Possible Involvement of Adipose Tissue in Patients With Older Age, Obesity, and Diabetes With SARS-CoV-2 Infection (COVID-19) via GRP78 (BIP/HSPA5): Significance of Hyperinsulinemia Management in COVID-19.
Adipose Tissue
/ metabolism
Adrenergic beta-3 Receptor Agonists
/ pharmacology
Aged
Aging
Angiotensin-Converting Enzyme 2
/ metabolism
Animals
COVID-19
/ complications
Cell Line
Diabetes Mellitus
Endoplasmic Reticulum Chaperone BiP
/ genetics
Humans
Hyperinsulinism
/ complications
Hypoglycemic Agents
/ pharmacology
Metformin
/ therapeutic use
Mice
Obesity
/ complications
SARS-CoV-2
Sodium-Glucose Transporter 2 Inhibitors
/ pharmacology
Spike Glycoprotein, Coronavirus
/ metabolism
Up-Regulation
Virus Internalization
Journal
Diabetes
ISSN: 1939-327X
Titre abrégé: Diabetes
Pays: United States
ID NLM: 0372763
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
31
10
2020
accepted:
29
09
2021
pubmed:
8
10
2021
medline:
17
12
2021
entrez:
7
10
2021
Statut:
ppublish
Résumé
Aging, obesity, and diabetes are major risk factors for the severe progression and outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 2019 [COVID-19]), but the underlying mechanism is not yet fully understood. In this study, we 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 with older age, obesity, and diabetes. The overexpression of GRP78 was attributed to hyperinsulinemia in adipocytes, which was in part mediated by the stress-responsive transcription factor XBP-1s. 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. Environmental interventions, including exercise, calorie restriction, fasting, or cold exposure, reduced the gene expression of GRP78 in adipose tissue. 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 patients with older age, obesity, and diabetes. The management of hyperinsulinemia and the related GRP78 expression could be a therapeutic or preventative target.
Identifiants
pubmed: 34615619
pii: db20-1094
doi: 10.2337/db20-1094
pmc: PMC8660985
doi:
Substances chimiques
Adrenergic beta-3 Receptor Agonists
0
Endoplasmic Reticulum Chaperone BiP
0
HSPA5 protein, human
0
Hypoglycemic Agents
0
Sodium-Glucose Transporter 2 Inhibitors
0
Spike Glycoprotein, Coronavirus
0
spike protein, SARS-CoV-2
0
Metformin
9100L32L2N
Angiotensin-Converting Enzyme 2
EC 3.4.17.23
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
2745-2755Informations de copyright
© 2021 by the American Diabetes Association.
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