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

Wan, L.; Yang, H.; Li, H.; Gong, J.; Deng, Y.; Ke, Y.; Yang, X.; Lin, H.; Zhang, Y.; Wang, C.; Li, D.; Wang, H.; Peng, Y.; Yan, Q.; huang, L.; Wang, X.; Gao, Q.; Lin, C.; Zheng, F.; Xu, L.; Liu, J.; Zhang, X.; Qin, C.; Sun, Z.; Wu, F.; Wei, C.; Zhong, H.

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.