COVID-19 and metabolic disease: mechanisms and clinical management

Abstract

Up to 50% of the people who have died from COVID-19 had metabolic and vascular disorders. Notably, there are many direct links between COVID-19 and the metabolic and endocrine systems. Thus, not only are patients with metabolic dysfunction (eg, obesity, hypertension, non-alcoholic fatty liver disease, and diabetes) at an increased risk of developing severe COVID-19 but also infection with SARS-CoV-2 might lead to new-onset diabetes or aggravation of pre-existing metabolic disorders. In this Review, we provide an update on the mechanisms of how metabolic and endocrine disorders might predispose patients to develop severe COVID-19. Additionally, we update the practical recommendations and management of patients with COVID-19 and post-pandemic. Furthermore, we summarise new treatment options for patients with both COVID-19 and diabetes, and highlight current challenges in clinical management.

Figure 1

The RAAS in COVID-19 (A) When the RAAS is activated, angiotensinogen produced in the liver is cleaved to angiotensin I in the kidney. Angiotensin I is further converted to angiotensin II by ACE. Angiotensin II binds to its receptors, AT1R and AT2R, causing the release of aldosterone from the zona glomerulosa in the adrenal cortex. In the second part of the RAAS, angiotensin II is converted by ACE2 to the vasodilatory angiotensin 1–7, which binds to its Mas receptor, thereby possessing opposing actions of angiotensin II and ACE. (B) ACE2 consists of two forms, a membrane-spanning protein and a circulating soluble form, both capable of binding to the spike protein on the surface of SARS-CoV-2. Expression of ACE2 is regulated by HMGB1 and SMARCA4. Following infection with SARS-CoV-2, the viral spike protein is cleaved by TMPRSS2 and the membrane form of ACE2 is internalised with the virus, leading to a decrease in ACE2. This stage might result in overactivation of the ACE or angiotensin II part of the RAAS, thereby augmenting signalling through AT1R and AT2R. Virus entry is facilitated by NRP1, which promotes the interaction between SARS-CoV-2 and ACE2. A suggested alternative receptor for virus entry is DPP-4. RAAS=renin–angiotensin–aldosterone system. ACE=angiotensin-converting enzyme.

Figure 2

Clinical manifestations and complications of diabetes or obesity and COVID-19 In the white adipose tissue of individuals with obesity, adipocytes are hypertrophic and the tissue is infiltrated with proinflammatory immune cells that secrete cytokines, chemokines, and adipokines, leading to a permanent inflammatory phenotype. In diabetes, insulin resistance also leads to an increased infiltration of M1 macrophages into adipose tissue. Following infection with SARS-CoV-2, this chronic inflammation might aggravate COVID-19 symptoms in a synergy effect, resulting in metaflammation and a cytokine storm, which contribute to severe COVID-19.

Figure 3

Interplay between metabolic diseases and COVID-19 On one hand, metabolic diseases increase the risk of severe COVID-19. On the other hand, COVID-19 might lead to new-onset metabolic diseases or worsening of already existing metabolic disorders.