was not validated, and in addition to effects of insulin treatment on C-peptide and glucose, concentrations were not measured concomitantly. Finally, the finding of predominant beta-cell failure in non-COVID critical illness contradicts with preceding evidence [3, 14], which demonstrated ubiquitous insulin resistance and which questions the used tool to define insulin resistance in this study.

In contrast, other mechanistic studies have put forward virus-induced beta-cell dysfunction or damage as potential mediator of hyperglycemia in COVID-19 [8,9,10]. In human islets, SARS-CoV-2 was able to infect beta-cells, leading to cell death [9]. Also autopsy studies in patients dying with COVID-19 revealed presence of SARS-CoV-2 transcript and/or antigen in beta-cells of some, but not all patients [8,9,10]. However, apart from the low number of included patients, several issues warrant caution not to overinterpret these findings, including the suboptimal tissue quality due to autolysis, conflicting data regarding the pancreatic expression of SARS-CoV-2 receptors and the beta-cell selectivity of viral damage, and the lack of in vivo evidence [8,9,10]. If virus-mediated beta-cell death would be a primary mechanism of hyperglycemia in severe COVID-19, one would expect persistent insulin need in the majority of patients, which is not the case [2]. Whether COVID-19 associates with an increased incidence of persistent diabetes mellitus or not, is currently being investigated [2]. Interestingly, a recent mechanistic study found potentially reversible beta-cell transdifferentiation rather than cell death in human islets exposed to SARS-CoV-2, characterized by lower expression of insulin and upregulated expression of alpha-cell markers [10]. Also in this case, it remains unclear whether such transdifferentiation also occurs in vivo.

From a clinical perspective, the question is to what extent COVID-19-associated hyperglycemia should be treated, for which there is yet no solid RCT evidence. Also in non-COVID critical illness, the ideal glucose target remains debated [1]. Our research group showed via three RCTs improved morbidity and mortality of critically ill children and adults by maintaining blood glucose with insulin in the healthy, normal range. Clinical benefit was subsequently attributed to prevention of glucose overload and associated mitochondrial damage. In contrast, the largest multicenter RCT in critically ill adults found an opposite impact of tight glucose control on mortality, which was attributed to an increased incidence of hypoglycemia. The differences between the subsequent RCTs could be explained by differences in accuracies of the glucose control protocols and differences in feeding strategies [1]. The multicenter TGC-fast RCT is currently investigating whether tight glucose control performed with a validated protocol that minimizes the incidence of hypoglycemia is still beneficial in the absence of early full feeding (clinicaltrials.gov NCT03665207).

Stress hyperglycemia and insulin resistance are characteristic of acute critical illness. It remains unclear if COVID-19-associated hyperglycemia and insulin resistance is more severe than in non-COVID patients with similar disease severity, and (in that case), whether this is mediated by viral infection of beta-cells and/or adipocytes. As in non-COVID critically ill patients, the ideal blood glucose target remains to be defined.

Not applicable.

RCT:: Randomized controlled trial

1.
Gunst J, De Bruyn A, Van den Berghe G. Glucose control in the ICU. Curr Opin Anaesthesiol. 2019;32(2):156–62.
Article Google Scholar
2.
Khunti K, Del Prato S, Mathieu C, Kahn SE, Gabbay RA, Buse JB. COVID-19, hyperglycemia, and new-onset diabetes. Diabetes Care. 2021;44(12):2645–55.
Article Google Scholar
3.
Dungan KM, Braithwaite SS, Preiser JC. Stress hyperglycaemia. Lancet. 2009;373(9677):1798–807.
CAS Article Google Scholar
4.
Morse J, Gay W, Korwek KM, McLean LE, Poland RE, Guy J, Sands K, Perlin JB. Hyperglycaemia increases mortality risk in non-diabetic patients with COVID-19 even more than in diabetic patients. Endocrinol Diabetes Metab. 2021;4(4):e00291.
CAS PubMed PubMed Central Google Scholar
5.
Xie W, Wu N, Wang B, Xu Y, Zhang Y, Xiang Y, Zhang W, Chen Z, Yuan Z, Li C, et al. Fasting plasma glucose and glucose fluctuation are associated with COVID-19 prognosis regardless of pre-existing diabetes. Diabetes Res Clin Pract. 2021;180:109041.
CAS Article Google Scholar
6.
Bermejo-Martin JF, González-Rivera M, Almansa R, Micheloud D, Tedim AP, Domínguez-Gil M, Resino S, Martín-Fernández M, Ryan Murua P, Pérez-García F, et al. Viral RNA load in plasma is associated with critical illness and a dysregulated host response in COVID-19. Crit Care. 2020;24(1):691.
Article Google Scholar
7.
Yu B, Li C, Sun Y, Wang DW. Insulin treatment is associated with increased mortality in patients with COVID-19 and type 2 diabetes. Cell Metab. 2021;33(1):65–77.
CAS Article Google Scholar
8.
Müller JA, Groß R, Conzelmann C, Krüger J, Merle U, Steinhart J, Weil T, Koepke L, Bozzo CP, Read C, et al. SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas. Nat Metab. 2021;3(2):149–65.
Article Google Scholar
9.
Wu CT, Lidsky PV, Xiao Y, Lee IT, Cheng R, Nakayama T, Jiang S, Demeter J, Bevacqua RJ, Chang CA, et al. SARS-CoV-2 infects human pancreatic β cells and elicits β cell impairment. Cell Metab. 2021;33(8):1565–76.
CAS Article Google Scholar
10.
Tang X, Uhl S, Zhang T, Xue D, Li B, Vandana JJ, Acklin JA, Bonnycastle LL, Narisu N, Erdos MR, et al. SARS-CoV-2 infection induces beta cell transdifferentiation. Cell Metab. 2021;33(8):1577–91.
CAS Article Google Scholar
11.
Reiterer M, Rajan M, Gómez-Banoy N, Lau JD, Gomez-Escobar LG, Ma L, Gilani A, Alvarez-Mulett S, Sholle ET, Chandar V, et al. Hyperglycemia in acute COVID-19 is characterized by insulin resistance and adipose tissue infectivity by SARS-CoV-2. Cell Metab. 2021;33(11):2174–88.
CAS Article Google Scholar
12.
Klein SJ, Mayerhöfer T, Fries D, Preuß Hernández C, Joannidis M, Collaborators. Elevated HbA1c remains a predominant finding in severe COVID-19 and may be associated with increased mortality in patients requiring mechanical ventilation. Crit Care. 2021;25(1):300.
Article Google Scholar
13.
Marques MB, Langouche L. Endocrine, metabolic, and morphologic alterations of adipose tissue during critical illness. Crit Care Med. 2013;41(1):317–25.
Article Google Scholar
14.
Langouche L, Vander Perre S, Wouters PJ, D’Hoore A, Hansen TK, Van den Berghe G. Effect of intensive insulin therapy on insulin sensitivity in the critically ill. J Clin Endocrinol Metab. 2007;92(10):3890–7.
CAS Article Google Scholar
15.
Langouche L, Vander Perre S, Frystyk J, Flyvbjerg A, Hansen TK, Van den Berghe G. Adiponectin, retinol-binding protein 4, and leptin in protracted critical illness of pulmonary origin. Crit Care. 2009;13(4):R112.
Article Google Scholar

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JG receives a postdoctoral research fellowship from the University Hospitals Leuven, and C2 project funding from KU Leuven (C24/17/070). GVdB and LL, via the KU Leuven, receive long-term structural research support from the Methusalem Program funded by the Flemish Government (METH14/06). The authors receive research funding from the Research Foundation Flanders (G069421N to LL and GVdB; T003617N to GVdB and JG). GVdB holds an Advanced Research Grant [AdvG 2017-785809] from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program.

Affiliations

Clinical Department and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium
Lies Langouche, Greet Van den Berghe & Jan Gunst

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Lies LangoucheView author publications
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JG wrote the first draft, which was revised by LL and GVdB. All authors read and approved the final manuscript.

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Correspondence to Jan Gunst.

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Langouche, L., Van den Berghe, G. & Gunst, J. Hyperglycemia and insulin resistance in COVID-19 versus non-COVID critical illness: Are they really different?. Crit Care 25, 437 (2021). https://doi.org/10.1186/s13054-021-03861-6

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Received: 03 December 2021
Accepted: 08 December 2021
Published: 17 December 2021
DOI: https://doi.org/10.1186/s13054-021-03861-6

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Keywords

COVID-19
Hyperglycemia
Insulin
Diabetes

中文翻译：

COVID-19 与非 COVID 危重疾病中的高血糖和胰岛素抵抗：它们真的不同吗？

与非 COVID-19 危重患者一样，无论入院前糖尿病状态如何，重度 COVID-19 患者都经常出现高血糖 [1, 2]。在非 COVID 患者中，由于反调节激素、细胞因子和包括类固醇在内的药物升高，应激性高血糖症归因于胰岛素抵抗，尽管长期高血糖导致 β 细胞功能障碍、β 细胞储备不足、低灌注和炎症可能共存于一些患者（图 1）[3]。与非 COVID 患者一样，许多观察性研究将更严重的高血糖症和增加的葡萄糖变异性与 COVID-19 患者的不良预后联系起来 [1, 2, 4, 5]。然而，因果关系仍不清楚，因为胰岛素抵抗和由此产生的高血糖与疾病的严重程度密切相关 [1, 6]。在这方面，最近的一项观察性研究也将胰岛素治疗与 COVID-19 死亡率增加联系起来 [7]。显然，观察性研究具有残留混杂的内在风险，因此理想的血糖目标只能从具有足够效力的随机对照试验 (RCT) 中得出。

尽管与非 COVID 危重病有很多相似之处，但一些研究人员认为，由于病毒介导的对 β 细胞功能和/或胰岛素敏感性的影响，COVID-19 患者可能面临更严重的高血糖症的风险增加（图 1）。 8,9,10,11]，这可能会使 COVID-19 患者易患糖尿病紧急情况。另一方面，重度 COVID-19 患者更常见的是预先存在糖尿病和/或体重指数升高作为胰岛素抵抗的危险因素，而常规类固醇治疗会加剧这种情况 [2, 12]。证实与 COVID-19 激增相关的糖尿病急症发生率增加的临床证据并不一致，关于潜在病毒诱导的葡萄糖稳态改变的机制研究也是如此 [2, 8,9,10,11]。

在最近的机械研究中，Reiterer 等人。据报道，与 COVID-19 相关的高血糖可能是由病毒脂肪细胞感染引起的，导致脂联素（一种葡萄糖调节激素）的释放减少，继发性胰岛素抵抗 [11]。事实上，在动物和体外研究中，脂肪细胞可能被 SARS-CoV-2 感染，这与脂联素表达降低有关。此外，在一项相对较小的人体研究中（N = 101)，与没有 COVID-19 的重症监护患者相比，患有 COVID-19 相关的急性呼吸窘迫综合征的患者循环脂联素较低，C 肽高于葡萄糖水平，这可能表明胰岛素抵抗和 β 细胞储备。归类为具有（主要）β细胞衰竭作为高血糖的原因[11]。然而，尚不清楚这些发现是否揭示了对 SARS-CoV-2 的特定病理生理反应，因为在非 COVID 危重疾病中也报告了低脂联素浓度 [13]。此外，许多潜在的混杂因素需要谨慎。首先，患者的基线特征不匹配，非 COVID 队列中有更多的糖尿病患者，并且可能在 COVID-19 队列中有更高的疾病严重程度，鉴于在这些患者中观察到的峰值葡萄糖浓度较高。因此，基线不平衡可以解释队列之间声称的胰岛素抵抗与 β 细胞衰竭的差异。其次，循环葡萄糖、C肽和脂联素受营养和胰岛素治疗的影响[14, 15]，未见报道，各组间存在差异，采血时间不规范。最后，胰岛素抵抗和 β 细胞衰竭的使用定义是有争议的。胰岛素抵抗被定义为不存在 β 细胞衰竭，尽管这两种情况可能共存。此外，C 肽相对于葡萄糖的临界值没有得到验证，并且除了胰岛素治疗对 C 肽和葡萄糖的影响之外，没有同时测量浓度。最后，

相比之下，其他机制研究提出病毒诱导的 β 细胞功能障碍或损伤是 COVID-19 高血糖的潜在介质 [8,9,10]。在人类胰岛中，SARS-CoV-2 能够感染 β 细胞，导致细胞死亡 [9]。此外，对死于 COVID-19 的患者的尸检研究显示，部分患者的 β 细胞中存在 SARS-CoV-2 转录物和/或抗原，但并非所有患者 [8,9,10]。然而，除了纳入的患者数量很少外，还有几个问题需要谨慎，不要过度解释这些发现，包括由于自溶导致的组织质量欠佳、关于 SARS-CoV-2 受体胰腺表达的相互矛盾的数据以及 β 细胞选择性病毒损伤，以及缺乏体内证据 [8,9,10]。如果病毒介导的 β 细胞死亡是严重 COVID-19 中高血糖的主要机制，人们会认为大多数患者需要持续胰岛素，但事实并非如此 [2]。目前正在调查 COVID-19 是否与持续性糖尿病发病率增加有关 [2]。有趣的是，最近的一项机制研究发现，暴露于 SARS-CoV-2 的人类胰岛可能存在可逆的 β 细胞转分化而不是细胞死亡，其特征是胰岛素表达降低和 α 细胞标志物表达上调 [10]。同样在这种情况下，尚不清楚这种转分化是否也在体内发生。目前正在调查 COVID-19 是否与持续性糖尿病发病率增加有关 [2]。有趣的是，最近的一项机制研究发现，暴露于 SARS-CoV-2 的人类胰岛可能存在可逆的 β 细胞转分化而不是细胞死亡，其特征是胰岛素表达降低和 α 细胞标志物表达上调 [10]。同样在这种情况下，尚不清楚这种转分化是否也在体内发生。目前正在调查 COVID-19 是否与持续性糖尿病发病率增加有关 [2]。有趣的是，最近的一项机制研究发现，暴露于 SARS-CoV-2 的人类胰岛可能存在可逆的 β 细胞转分化而不是细胞死亡，其特征是胰岛素表达降低和 α 细胞标志物表达上调 [10]。同样在这种情况下，尚不清楚这种转分化是否也在体内发生。

从临床角度来看，问题是应在多大程度上治疗 COVID-19 相关的高血糖症，对此尚无可靠的 RCT 证据。同样在非 COVID 危重疾病中，理想的血糖目标仍然存在争议 [1]。我们的研究小组通过三项 RCT 表明，通过使用胰岛素将血糖维持在健康、正常范围内，可以改善危重儿童和成人的发病率和死亡率。临床益处随后归因于预防葡萄糖超负荷和相关的线粒体损伤。相比之下，最大的危重成人多中心 RCT 发现严格的血糖控制对死亡率有相反的影响，这归因于低血糖发生率的增加。随后的 RCT 之间的差异可以用血糖控制方案的准确性差异和喂养策略的差异来解释 [1]。多中心 TGC-fast RCT 目前正在研究在没有早期完全喂养的情况下，使用经验证的方案进行严格的血糖控制是否仍然有益，该方案可最大限度地减少低血糖的发生率 (clinicaltrials.gov NCT03665207)。

应激性高血糖和胰岛素抵抗是急性危重症的特征。目前尚不清楚 COVID-19 相关的高血糖和胰岛素抵抗是否比具有相似疾病严重程度的非 COVID 患者更严重，以及（在这种情况下），这是否是由 β 细胞和/或脂肪细胞的病毒感染介导的。与非 COVID 危重患者一样，理想的血糖目标仍有待确定。

不适用。

随机对照试验：: 随机对照试验

1.
Gunst J、De Bruyn A、Van den Berghe G. ICU 中的葡萄糖控制。Curr Opin 麻醉剂。2019;32(2):156-62。
文章谷歌学术
2.
Khunti K、Del Prato S、Mathieu C、Kahn SE、Gabbay RA、Buse JB。COVID-19、高血糖症和新发糖尿病。糖尿病护理。2021；44（12）：2645-55。
文章谷歌学术
3.
Dungan KM、Braithwaite SS、Preiser JC。应激性高血糖。柳叶刀。2009;373(9677):1798-807。
CAS 文章 Google Scholar
4.
Morse J、Gay W、Korwek KM、McLean LE、Poland RE、Guy J、Sands K、Perlin JB。与糖尿病患者相比，高血糖症对 COVID-19 非糖尿病患者的死亡风险增加更多。内分泌糖尿病代谢。2021;4(4):e00291。
CAS PubMed PubMed Central Google Scholar
5.
Xie W, Wu N, Wang B, Xu Y, Zhang Y, Xiang Y, Zhang W, Chen Z, Yuan Z, Li C, et al. 无论先前是否患有糖尿病，空腹血糖和血糖波动都与 COVID-19 预后相关。糖尿病研究临床实践。2021;180:109041。
CAS 文章 Google Scholar
6.
Bermejo-Martin JF、González-Rivera M、Almansa R、Micheloud D、Tedim AP、Domínguez-Gil M、Resino S、Martín-Fernández M、Ryan Murua P、Pérez-García F 等。血浆中的病毒 RNA 载量与 COVID-19 中的危重疾病和宿主反应失调有关。暴击护理。2020;24(1):691。
文章谷歌学术
7.
于 B, Li C, Sun Y, Wang DW. 胰岛素治疗与 COVID-19 和 2 型糖尿病患者的死亡率增加有关。细胞元数据。2021；33(1):65–77。
CAS 文章 Google Scholar
8.
Müller JA、Groß R、Conzelmann C、Krüger J、Merle U、Steinhart J、Weil T、Koepke L、Bozzo CP、Read C 等。SARS-CoV-2 感染并在人类内分泌和外分泌胰腺细胞中复制。纳特元。2021；3(2)：149–65。
文章谷歌学术
9.
Wu CT、Lidsky PV、Xiao Y、Lee IT、Cheng R、Nakayama T、Jiang S、Demeter J、Bevacqua RJ、Chang CA 等。SARS-CoV-2 感染人胰腺 β 细胞并引起 β 细胞损伤。细胞元数据。2021；33(8)：1565-76。
CAS 文章 Google Scholar
10.
Tang X、Uhl S、Zhang T、Xue D、Li B、Vandana JJ、Acklin JA、Bonnycastle LL、Narisu N、Erdos MR 等。SARS-CoV-2感染诱导β细胞转分化。细胞元数据。2021；33(8)：1577-91。
CAS 文章 Google Scholar
11.
Reiterer M、Rajan M、Gómez-Banoy N、Lau JD、Gomez-Escobar LG、Ma L、Gilani A、Alvarez-Mulett S、Sholle ET、Chandar V 等。急性 COVID-19 的高血糖症的特征是胰岛素抵抗和 SARS-CoV-2 对脂肪组织的感染性。细胞元数据。2021；33（11）：2174-88。
CAS 文章 Google Scholar
12.
Klein SJ、Mayerhöfer T、Fries D、Preuß Hernández C、Joannidis M，合作者。HbA1c 升高仍然是重症 COVID-19 的主要发现，可能与需要机械通气的患者死亡率增加有关。暴击护理。2021;25(1):300。
文章谷歌学术
13.
Marques MB、Langouche L. 危重疾病期间脂肪组织的内分泌、代谢和形态学改变。暴击护理医学。2013;41(1):317-25。
文章谷歌学术
14.
Langouche L、Vander Perre S、Wouters PJ、D'Hoore A、Hansen TK、Van den Berghe G。强化胰岛素治疗对危重患者胰岛素敏感性的影响。J Clin 内分泌代谢杂志。2007;92(10):3890-7。
CAS 文章 Google Scholar
15.
Langouche L、Vander Perre S、Frystyk J、Flyvbjerg A、Hansen TK、Van den Berghe G. 脂联素、视黄醇结合蛋白 4 和瘦素在肺源性慢性危重症中。暴击护理。2009；13(4)：R112。
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下载参考

不适用。

JG 获得了鲁汶大学医院的博士后研究奖学金和鲁汶大学 (C24/17/070) 的 C2 项目资助。GVdB 和 LL 通过 KU Leuven 获得佛兰德政府资助的 Methusalem 计划的长期结构研究支持 (METH14/06)。作者从法兰德斯研究基金会获得研究资金（G069421N 到 LL 和 GVdB；T003617N 到 GVdB 和 JG）。GVdB 拥有欧洲研究理事会 (ERC) 授予欧盟地平线 2020 研究和创新计划的高级研究资助 [AdvG 2017-785809]。

隶属关系

重症监护医学临床科和实验室，细胞和分子医学科，KU Leuven, Herestraat 49, 3000, Leuven, Belgium
《Lies Langouche》、《Greet Van den Berghe》和《扬·冈斯特》

作者

Lies Langouche查看作者出版物
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问候 Van den Berghe查看作者出版物
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Jan Gunst查看作者出版物
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贡献

JG 编写了初稿，由 LL 和 GVdB 修改。所有作者阅读并认可的终稿。

通讯作者

与扬·冈斯特 (Jan Gunst) 的通信。

伦理批准和同意参与

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同意发表

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利益争夺

作者声明他们没有竞争利益。

出版商注

Springer Nature 对已发布地图和机构附属机构中的管辖权主张保持中立。

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重印和许可

引用这篇文章

Langouche, L.、Van den Berghe, G. 和 Gunst, J. COVID-19 与非 COVID 危重疾病中的高血糖和胰岛素抵抗：它们真的不同吗？。暴击护理 25, 437 (2021)。https://doi.org/10.1186/s13054-021-03861-6

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