My colleagues and I published a comprehensive Review on coronavirus disease 2019 (COVID-19) and diabetes mellitus in November 2020 (Lim, S., Bae, J. H., Kwon, H. S. & Nauck, M. A. COVID-19 and diabetes mellitus: from pathophysiology to clinical management. Nat. Rev. Endocrinol. 17, 11–30 (2021)1). In her correspondence on our Review, Virginia Boccardi suggested that, in patients with diabetes mellitus and COVID-19, we should also consider imbalances in the sympathetic and parasympathetic nervous systems occurring, for example, as a consequence of diabetes mellitus, as important factors that might contribute to COVID-19 severity (Boccardi, V. Autonomic dyshomeostasis in patients with diabetes mellitus during COVID-19. Nat. Rev. Endocrinol. https://doi.org/10.1038/s41574-021-00466-5 (2021)2).
Dysregulated glucose metabolism is associated with autonomic nervous system dysfunction, leading to an imbalance between sympathetic and parasympathetic activity3. This lack of homoeostatic control is affected by acute infections, potentially augmenting instability in vital functions in patients affected by COVID-19 (refs4,5). It is well known that patients with a loss of homoeostatic control of glucose metabolism release potentially damaging cytokines, including IL-6 and tumour necrosis factor6, which are involved in the development of complications of diabetes mellitus as well as COVID-19 (ref.7). The synthesis and secretion of other cytokines, such as plasminogen activator inhibitor 1 and adhesion molecules associated with overactive coagulation, are also increased in patients with hyperglycaemia8. All these phenomena are, likewise, induced by SARS-CoV-2 infection9.
In the DCCT–EDIC study, which included patients with type 1 diabetes mellitus, individuals diagnosed with autonomic neuropathy experienced an increased long-term risk of adverse cardiovascular events10. Another study of patients with diabetes mellitus reported that activation of the sympathetic nervous system resulted in diffuse endothelial dysfunction and an increased pro-inflammatory, pro-atherothrombotic and procoagulant state11. Conditions that cause acute serious stress such as COVID-19, when combined with underlying inflammation, can induce overactivation of sympathetic functions, and this sympathetic dominance can disturb the balance within the autonomic nervous system12. This alteration is probably unfavourable for cardiometabolic health, and potentially leads to worse outcomes and increased mortality. Thus, COVID-19 can be a triggering factor that initiates the harmful development of cardiorespiratory distress and, in particular in patients characterized by sympathetic overactivity, might lead to multiorgan failure.
We fully agree with Boccardi2 that early identification of autonomic imbalance is critical in patients with diabetes mellitus to concentrate therapeutic measures on those at risk of deteriorating health. We also agree that the autonomic nervous system interacts with the immune system via neuroinflammatory pathways, which eventually might affect the function of cardiac and respiratory systems13. Moreover, we agree that therapeutic modulation of a disturbed autonomic nervous system to achieve an improved balance might improve the prognosis of COVID-19 in patients with diabetes mellitus. Although more evidence is needed, various methods, such as non-invasive electrical stimulation on the vagal nerve system, offer useful potential along these lines14. Thus, it has been reported that vagus nerve stimulation in the auricular area could be an effective modality to improve the acute respiratory distress conditions seen in patients with COVID-19 (ref.15).
As of 13 January 2021, the World Health Organization reports (see Related links) that more than 91 million people have been infected with SARS-CoV-2 worldwide, and of those, 1.9 million have died. Fortunately, vaccines have been developed (see Related links) and are currently being administered to people at high risk, such as the elderly and medical personnel. Before the vaccination programme becomes effective, people at high risk of COVID-19, such as those with diabetes mellitus, cardiovascular diseases or immunocompromised disorders, should receive priority attention and treatment if they contract COVID-19. We hope that further medical approaches will be discovered to reduce the morbidity and mortality associated with COVID-19 in people at high risk.
References
Lim, S., Bae, J. H., Kwon, H. S. & Nauck, M. A. COVID-19 and diabetes mellitus: from pathophysiology to clinical management. Nat. Rev. Endocrinol. 17, 11–30 (2021).
Boccardi, V. Autonomic dyshomeostasis in patients with diabetes mellitus during COVID-19. Nat. Rev. Endocrinol. https://doi.org/10.1038/s41574-021-00466-5 (2021).
Andersen, S. T. et al. Risk factors for the presence and progression of cardiovascular autonomic neuropathy in type 2 diabetes: ADDITION-Denmark. Diabetes Care 41, 2586–2594 (2018).
Porzionato, A. et al. Sympathetic activation: a potential link between comorbidities and COVID-19. FEBS J. 287, 3681–3688 (2020).
Dani, M. et al. Autonomic dysfunction in ‘long COVID’: rationale, physiology and management strategies. Clin. Med. https://doi.org/10.7861/clinmed.2020-0896 (2020).
Liu, C. et al. Adiponectin, TNF-alpha and inflammatory cytokines and risk of type 2 diabetes: A systematic review and meta-analysis. Cytokine 86, 100–109 (2016).
Kleemann, R., Zadelaar, S. & Kooistra, T. Cytokines and atherosclerosis: a comprehensive review of studies in mice. Cardiovasc. Res. 79, 360–376 (2008).
Meigs, J. B., Hu, F. B., Rifai, N. & Manson, J. E. Biomarkers of endothelial dysfunction and risk of type 2 diabetes mellitus. JAMA 291, 1978–1986 (2004).
Gu, S. X. et al. Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation. Nat. Rev. Cardiol. https://doi.org/10.1038/s41569-020-00469-1 (2020).
Pop-Busui, R. et al. Cardiovascular autonomic neuropathy and cardiovascular outcomes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study. Diabetes Care 40, 94–100 (2017).
Joy, N. G., Mikeladze, M., Younk, L. M., Tate, D. B. & Davis, S. N. Effects of equivalent sympathetic activation during hypoglycemia on endothelial function and pro-atherothrombotic balance in healthy individuals and obese standard treated type 2 diabetes. Metabolism 65, 1695–1705 (2016).
Leitzke, M., Stefanovic, D., Meyer, J. J., Schimpf, S. & Schonknecht, P. Autonomic balance determines the severity of COVID-19 courses. Bioelectron. Med. 6, 22 (2020).
Carnevale, D. & Lembo, G. Neuroimmune interactions in cardiovascular diseases. Cardiovasc. Res. https://doi.org/10.1093/cvr/cvaa151 (2020).
Carnevale, L. et al. Celiac vagus nerve stimulation recapitulates angiotensin ii-induced splenic noradrenergic activation, driving egress of CD8 effector cells. Cell Rep. 15, 108494 (2020).
Kaniusas, E. et al. Non-invasive auricular vagus nerve stimulation as a potential treatment for covid19-originated acute respiratory distress syndrome. Front. Physiol. https://doi.org/10.3389/fphys.2020.00890 (2020).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Related links
WHO COVID-19 dashboard: https://covid19.who.int/
WHO COVID-19 vaccine information: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/covid-19-vaccines
Rights and permissions
About this article
Cite this article
Lim, S., Bae, J.H., Kwon, HS. et al. Reply to: Autonomic dyshomeostasis in patients with diabetes mellitus during COVID-19. Nat Rev Endocrinol 17, 189–190 (2021). https://doi.org/10.1038/s41574-021-00467-4
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41574-021-00467-4