In November 2020, Soo Lim and collaborators published a complete Review on coronavirus disease 2019 (COVID-19) and diabetes mellitus (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 this Review, they clearly explained that hyperglycaemia might interact with other risk factors to modulate immune and inflammatory responses, thus predisposing patients with diabetes mellitus to severe COVID-19 and possible lethal outcomes. From the epidemiological data or from bedside experience on COVID-19 wards, we have learned that in patients with diabetes mellitus and its complications, infection with SARS-CoV-2 is associated with increased morbidity and mortality2. However, it is still impossible to predict which infected people will experience the rapid evolution to acute respiratory distress and multi-organ failure.

From the hard work in hospital wards, we know that there are some laboratory and clinical biomarkers that might indicate a high risk of progression to severe COVID-19; these biomarkers include hyperglycaemia as well as hyponatraemia, hyperinflammation, abnormal heart rate variability (from severe bradycardia to tachycardia and arrhythmia), haemodynamic instability and altered mental status. Thus, it seems that the pathophysiological processes of COVID-19 change the interplay of the immune, endocrine and nervous systems. These systems interact with each other by means of cytokines, hormones and neurotransmitters3.

Interestingly, the nervous systems communicate with the immune system and regulate its activity through the autonomic nervous system (via sympathetic and parasympathetic activity)3. It is well established that diabetes mellitus is a condition associated with autonomic dysfunction, where sympathetic activity is hyperactivated alongside withdrawal of parasympathetic activity4. Moreover, when the balance between the sympathetic and parasympathetic nervous systems is disturbed by certain events, such as serious stress and inflammation during COVID-19, a stronger sympathetic impulse might shift homeostasis of the autonomic nervous system towards further sympathetic dominance, potentially leading to increased mortality. The autonomic nervous system interacts with the immune system via the neuro-inflammatory pathway and via the cholinergic anti-inflammatory pathway, and also controls the function of the respiratory system5. Thus, the early identification of autonomic dyshomeostasis in patients with diabetes mellitus and COVID-19 is clinically important. Indeed, it is possible to hypothesize that the modulation of autonomic nervous system homeostasis (such as with the use of non-invasive transcutaneous electrical vagal nerve stimulation) might improve clinical outcomes in patients at risk of progressing to severe COVID-19.

There is a reply to this letter by Lim, S., Bae, J. H., Kwon, H. S. & Nauck, M. A. Nat. Rev. Endocrinol. https://doi.org/10.1038/s41574-021-00467-4 (2021)