image: 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. view more
Credit: The American Diabetes Association
Osaka, Japan - Keeping blood insulin levels within strict, healthy parameters is a daily goal for people with diabetes. But now, researchers from Japan have found that regulating blood insulin levels may even help lower the risk of getting COVID-19.
In a study published this month in Diabetes, researchers from Osaka University have revealed that a protein called GRP78 helps the virus that causes COVID-19 bind to and enter cells. GRP78 is a protein that is found in adipose tissue (i.e., fat). Older, obese, and diabetic people are all more vulnerable to COVID-19 and, while the reasons for this are still not completely clear, the team from Osaka University sheds some light on this issue.
“It was recently suggested that adipose tissue might be a major reservoir for SARS-CoV-2, the virus that causes COVID-19,” says lead author of the study Jihoon Shin. “Because of this, we wanted to investigate whether there is any link between the excess adipose tissue in older, obese, and diabetic patients and their vulnerability to COVID-19.”
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.
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The article, “Possible involvement of adipose tissue in patients with older age, obesity, and diabetes with coronavirus SARS-CoV-2 infection (COVID-19) via GRP78 (BIP/HSPA5): Significance of hyperinsulinemia management in COVID-19,” was published in Diabetes at DOI: https://doi.org/10.2337/db20-1094
About Osaka University
Osaka University was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world, being named Japan's most innovative university in 2015 (Reuters 2015 Top 100) and one of the most innovative institutions in the world in 2017 (Innovative Universities and the Nature Index Innovation 2017). Now, Osaka University is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.
Website: https://resou.osaka-u.ac.jp/en
Journal
Diabetes
Method of Research
Experimental study
Subject of Research
Cells
Article Title
Possible involvement of adipose tissue in patients with older age, obesity, and diabetes with coronavirus SARS-CoV-2 infection (COVID-19) via GRP78 (BIP/HSPA5): Significance of hyperinsulinemia management in COVID-19
Article Publication Date
6-Oct-2021