Glycated ACE2 receptor in diabetes: open door for SARS-COV-2 entry in cardiomyocyte.
Level 4 - case-series / case-control
Comparative autopsy case series combined with in vitro laboratory mechanistic study.
PubMed 33962629 · doi:10.1186/s12933-021-01286-7
What was done
Researchers evaluated cardiac tissue from 97 consecutive COVID-19 autopsy cases in Italy (April 2020 to January 2021) divided into patients with diabetes mellitus (DM, n=37) and without diabetes (Non-DM, n=60). They quantified cardiomyocyte SARS-CoV-2 RNA and measured protein expression of total ACE2, glycosylated ACE2, and TMPRSS2. To assess baseline diabetic alterations independent of infection, these markers were also evaluated in explanted hearts from DM and Non-DM subjects. Additionally, recombinant human ACE2 (hACE2) was exposed in vitro to 120 mM glucose for 12 days to analyze non-enzymatic glycation and binding alterations.
What was found
SARS-CoV-2 RNA was identified in cardiomyocytes from 48% (47/97) of all autopsy cases, occurring in 81% (30/37) of DM patients compared to 28% (17/60) of Non-DM patients. Expression levels of total ACE2, glycosylated ACE2, and TMPRSS2 were higher in cardiomyocytes from DM versus Non-DM subjects in both COVID-19 autopsies and explanted hearts. In vitro exposure of hACE2 to glucose led to non-enzymatic glycation of four lysine residues in the neck domain, altering protein oligomerization.
Why it matters
This study provides molecular and histopathological evidence explaining why patients with diabetes experience higher rates of COVID-19-related myocardial injury, highlighting upregulation and non-enzymatic glycation of the ACE2 receptor as potential drivers of viral entry into cardiomyocytes.
Limits
Findings rely on post-mortem tissue from fatal COVID-19 cases, which limits generalizability to non-fatal or milder infections. The in vitro experiment utilized a supra-physiological glucose concentration (120 mM), and the abstract does not report clinical confounders such as glycemic control quality, medication regimens, or pre-existing cardiovascular comorbidities.
Cited by
- contradicts High blood glucose crystallizes around ACE2 molecules to keep them open, increasing susceptibility to COVID-19 infection.