Lowering blood insulin levels may even help lower risk of getting COVID-19, finds study

To do this, the researchers looked at GRP78, which has recently been suggested to be involved in the interaction of SARS-CoV-2 with human cells. The major method by which SARS-CoV-2 enters human cells is by a spike protein on the viral surface binding to a human cell-surface protein called angiotensin-converting enzyme 2 (ACE2). Shin and colleagues discovered that the spike protein can also directly bind to GRP78, and that the presence of GRP78 increases the binding with ACE2. To get an idea of GRP78's involvement in COVID-19 vulnerability they investigated how much GRP78 protein is present in tissues from older, obese, and diabetic patients.

"The results were very clear," explains senior author Iichiro Shimomura. "GRP78 gene expression was highly upregulated in adipose tissue, and was elevated with increasing age, obesity, and diabetes."

Aging, obesity, and diabetes are known to be associated with increased blood insulin levels. Therefore, the group wondered whether insulin was involved in GRP78 expression. They found that exposing cells to insulin did induce expression of GRP78. Importantly, they discovered that treatment using widely prescribed anti-diabetic drugs that reduce insulin levels successfully reduce expression level of GRP78. They went a step further and showed that exercise and calorie restriction in a mouse-model also worked to reduce GRP78 levels in adipose tissue.

"Our findings suggest that a high blood insulin level is an important risk factor that can predispose older, obese, and diabetic individuals to COVID-19 infection. As such, controlling blood insulin with pharmacological interventions or with environmental interventions, such as exercise, could help lower these patients' risk," says Shin.

Given the global impact of the SARS-CoV-2 pandemic, the results from this study provide important insights into how to lower the risk of infection in these vulnerable patients. Reducing GRP78 expression by pharmacological or environmental interventions may improve outcomes in these patients.

In older and obese diabetic patients①, hyperinsulinemia② causes cellular stress and induces the XBP-1-mediated overexpression of GRP78③ in adipose tissue, which promotes localization of GRP78 to the circulation④ and cell surface⑤, not only to endoplasmic reticulum (ER)⑥. GRP78 physically interacts with the SARS-CoV-2 spike protein, which may play a number of crucial roles in the viral lifecycle. The interaction of the spike protein with soluble and cell surface GRP78 may facilitate the SARS-CoV-2 binding to and infection of ACE2-expressing host cells. Soluble GRP78 bound to SARS-CoV-2 in the circulation could induce the systemic viral spread and infection. Binding of SARS-CoV-2 to cell surface GRP78 or related stimuli could activate the NF-κB or JNK/STAT3 transcriptional pathway and induce cellular inflammatory responses. SARS-CoV-2 potentially exploits ER-located GRP78 as a molecular chaperone to produce and assemble viral particles, which enables successful viral replication (brown virus indicates newly replicated SARS-CoV-2). The high expression of GRP78 in older and obese diabetic patients may contribute to the COVID-19 progression and severe outcomes