Abstract
Severe cases of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with elevated blood glucose levels and metabolic complications. However, the molecular mechanisms for how SARS-CoV-2 infection alters glycometabolic control are incompletely understood. Here, we connect the circulating protein GP73 with enhanced hepatic gluconeogenesis during SARS-CoV-2 infection. We first demonstrate that GP73 secretion is induced in multiple tissues upon fasting and that GP73 stimulates hepatic gluconeogenesis through the cAMP/PKA signaling pathway. We further show that GP73 secretion is increased in cultured cells infected with SARS-CoV-2, after overexpression of SARS-CoV-2 nucleocapsid and spike proteins and in lungs and livers of mice infected with a mouse-adapted SARS-CoV-2 strain. GP73 blockade with an antibody inhibits excessive glucogenesis stimulated by SARS-CoV-2 in vitro and lowers elevated fasting blood glucose levels in infected mice. In patients with COVID-19, plasma GP73 levels are elevated and positively correlate with blood glucose levels. Our data suggest that GP73 is a glucogenic hormone that likely contributes to SARS-CoV-2-induced abnormalities in systemic glucose metabolism.
Highlights
Excessive HGP contributes to exaggerated fasting and postprandial hyperglycemia in patients with type 1 diabetes (T1D)
As intracellular GP73 overexpression led to the release of GP73 into the extracellular space (Extended Data Fig. 1a,b), we examined and compared GP73 expression in metabolically important organs isolated from ad libitum-fed and fasted mice to delineate the source of GP73 under fasting conditions
Secreted GP73 primarily targets the liver to promote gluconeogenesis via activation of PKA signaling in endocrine and autocrine manners
Summary
Excessive HGP contributes to exaggerated fasting and postprandial hyperglycemia in patients with type 1 diabetes (T1D). Preexisting diabetes substantially increases COVID-19 mortality and morbidity. An increase in new-onset hyperglycemia, diabetic ketoacidosis (DKA) and diabetes in patients with COVID-19 is commonly observed. Impaired insulin secretion due to β-cell infection could plausibly contribute to the metabolic dysregulation observed in patients with COVID-19 GP73 is a type II transmembrane Golgi protein located at the luminal surface of the Golgi apparatus, consisting of a short N-terminal cytoplasmic domain, a transmembrane domain and a large C-terminal domain[18]. The present study provides evidence that circulating GP73 promotes HGP in endocrine and autocrine manners. COVID-19 and GP73 is necessary for excessive glucogenesis stimulated by SARS-CoV-2 infection. Targeting GP73 might be a potential therapeutic strategy for patients presenting alterations in the levels of this hormone
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