Individuals with certain comorbidities, such as obesity and diabetes, are at a higher risk of being severely infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causal agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic.
The etiopathogenetic mechanisms associated with unfavorable COVID-19 outcomes in diabetes patients are not yet clear; however, these mechanisms could trigger a greater inflammatory process that was already dysregulated by COVID-19.
Study: Diabetes and COVID-19: the potential role of mTOR. Image Credit: Design_Cells / Shutterstock.com
About the study
A new Diabetes Research and Clinical Practice research paper discusses the possible etiopathogenetic mechanisms associated with diabetes that could enhance the severity of COVID-19. In particular, the authors focus on the role of the mammalian Target of Rapamycin (mTOR) pathway.
Herein, researchers used PubMed and Scopus databases to obtain articles related to diabetes and the mTOR pathway in COVID-19. The authors believe that the mTOR pathway could be involved in this etiopathogenetic mechanism, as triggering and simulating this pathway would activate an inflammatory process that is already dysregulated by COVID-19. Thus, the inhibition of the mTOR pathway could potentially help control this dysregulated inflammatory process.
Inhibition of mTOR pathway and COVID-19
Several studies have shown that mTOR is a crucial pathway for cell cycle progression, translation, transcription, differentiation, apoptosis, and many other physiological processes. Many viruses such as the Middle Eastern Respiratory Syndrome Coronavirus (MERS–CoV), adenovirus, cytomegalovirus, and herpesvirus utilize the mTOR pathway for their replication.
Importantly, researchers have reported that the mTOR pathway regulates the life cycle of SARS-CoV-2 infection. Blocking of the mTOR pathway causes inhibition of protein synthesis, prevents the activation of lymphocytes, and suppresses the cytokine storm. One of the common inhibitors of the mTOR pathway is rapamycin, which disrupts the cell cycle of T-cells by restraining signal-mediated interleukin.
One of the reviewed studies revealed that usage of rapamycin could stop the synthesis of virus particles and prevent cytokine storms. Other studies have shown that the mTOR pathway in combination with adenosine monophosphate-activated protein kinase (AMPK) is a potential target for controlling oxidative stress, cell damage, and mitochondrial dysfunction. Importantly, it can also regulate the onset of hyper-inflammation which is a key dysregulation associated with SARS-CoV-2 infection.
Previous studies have shown that mTOR inhibitors could restrict the proliferation of memory B-cell and T-cell responses. To this end, several studies have supported the use of mTOR pathway inhibitory drugs for the treatment of COVID-19, owing to its ability to regulate T-cells proliferation, reduce viral replication, and the production of pro-inflammatory cytokines, as well as manage the inflammatory process.
COVID-19 and diabetes
Diabetes or hyperglycemia leads to a poor prognosis in patients with COVID-19. Researchers revealed that a high prevalence of this disease makes it the most frequent comorbidity.
Diabetes patients with COVID-19 have an almost three-fold greater risk of developing the acute disease with a higher mortality rate as compared to non-diabetic individuals who contracted the infection. Although several observatory studies have indicated the correlation between severe COVID-19 infection, which required hospitalization and respiratory support, and diabetes, the etiopathogenetic mechanisms underlying these outcomes are not clear.
In the majority of studies, the etiopathogenetic role of insulin in patients with COVID-19 and type 2 diabetes mellitus has not been addressed. However, these studies have revealed that upon activation of the immune system by SARS-CoV-2, lymphocytes overexpress insulin receptors, thereby altering insulin signaling. These studies thus indicated that immune cells could be associated with the dysregulation of immune response in patients with COVID-19 and diabetes.
Insulin is also capable of activating and stimulating the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway. This pathway regulates cells of the immune system by determining their metabolic activity and influencing their survival and differentiation, both of which are processes associated with viral infection.
Hyperglycemia could also induce the up-regulation of mTOR receptors, which favor the inflammatory stimulus by insulin. Previous studies have also demonstrated that insulin could be a favorable substrate for the development of a severe inflammatory process, which has been already dysregulated by COVID-19.
Anti-diabetic medications and COVID-19
Metformin, dipeptidyl-peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) agonists, and pioglitazone are common oral antidiabetic drugs that have good tolerability profiles. These agents reduce postprandial insulin levels and peripheral insulin resistance that ultimately lowers the blood sugar level of an individual. The underlying mechanism of action is driven by the inhibition of key genes of cellular metabolism that include the PI3K/Akt/mTOR pathway.
More studies are required to elucidate the etiopathogenetic mechanisms underlying COVID-19 in patients with diabetes. However, this review highlights that the mTOR pathway has a key role in triggering an inflammatory process that is already dysregulated, thus providing preliminary evidence to support the use of mTOR inhibitors in treating this subset of COVID-19 patients.
- Pinchera, B., Scotto, R., Buonomo, A. R., et al. (2022) Diabetes and COVID-19: the potential role of mTOR. Diabetes Research and Clinical Practice. doi:10.1016/j.diabres.2022.109813.