Osaka University Study Shows That Older, Obese Diabetics Are At Risk Of Severe COVID-19 Due To GRP78 Receptors Which Are Highly Expressed In Fat Tissues

A new study by Japanese researchers from Osaka University shows that that older, obese patients with diabetes are more susceptible to severe COVID-19 infection because the SARS CoV-2 spike protein also binds to GRP78, which is highly expressed in fat tissue.

According to the study abstract, “Aging, obesity, and diabetes are major risk factors for the severe progression and outcome of SARS-CoV-2 infection that leads to the COVID-19 disease, but the underlying mechanism is not yet fully understood.”
 
The study team found that the SARS-CoV-2 spike protein physically interacts with cell surface GRP78, which promotes the binding to and accumulation in ACE2-expressing cells. GRP78 was highly expressed in adipose tissue and increased in humans and mice that were older, obese, and had diabetes. The overexpression of GRP78 was attributed to hyperinsulinemia in adipocytes, which was in part mediated by the stress-responsive transcription factor XBP-1s.
 
Importantly management of hyperinsulinemia by pharmacological approaches, including metformin, sodium–glucose cotransporter 2 inhibitor, or β3-adrenergic receptor agonist, decreased GRP78 gene expression in adipose tissue.
 
Also, environmental interventions, including exercise, calorie restriction, fasting, or cold exposure, reduced the gene expression of GRP78 in adipose tissue.
 
The study findings provide scientific evidence for the role of GRP78 as a binding partner of the SARS-CoV-2 spike protein and ACE2, which might be related to the severe progression and outcome of COVID-19 in older and obese patients with diabetes. The management of hyperinsulinemia and the related GRP78 expression could be a therapeutic or preventative target.
 
The study findings were published in the peer reviewed journal: diabetes (A journal of the American Diabetes Association) https://diabetes.diabetesjournals.org/content/early/2021/10/21/db20-1094

Unknown to many, the SARS-CoV-2 coronavirus does not only bind with the ACE-2 receptors to enter human host cells. Rather studies have shown that the SARS-CoV-2 coronavirus can also bind to a wide range of other receptors including the GRP78 receptors to gain entry into human host cells.
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Lead and corresponding author Dr Ji Hoon Shin told Thailand Medical News, “High GRP78 levels associated with the high insulin levels in older, obese, and diabetic patients may make them more vulnerable to COVID,thus, lowering insulin levels would be an important point for therapeutics and prevention of COVID-19.”
 
The study team suggests that managing hyperinsulinemia in these patients could reduce GRP78 expression and the risk of COVID-19.
 
Dr Hoon Shin further added, “Because the expression of GRP78, especially in the cell surface and circulation, is strongly correlated with hyperinsulinemia, pharmacological drugs such as metformin and sodium-glucose cotransporter 2 inhibitors (SGLT2i), or lifestyle interventions such as exercising, reducing calorie intake, and enhancing energy expenditure, could help to reduce the expression of GRP78 associated with the insulin levels, as shown in our study findings.”
 
The study team in laboratory experiments, found that the SARS-CoV-2 spike protein physically interacts with cell surface GRP78, which promotes binding and accumulation in ACE2-expressing cells.
In detailed analyses of transcriptome data sets of human and mouse tissues, GRP78 was highly expressed in adipose tissue, as Dr Hoon Shin indicated, and was increased both in humans and mice that were older, obese, and had diabetes.
 
The GRP78 overexpression was attributed to hyperinsulinemia in adipocytes, which was in part mediated by the stress-responsive transcription factor XBP-1s.
 
Importantly in human subcutaneous adipose tissue, management of hyperinsulinemia by pharmacological approaches, including metformin, SGLT2is, or b3-adrenergic receptor agonists, decreased GRP78 gene expression.
 
In animal studies involving mice, environmental interventions, for example, exercise, calorie restriction, fasting, or cold exposure, also reduced GRP78 gene expression in adipose tissue.
 
The study team concluded, “This study provides scientific evidence for the role of GRP78 as a binding partner of the SARS-CoV-2 spike protein and ACE2, which might be related to the severe progression and outcome of COVID-19 in older and obese patients with diabetes. The management of hyperinsulinemia and the related GRP78 expression could be a therapeutic or preventive target.”
 
Dr Hoon Shin further added, “Direct inhibition of GRP78 would be possible by a specific inhibitor, but great care should be taken in the dosage, timing, and duration since GRP78 also plays an important role in many physiological processes, such as the homeostasis of cellular proteins, and the loss of GRP78 could cause various cellular stresses.”
 
Leading endocrinologist Dr Dirk Homann of the Diabetes, Obesity, and Metabolism Institute and Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai told media, “The notion that enhanced GRP78 expression in fat deposits of aged, obese, and/or diabetic individuals may render their adipose tissues more susceptible to SARS-CoV-2 infection is indeed plausible. If it is probable, however, remains to be shown.”
 
He added, “To test the authors’ hypothesis, several lines of investigation will be necessary, and as far as I know, are actively pursued by a number of different investigator teams.”
These will include:
 
-More detailed analyses of protein (rather than just transcript) expression patterns of GRP78, ACE2, and other SARS-CoV-2 proviral host factors in adipose tissues from various patient cohorts (including both nonCOVID-19 and COVID-19 cases);
 
-Quantification of virus traces (that is, SARS-CoV-2 proteins and genes) in fat depots of COVID-19 patients;
 
-In vitro SARS-CoV-2 infection studies using primary human adipose tissue as well as suitable cell lines/in vitro-differentiated adipocytes etc.; and
 
-Development and interrogation of suitable animal models for in vivo SARS-CoV-2 infection (To date, the hamster model would constitute the most promising research avenue).
 
He said, “Currently, the study team’s sensible suggestions about careful management of hyperinsulinemia through pharmacological interventions as well as lifestyle adjustments (exercise, diet) are already part of standard clinical care.”
 
For the latest SARS-CoV-2 Research, keep on logging to Thailand Medical News.
 
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