GP73 is a glucogenic hormone regulating SARS-CoV-2-induced hyperglycemia

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces new-onset diabetes and severe metabolic complications of pre-existing diabetes. The pathogenic mechanism underlying this is incompletely understood. Here, we provided evidence linking circulating GP73 with the exaggerated gluconeogenesis triggered by SARS-CoV-2 infection. We found that SARS-CoV-2 infection or glucotoxic condition increased the cellular secretion of GP73. Secreted GP73 trafficked to the liver and kidney to stimulate gluconeogenesis through cAMP/PKA pathway. By using global phosphoproteomics, we found a drastic remodeling of PKA kinase hub exerted by GP73. Notably, COVID-19 patients showed pathologically elevated plasma GP73, and neutralization of the secreted GP73 inhibited enhanced PKA signaling and glucose production associated with SARS-CoV-2 infection. GP73 blockade also reduced gluconeogenesis and lowered hyperglycemia in type 2 (T2D) diabetic mice. Therefore, our findings provide novel insight into the roles of GP73 as a key glucogenic hormone and mechanistic clues underlying the development of SARS-CoV-induced glucose abnormalities.

2-Deoxy-d-glucose Inhibits Replication of Novel Coronavirus (SARS-CoV-2) with Adverse Effects on Host Cell Metabolism

“…25,26 The circulating levels of the protein are approximately 2x elevated in SARS-CoV-2infected patients relative to the reference population (p<0.0001) and its serum concentration correlates with the severity of COVID-19. 27 It exerts its effect primarily through upregulation of hepatic and renal gluconeogenesis with minimal effect on glycogenolysis. Increased expression of GP73 could be responsible for new onset increase in blood glucose levels associated with SARS-CoV-2 infection.…”

“…Increased expression of GP73 could be responsible for new onset increase in blood glucose levels associated with SARS-CoV-2 infection. 27 However, since evidence of raised liver enzymes is present in only 14-53% cases with COVID-19, 28 GP73 mediated gluconeogenesis can't explain the increased blood glucose levels associated with SARS-COV-2 infection with no hepatocyte injury.…”