key: cord-0927742-da0doozo authors: Subbaram, Kannan; Ali, P. Shaik Syed; Ali, Sheeza title: Enhanced endocytosis elevated virulence and severity of SARS-CoV-2 due to hyperglycemia in type 2 diabetic patients date: 2022-01-14 journal: Gene Rep DOI: 10.1016/j.genrep.2022.101495 sha: 15b298d7cb53e2d67595c29b60df72d931fee8d1 doc_id: 927742 cord_uid: da0doozo Diabetes mellitus is a metabolic disease that causes hyperglycemia. In COVID-19 patients the severity of the disease depends on myriad factors but diabetes mellitus is the most important comorbidity. The current review was conducted to investigate the virulence of SARS-CoV-2 and disease severity of COVID-19 in type 2 diabetes mellitus patients and relevant treatment. The literature published in PubMed, Scopus, Web of Science, and Google Scholar was reviewed up to September 2021. The keywords including SARS-CoV-2, type 2 diabetes mellitus in COVID-19, hyperglycemia in COVID-19, opportunistic infections in type 2 diabetes mellitus and COVID-19 were used in different combinations. Hyperglycemic individuals over-express ACE-2 receptors in the lungs thus increasing the SARS-CoV-2 susceptibility and replication. Although dipeptidyl peptidase-4 plays an important role in glucose homeostasis, additionally it also stimulates the production of proinflammatory cytokines such as IL-6 and TNF-α creating a cytokine storm. Cytokine storm might be responsible for respiratory insufficiency in severe COVID-19 patients. Type 2 diabetes mellitus is associated with immunosuppression and the patients are prone to get many opportunistic infections. Type 2 diabetes mellitus patients with severe COVID-19 have lymphopenia. Moreover, in type 2 diabetes mellitus patients the neutrophils exhibit decreased chemotaxis, hydrogen peroxide production, and phagocytosis. Reduction in lymphocyte count and defective neutrophil capacity renders them with COVID-19 susceptible to opportunistic bacterial and fungal infections increasing the mortality rate. The opportunistic bacterial infections in COVID-19 patients were due to Staphylococcus aureus, Streptococcus pneumonia, and coagulase-negative Staphylococci, E. coli, Pseudomonas aeruginosa, and Klebsiella sp. In COVID-19 patients with type 2 diabetes mellitus, mucormycosis was found to be the most common fungal infection with a higher predilection to males. Hyperglycemia in COVID-19 patients with type 2 diabetes mellitus enhances the SARS-CoV-2 replication with an adverse outcome. A strong correlation exists between the poor prognosis of COVID-19 and type 2 diabetes mellitus. Proper glycemic control in COVID-19 patients with diabetes mellitus might lessen the severity of the disease. Coronaviruses are diverse, spherical and enveloped RNA viruses with 80 -120 nm in Type 2 diabetes mellitus (T2DM) is a metabolic disease with increased levels of blood glucose, and its persistence over a period of time leads to severe damage of eyes, blood vessels, heart, nerves and kidneys. The untreated, uncontrolled and poorly managed diabetic patients may have severe health consequences (3) . Due to the presence of high glucose levels in the body, the normal metabolic activities are affected or may occur in abnormal way, leading to severe damage to the tissues. In addition, hyperglycemia might contribute to reduced mitochondrial metabolism and ATP synthesis due to metabolic changes in β-cells (4). Hyperglycemic environment in diabetes patients leads to immune dysfunction specifically neutrophils such as reduced chemotaxis and phagocytosis. On the other hand, it also causes angiopathies, neuropathy J o u r n a l P r e -p r o o f and gangrenous cholecystitis affecting many organs and tissues (5) . When compared to normal individuals, T2DM patients have been reported with severe and chronic infections. COVID-19 patients with preexisting T2DM have a higher susceptibility to SARS-CoV-2 infection, bacterial and fungal opportunistic infections, severe COVID-19 disease with poor prognosis and high mortality (6, 7) This review is focused on COVID-19 patients with T2DM as a comorbid condition. We The aim of this review was to investigate the relationship between hyperglycemia and virulence of SARS-CoV-2, severity of COVID-19 disease in type 2 diabetes mellitus patients as well as the available treatment options. T2DM affects the glucose metabolism and results in hyperglycemia. Many studies have indicated that there is notably increased severity of COVID-19 in diabetes patients (8, 9) . Lack of adequate insulin hormone and presence of high blood glucose in the body may play a significant role in the mortality of COVID-19 patients. Diabetes induced immunosuppression play an inevitable role in the severity of COVID-19 disease. Many studies revealed that diabetic patients possess excess free glucose molecules that may indirectly enhance the susceptibility to SARS-CoV-2 and enhance the severity of COVID-19 (10, 11) . Recently reported variant of SARS-CoV-2, delta variant expressed strong affinity in diabetic patients. In India the delta variant has caused a huge mortality especially among uncontrolled diabetic patients (12) . We speculate that there may be a strong relationship exist between hyperglycemia in T2DM and emergence of variants of SARS-CoV-2 from different parts of the world. So, we suggest that further detailed researches need to be conducted on this aspect. The replication of SARS-CoV-2 is initiated by the viral attachment of spike proteins to host receptors. In a normal host with optimal levels of insulin secretion and blood glucose levels, the initiation of viral replication by attachment is affected. In hyperglycemic individuals, it has been noted that expression and glycosylation of ACE-2 receptors is enhanced that might increase the susceptibility to SARS-CoV-2 entry (Figure 1 ) (13) . There is a link between hyperglycemia and oncogenesis and tumor progression (14, 15) . Similarly, hyperglycemic state might increase the viral replication. Many studies revealed that the cells infected with the virus increases the glycolytic metabolism to secure the precursors for the virus production and assembly (16, 17) . A J o u r n a l P r e -p r o o f study hypothesized that the human cells infected by SARS-CoV-2 leads to an excess of glucose utilization to synthesize the precursors for viral assembly (18) . In T2DM patients the total and glycosylated ACE-2 receptor overexpression could favor the SARS-CoV-2 entry into host cells thus increasing the infectivity with SARS-CoV-2 in these patients (19) . High blood glucose increases the exposure of SARS-CoV-2 host receptors like ACE-2 and TMPRSS2 (Transmembrane Serine Protease 2) (19) . In these categories of patients, hyperglycemic Majority of asymptomatic COVID-19 patients with normal blood glucose levels exhibited mild symptoms of COVID-19 disease. RT-PCR positive patients for SARS-CoV-2 with normal blood sugar showed less severe symptoms or no symptoms at all. In COVID-19 with T2DM the acute pulmonary and severe exaggerated inflammation is very frequent and common (26, 27) . Many COVID-19 patients with high blood glucose levels have exhibited cardiac dysfunction, renal and hepatic malfunction, in addition to respiratory problems (28) (29) (30) . Mortality rate was observed to be very high in COVID-19 patients with high blood glucose levels. A retrospective study was conducted with subjects involving well controlled diabetes with COVID-19 and poorly controlled diabetes with COVID-19. The study demonstrated that in poorly controlled diabetes patients the acute respiratory distress syndrome (ARDS) was approximately 3% and death was 4.4%. Whereas, in the case of poorly controlled diabetes the ARDS was 6% and the mortality rate was 18.5% (31) . Apart from other factors, cytokine storm is another important factor that can cause respiratory insufficiency in COVID-19 patients. In COVID-19 patients with diabetes, dipeptidylpeptidase 4 (DPP4) is suggested to be responsible for cytokine storm (Figure 1) (32) . DPP4, an J o u r n a l P r e -p r o o f enzyme found throughout the body, rapidly inactivates glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), decreases the secretion of insulin. GLP-1 and GIP are incretins, which are gastrointestinal peptides released after meals and augment the secretion of insulin by a glucose-dependent mechanism (Figure 1 ). DPP4 other than glucose metabolism might have proinflammatory action. It stimulates the production of IL-6 and TNF-α in monocytes, as well as exert a possible modulating function in the immune system (33) . DPP4/CD26 is directly involved in various immune or inflammatory diseases. DPP4/CD26 is mainly present on type I and II alveolar cells, alveolar macrophages, vascular endothelium, and pleural mesothelium in the lungs of healthy subjects. In pulmonary diseases, such as asthma, chronic obstructive pulmonary disease, and lung fibrosis, there is a direct functional role of DPP4/CD26 (34) . It was observed that excess glucose molecules circulating in the blood will not allow the immune cells to act on SARS-CoV-2 in the process of eviction of viruses (10) . This may be the reason that the rapid replication of SARS-CoV-2 leads to increased severity of fatal COVID-19 symptoms in diabetic patients. Independent studies showed that nearly 7.2 % -12.7 % of the COVID-19 patients were diagnosed with bacterial coinfection. A myriad of factors were associated with bacterial coinfection in COVID-19 patients such as intensive care unit (ICU) hospitalization, severity of illness, ventilation treatment, glucocorticoids therapy and T2DM (35, 37) . Among them T2DM J o u r n a l P r e -p r o o f was found to be one of the predominant comorbidities (38, 39) . In COVID-19 patients, 85% of the patients showed lymphopenia (Figure 2 ) (10). A lower lymphocyte count and a higher neutrophil count was noted in COVID-19 patients with diabetes compared to COVID-19 patients without diabetes. A recent study by Guo et al (2020) showed that individuals with diabetes and COVID-19 had a lower lymphocyte count, higher absolute neutrophil count, and high levels of IL-6, ferritin, ESR, and CRP compared to patients with COVID-19 without diabetes. The reduced numbers of B/T-cells might increase the susceptibility to bacterial infections (40) . It has been shown previously that neutrophils in T2DM patients exhibited decreased phagocytosis, chemotaxis that resulted in poor bacterial killing. Additionally, diabetic monocytes demonstrated decreased chemotaxis to bacteria and reduced hydrogen peroxide production (41) . These factors in diabetic COVID-19 patients in addition to lymphopenia might have increased the susceptibility to bacterial coinfections. Although a myriad of factors contributes to the mortality and morbidity of COVID-19 patients, another factor that should be accounted for is opportunistic fungal infections. Opportunistic fungal infections are common among influenza patients with majority of the cases reported to be an invasive Aspergillosis due to Aspergillus fumigatus (42) . Similarly, several cases of opportunistic fungal infections in COVID-19 patients have been reported globally from various countries including USA, Western European countries, India and China (43) (44) (45) (46) . In severe cases of COVID-19 sustained lymphopenia has been demonstrated. Lymphopenia dents the adaptive immunity ability and thus compromises the immune system (47) (48) (49) . 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