The Mechanistic Link Between SARS-CoV-2 Infection and Hyperglycemia in COVID-19: Insights from Hepatocyte Infection


Diabetes has emerged as a significant risk factor for severe COVID-19 cases, and numerous studies have associated hyperglycemia in COVID-19 patients with worse clinical outcomes and extended hospitalization periods.

Interestingly, hyperglycemia has been observed in patients without a prior history of diabetes, implying that SARS-CoV-2 may directly impact glucoregulatory pathways, leading to elevated blood glucose levels.

Exploring the Mechanistic Link between SARS-CoV-2 and Hyperglycemia

Several research groups have attempted to unravel the underlying mechanisms connecting viral infection and hyperglycemia in COVID-19.

Studies have demonstrated that SARS-CoV-2 can infect and damage beta cells in vitro, which are responsible for insulin production, but its clinical relevance remains debatable.

Moreover, COVID-19 has been linked to the onset of insulin resistance, further contributing to imbalanced blood glucose control.

Drawing Parallels with Other RNA Viruses

Other RNA viruses like hepatitis C and B have been shown to induce hepatic glucose production through the stimulation of gluconeogenesis in hepatocytes. This leads to the plausible hypothesis that SARS-CoV-2 might act similarly and impact glucose production in the liver.

Evidence of Liver Infection by SARS-CoV-2

Several studies using postmortem biopsies have demonstrated SARS-CoV-2 infection in hepatocytes, causing liver damage. A gluconeogenic protein called GP73 secreted under SARS-CoV-2 infection has also been identified as capable of stimulating gluconeogenesis in liver cells. However, questions still remain regarding whether SARS-CoV-2 directly stimulates glucose production in hepatocytes and the mechanism of infection in these cells.

The Present Study: Integrating Clinical and Experimental Approaches

The present study takes a comprehensive approach by combining a retrospective clinical study with ex vivo and in vitro experimental strategies. The main aim is to demonstrate that SARS-CoV-2 infects hepatocytes via ACE2 and GRP78 mediated cotransport, leading to an increase in hepatic glucose production in a PEPCK-dependent manner.

Clinical Implications

The study’s findings highlight the independent association of COVID-19 with hyperglycemia, emphasizing the direct viral action on hepatocytes as a potential cause. The retrospective clinical study design aimed to differentiate between COVID-19-induced hyperglycemia and that observed in COVID-19-negative patients admitted for other pathologies.

Linking Hyperglycemia to Liver Infection and Gluconeogenesis

The evidence of replicating infectious viruses in human hepatocytes supports the notion of liver infection by SARS-CoV-2. Additionally, infected hepatocytes were shown to increase glucose production, possibly due to the stimulation of PEPCK activity. This study adds to the growing body of evidence showing SARS-CoV-2 infection in hepatocytes and its potential role in COVID-19-induced hyperglycemia.

Differentiating Hepatic Infection in SARS-CoV-2 Variants

The study also explored the effects of different SARS-CoV-2 variants on hepatocytes. While all variants of concern were able to infect hepatocytes, the omicron variant demonstrated lower pathogenicity but still induced gluconeogenesis. This highlights the importance of understanding the potential impacts of different viral strains on hepatic glucose production.

The Role of ACE2 and GRP78 in Hepatocyte Infection

The study revealed that hepatocytes express the short ACE2 isoform, which may play a role in the entry of SARS-CoV-2 into these cells. Additionally, GRP78 was identified as an essential entry factor expressed at high levels in hepatocytes. The simultaneous blockade of both receptors partially reduced virus entry, suggesting potential cooperation between ACE2 and GRP78 in viral internalization.


This study provides valuable insights into the mechanistic link between SARS-CoV-2 infection and hyperglycemia in COVID-19. The evidence of direct viral action on hepatocytes leading to increased hepatic glucose production sheds light on the need for better glycemic control in COVID-19 patients to improve clinical outcomes.

Understanding the role of ACE2, GRP78, and PEPCK in this process may pave the way for targeted therapeutic approaches to mitigate hyperglycemia-associated complications in COVID-19 patients. Further research is warranted to explore the implications of different SARS-CoV-2 variants and identify additional viral entry receptors in hepatocytes.

in deep…

Type of Diabetes
It is currently unclear whether the new-onset diabetes associated with COVID-19 is type 1, type 2, or a complex subtype of diabetes. Although in T1D insulin deficiency is usually the result of an autoimmune process, in SARS-CoV-2 infection it could be due to destruction of the β-cells. Unfortunately, studies of islet cell antibodies in people with new-onset diabetes have been limited to a few case reports (19,20). Multiple studies have reported a high number of incidents of DKA in people with and without COVID-19, suggesting a direct effect of SARS-CoV-2 on pancreatic β-cells. One study of hospitalized patients with SARS-CoV-1 infection showed that immunostaining for angiotensin-converting enzyme 2 (ACE2) protein was strong in pancreatic islets but weak in exocrine tissues (21). However, a recent study from India compared new-onset diabetes in hospitalized patients prior to COVID-19 with new-onset diabetes during COVID-19 and found worse glycemic parameters in new-onset diabetes during COVID-19 and diabetes but no difference in symptoms, phenotype, or C-peptide levels (22).

Potential Mechanisms for New-Onset Diabetes
The precise mechanisms behind the development of new-onset diagnosis in people with COVID-19 are not known, but it is likely that a number of complex, interrelated etiologies are responsible, including impairments in both glucose disposal and insulin secretion, stress hyperglycemia, preadmission diabetes, and steroid-induced diabetes (Fig. 1). One recent article reported an increase in the number of children admitted to pediatric intensive care unit with new-onset T1D with severe DKA and a smaller increase in incidence of new-onset T1D (23). Overall, 7/20 (35%) of the children diagnosed in 2020 were tested for SAR-CoV-2, with all being negative. The authors suggested that the increase in incidence and severity were due to altered presentation during the pandemic rather than direct effects of COVID-19. Current data also suggest a bidirectional relationship between T2D and COVID-19 (24), but whether there is a bidirectional relationship between hyperglycemia and COVID-19 is not known (Fig. 2). The following sections give more detailed discussions of some of the proposed mechanisms for new-onset diabetes associated with COVID-19.

Figure 1 – Potential mechanisms for development of new-onset diabetes in people with COVID-19.

Figure 2 – Bidirectional relationship between T2D, hyperglycemia, and COVID-19. CVD, cardiovascular disease; CKD, chronic kidney disease; HHS, hyperosmolar hyperglycemic syndrome.

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