GP73 is a glucogenic hormone contributing to SARS-CoV-2-induced hyperglycemia

Nat Metab. 2022 Jan;4(1):29-43. doi: 10.1038/s42255-021-00508-2. Epub 2022 Jan 6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • COVID-19 / complications*
  • COVID-19 / virology*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Diet, High-Fat
  • Disease Models, Animal
  • Fasting
  • Gene Expression
  • Gluconeogenesis / drug effects
  • Gluconeogenesis / genetics
  • Glucose / metabolism*
  • Host-Pathogen Interactions
  • Humans
  • Hyperglycemia / blood
  • Hyperglycemia / etiology*
  • Hyperglycemia / metabolism*
  • Liver / metabolism
  • Liver / pathology
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / blood
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Organ Specificity / genetics
  • SARS-CoV-2*


  • Biomarkers
  • GOLM1 protein, human
  • Membrane Proteins
  • Cyclic AMP-Dependent Protein Kinases
  • Glucose