Lowering Your Blood Insulin Levels Could Lower Risk of Getting COVID-19

In elderly and obese diabetic patients①, hyperinsulinemia② induces cellular stress and induces the XBP-1-mediated overexpression of GRP78③ in adipose tissue, promoting GRP78 localization to the circulatory system④ and cell surface⑤, not just to the endoplasmic reticulum (ER)⑥. GRP78 physically interacts with the SARS-CoV-2 spike protein, which may play a number of critical roles in the viral life cycle. The interaction of the spike protein with soluble and cell surface GRP78 may facilitate SARS-CoV-2 binding to and infection of host cells expressing ACE2. Soluble GRP78 bound to SARS-CoV-2 in the circulation could cause the systemic viral spread and infection. Binding of SARS-CoV-2 to cell surface GRP78 or related stimuli could activate the NF-KB or JNK/STAT3 transcription pathway and induce cellular inflammatory responses. SARS-CoV-2 may use ER-localized GRP78 as a molecular chaperone to produce and assemble viral particles, enabling successful viral replication (brown virus indicates newly replicated SARS-CoV-2). The high expression of GRP78 in elderly and obese diabetic patients may contribute to the COVID-19 progression and severe outcomes. Credit: The American Diabetes Association

Osaka University researchers discover that SARS-CoV-2 binds to a cell surface protein whose expression is promoted by high blood insulin levels in elderly, obese and diabetic individuals.

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 contracting COVID-19.

In a study published this month in Diabetes, researchers from Osaka University revealed that a protein called GRP78 helps the virus that causes COVID-19 to bind to and invade cells. GRP78 is a protein found in adipose tissue (ie, fat). Older, obese and diabetic people are all more vulnerable to COVID-19 and while the reasons for this are not fully understood, the Osaka University team is shedding some light on this issue.

“It was recently suggested that adipose tissue could be an important reservoir for SARS-CoV-2, the virus that causes COVID-19,” said lead author of the study Jihoon Shin. “We therefore wanted to investigate whether there is a link between the excess adipose tissue in elderly, 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 SARS-CoV-2’s interaction with human cells. The main method by which SARS-CoV-2 enters human cells is by binding a spike protein on the viral surface to a human cell surface protein called angiotensin-converting enzyme 2 (ACE2). Shin and colleagues found that the spike protein can also bind directly to GRP78, and that the presence of GRP78 increases binding to ACE2. To get an idea of ​​GRP78’s involvement in COVID-19 vulnerability, they examined how much GRP78 protein is present in tissues of elderly, obese and diabetic patients.

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

Aging, obesity and diabetes are known to be associated with elevated insulin levels in the blood. Therefore, the group wondered whether insulin was involved in the expression of GRP78. They found that exposing cells to insulin induced the expression of GRP78. Importantly, they found that treatment with commonly prescribed antidiabetic drugs that lower insulin levels successfully lowers the expression level of GRP78. They took it one step further and showed that exercise and calorie restriction in a mouse model also worked to lower GRP78 levels in adipose tissue.

“Our findings suggest that high blood insulin levels are an important risk factor that may predispose elderly, 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,” Shin says.

Given the global impact of the SARS-CoV-2 pandemic, the results of 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.

Reference: “Possible involvement of adipose tissue in patients of older age, obesity and diabetes with coronavirus SARS-CoV-2 infection (COVID-19) via GRP78 (BIP/HSPA5): significance of hyperinsulinemia management in COVID-19” by Jihoon Shin, Shinichiro Toyoda, Shigeki Nishitani, Atsunori Fukuhara, Shunbun Kita, Michio Otsuki and Iichiro Shimomura, October 6, 2021, Diabetes.
DOI: 10.2337 / db20-1094