SARS-CoV-2 Infection Induces Increase Of GP73 That Causes Dysglycaemia


A new study led by researchers from the Beijing Institute of Biotechnology involving more than 8 other research institutions and  hospitals in China has found that SARS-CoV-2 infection induces the increase of the circulating protein GP73 that causes dysglycaemia, more specifically the GP73 proteins act as a kind of glucogenic hormone contributing to SARS-CoV-2-induced hyperglycemia.

The study findings were published in the peer reviewed journal: Nature Metabolism.

Under physiological conditions, blood glucose levels are maintained within a narrow range to prevent hypoglycemia during fasting and excessive hyperglycemia following intake of a high-carbohydrate meal1. Glucose homeostasis is achieved primarily via hormonal modulation of glucose production by the liver2 and glucose uptake by skeletal muscle, heart muscle and adipose tissue3,4.

Hepatic glucose production (HGP) involves a combination of glycogen breakdown (glycogenolysis) and de novo synthesis of glucose from noncarbohydrate precursors (gluconeogenesis)2. Gluconeogenesis is the main contributor to hepatic and renal glucose production during prolonged fasting states5.

The rate of gluconeogenic flux is controlled by the activities of key unidirectional enzymes, such as pyruvate carboxylase (PCX), phosphoenolpyruvate carboxykinase 1 (PCK1), fructose 1,6-bisphosphatase (FBP1) and glucose-6-phosphatase (G6Pase)6. The genes encoding these proteins are strongly controlled at the transcriptional level by key hormones, including insulin, glucagon and glucocorticoids7.

Excessive HGP not only contributes to exaggerated fasting and postprandial hyperglycemia in patients with type 1 diabetes (T1D) and type 2 diabetes (T2D) but also contributes to stress-, infection- and inflammation-associated hyperglycemia8,9.

Since January 2020, the world has been facing an unprecedented outbreak of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2. Recent clinical data have suggested a close interaction between COVID-19 and diabetes10,11,12,13,14. 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. Although impaired insulin secretion due to β-cell infection could plausibly contribute to the metabolic dysregulation observed in patients with COVID-19 (refs. 15,16,17), the pathogenic mechanisms underlying new-onset T2D are largely unknown.

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 domain18. GP73 cycles out of the cis-Golgi to endosomes for cleavage by the convertase furin, resulting in its release into the extracellular space19,20.

Circulating GP73 is implicated in the regulation of cell-to-cell communication triggered by the unfolded protein response21.

The present study provides evidence that circulating GP73 promotes HGP in endocrine and autocrine manners. Notably, plasma GP73 levels are elevated in patients with COVID-19 and GP73 is necessary for excessive glucogenesis stimulated by SARS-CoV-2 infection.

Therefore, targeting GP73 might be a potential therapeutic strategy for patients presenting alterations in the levels of this hormone.

. . . . .

Epidemiological and experimental data indicate that SARS-CoV-2 infection is associated with new-onset diabetes28,29. The mechanisms underlying this phenomenon are likely complex and may include the promotion of inflammation, structural lung damage and systemic effects30.

The present study reported that SARS-CoV-2 infection was associated with insulin resistance via pathways involved in endogenous glucose production31. We demonstrated that enhanced gluconeogenic metabolism following SARS-CoV-2 infection was primarily dependent on GP73.

In patients with COVID-19, as opposed to significantly elevated GP73 levels in patients with severe disease, serum GP73 levels in patients with mild disease were comparable to those observed in healthy controls, suggesting the presence of a threshold of disease severity or chronicity required for GP73 upregulation.

Although the SARS-CoV-2 N and S proteins stimulated GP73 secretion, our data raise the question of whether GP73 expression is limited to SARS-CoV-2 replication.

In fact, the levels of GP73 remained elevated after recovery. It has been observed that hyperglycemia persists for 3 years after recovery from SARS and can be detected for at least 2 months in patients recovered from COVID-19 (refs. 13,32).

A previous study showed that GP73 production is activated and correlated with interferon-β activation during RNA viral infection through MAVS33. Potential mechanisms for the regulation of GP73 expression demonstrated the involvement of cytokines, liver damage and mTOR signaling34,35,36.

Therefore, GP73 expression may be controlled in SARS-CoV-2-dependent and SARS-CoV-2-independent manners. It should be noted that HFD and HBV/HCV infection also induce circulating GP73 levels37,38. As a Golgi-resident protein exhibiting glucoregulatory actions, the potential contribution of GP73 to glucose abnormalities in the context of infection with other viruses, or in metabolic diseases, including diabetes, warrants further investigation.

Apart from the role of GP73 in promoting cell proliferation, tumor development and metastasis, GP73 also represses the host innate immune response to promote RNA virus replication33,39. Therefore, long-term follow-up of infected patients is warranted.

Due to the urgent circumstance of the COVID-19 pandemic, we were unable to retrieve more clinical data including information on body mass index, steatohepatitis and fibrosis status from the current patient cohort. Although all patients were HBV, HCV and HIV negative, the possibility that NASH might have influenced GP73 release cannot be fully excluded.


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