Comparative study of CNR1 and CNR2 cannabinoid receptors expression levels in COVID-19 patients with and without diabetes mellitus: Recommendations for future research targets.

BACKGROUND AND AIMS: The COVID-19 pandemic has prompted researchers to look for effective therapeutic targets. The effect of endocannabinoid system against infectious diseases is investigated for several years. In this study, we evaluated the expression level of CNR1 and CNR2 genes in patients with COVID-19 with and without diabetes to provide new insights regarding these receptors and their potential effect in COVID-19 disease. METHODS: In this study, peripheral blood monocytes cells (PBMCs) were isolated from eight different groups including COVID-19 patients, diabetic patients, and healthy individuals. RNA were extracted to evaluate the expression level of CNR1 and CNR2 genes using real-time PCR. The correlation between the expression levels of these genes in different groups were assessed. RESULTS: A total of 80 samples were divided into 8 groups, with each group consisting of ten samples. When comparing severe and moderate COVID-19 groups to healthy control group, the expression levels of the CNR1 and CNR2 genes were significantly higher in the severe and moderate COVID-19 groups. There were no significant differences between the mild COVID-19 group and the healthy control group. It was found that the expression levels of these genes in patients with diabetes who were infected with SARS-COV-2 did not differ across COVID-19 groups with varying severity, but they were significantly higher when compared to healthy controls. CONCLUSION: Our study suggests the possible role of endocannabinoid system during SARS-COV-2 pathogenicity as the expression of CNR1 and CNR2 were elevated during the disease.

Severe COVID-19 is associated with hyperactivation of the alternative complement pathway.

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) is characterized by impaired type I interferon activity and a state of hyperinflammation leading to acute respiratory distress syndrome. The complement system has recently emerged as a key player in triggering and maintaining the inflammatory state, but the role of this molecular cascade in severe COVID-19 is still poorly characterized. OBJECTIVE: We aimed at assessing the contribution of complement pathways at both the protein and transcriptomic levels. METHODS: To this end, we systematically assessed the RNA levels of 28 complement genes in the circulating whole blood of patients with COVID-19 and healthy controls, including genes of the alternative pathway, for which data remain scarce. RESULTS: We found differential expression of genes involved in the complement system, yet with various expression patterns: whereas patients displaying moderate disease had elevated expression of classical pathway genes, severe disease was associated with increased lectin and alternative pathway activation, which correlated with inflammation and coagulopathy markers. Additionally, properdin, a pivotal positive regulator of the alternative pathway, showed high RNA expression but was found at low protein concentrations in patients with a severe and critical disease, suggesting its deposition at the sites of complement activation. Notably, low properdin levels were significantly associated with the use of mechanical ventilation (area under the curve = 0.82; P = .002). CONCLUSION: This study sheds light on the role of the alternative pathway in severe COVID-19 and provides additional rationale for the testing of drugs inhibiting the alternative pathway of the complement system.

Perspectives and potential approaches for targeting neuropilin 1 in SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel type b coronavirus responsible for the COVID-19 pandemic. With over 224 million confirmed infections with this virus and more than 4.6 million people dead because of it, it is critically important to define the immunological processes occurring in the human response to this virus and pathogenetic mechanisms of its deadly manifestation. This perspective focuses on the contribution of the recently discovered interaction of SARS-CoV-2 Spike protein with neuropilin 1 (NRP1) receptor, NRP1 as a virus entry receptor for SARS-CoV-2, its role in different physiologic and pathologic conditions, and the potential to target the Spike-NRP1 interaction to combat virus infectivity and severe disease manifestations.

Mortality and Clinical Outcomes among Patients with COVID-19 and Diabetes.

Background Diabetes mellitus (DM) is a decisive risk factor for severe illness in coronavirus disease 2019 (COVID-19). India is home to a large number of people with DM, and many of them were infected with COVID-19. It is critical to understand the impact of DM on mortality and other clinical outcomes of COVID-19 infection from this region. Aims The primary objective of our study was to analyze the mortality rate in people with DM infected with COVID-19. The secondary objectives were to assess the effect of various comorbidities on mortality and study the impact of DM on other clinical outcomes. Methods This is a retrospective study of COVID-19 infected patients admitted to a tertiary care hospital in north India in the early phase of the pandemic. Results Of the 1211 cases admitted, 19 were excluded because of incomplete data, and 1192 cases were finally considered for analysis. DM constituted 26.8% of total patients. The overall mortality rate was 6.1%, and the rate was 10.7% in the presence of diabetes (p < 0.01, OR 2.55). In univariate analysis, increased age, chronic kidney disease (CKD), coronary artery disease (CAD), stroke, and cancer were associated with mortality. On multiple logistic regression, the independent predictors of mortality were CAD, CKD, and cancer. Breathlessness and low SpO2 at presentation, extensive involvement in CXR, and elevated ANC/ALC ratio were also significantly associated with mortality. Conclusions The presence of comorbidities such as DM, hypertension, CAD, CKD, and cancer strongly predict the risk of mortality in COVID-19 infection. Early triaging and aggressive therapy of patients with these comorbidities can optimize clinical outcomes.

Pancreatic ß-cell fate in subjects with COVID-19.

Two recent reports denoted the potential of SARS-CoV-2 to directly infect ß-cells and the possible fate of ß-cells under COVID-19. The fight against SARS-CoV-2 will continue to develop more effective therapeutic strategies for diabetes.

Clinical outcomes in patients infected with different SARS-CoV-2 variants at one hospital during three phases of the COVID-19 epidemic in Marseille, France.

OBJECTIVES: To compare the demographics, clinical characteristics and severity of patients infected with nine different SARS-CoV-2 variants, during three phases of the COVID-19 epidemic in Marseille. METHODS: A single centre retrospective cohort study was conducted in 1760 patients infected with SARS-CoV-2 of Nextstrain clades 20A, 20B, and 20C (first phase, February-May 2020), Pangolin lineages B.1.177 (we named Marseille-2) and B.1.160 (Marseille-4) variants (second phase, June-December 2020), and B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma) and A.27 (Marseille-501) variants (third phase, January 2021-today). Outcomes were the occurrence of clinical failures, including hospitalisation, transfer to the intensive-care unit, and death. RESULTS: During each phase, no major differences were observed with regards to age and gender distribution, the prevalence of chronic diseases, and clinical symptoms between variants circulating in a given phase. The B.1.177 and B.1.160 variants were associated with more severe outcomes. Infections occurring during the second phase were associated with a higher rate of death as compared to infections during the first and third phases. Patients in the second phase were more likely to be hospitalised than those in the third phase. Patients infected during the third phase were more frequently obese than others. CONCLUSION: A large cohort study is recommended to evaluate the transmissibility and to better characterise the clinical severity of emerging variants.

Diabetes Mellitus and COVID-19: Review Article.

BACKGROUND AND AIMS: We aim to cover most of the current evidence on the mutual effect of diabetes & COVID-19 infection on each other and the management of the COVID-19 patients with diabetes. METHODS: We utilized databases to review the current evidence related to diabetes mellitus and COVID-19. RESULTS: We discussed the most recent evidence of diabetes milieus and COVID-19 regarding risk factors, management, complications, and telemedicine. CONCLUSION: Diabetes mellitus is associated with a significant risk of complications, extended hospital stays, and mortality in COVID-19 infected patients.

Therapeutic interventions of remdesivir in diabetic and nondiabetic COVID-19 patients: A prospective observational study conducted on Pakistani population.

We aimed to investigate the interventions of remdesivir in both diabetic and nondiabetic individuals who were suffering from a severe infection of novel coronavirus disease (COVID-19). In this study, we aimed to explore the relationship between therapeutic effectiveness of remdesivir and complications of diabetes mellitus by observing the recovery period among diabetic and nondiabetic patients associated with COVID-19 infection. A total of 850 COVID-19 patients were recruited for this study, out of which 48% were diabetic and 52% were nondiabetics. The results of this study indicated that nondiabetic individuals administered with remdesivir recovered from COVID-19 within 10 days showing a 95% confidence interval (p < 0.01), while the diabetic individuals recovered in 15 days. Nondiabetic patients administered with remdesivir exhibited higher chances of clinical improvement at 15th day than those who were associated with diabetes. Remdesivir administration improved the levels of various biochemical parameters, such as C-reactive protein, lactate dehydrogenase, d-Dimer, and ferritin both in diabetic and nondiabetic patients. However, a significant improvement (p < 0.01) was seen in the level of biochemical parameters among nondiabetic patients as compared to that of diabetic patients administered with remdesivir treatment. In the end, it was concluded that remdesivir could be considered as a possible therapeutic agent in the treatment of COVID-19 both in diabetic and nondiabetic situations. However, diabetic patients showed a delayed recovery as compared with that of nondiabetic patients, in which the recovery rate was high.

Decreased inhibition of exosomal miRNAs on SARS-CoV-2 replication underlies poor outcomes in elderly people and diabetic patients.

Elderly people and patients with comorbidities are at higher risk of COVID-19 infection, resulting in severe complications and high mortality. However, the underlying mechanisms are unclear. In this study, we investigate whether miRNAs in serum exosomes can exert antiviral functions and affect the response to COVID-19 in the elderly and people with diabetes. First, we identified four miRNAs (miR-7-5p, miR-24-3p, miR-145-5p and miR-223-3p) through high-throughput sequencing and quantitative real-time PCR analysis, that are remarkably decreased in the elderly and diabetic groups. We further demonstrated that these miRNAs, either in the exosome or in the free form, can directly inhibit S protein expression and SARS-CoV-2 replication. Serum exosomes from young people can inhibit SARS-CoV-2 replication and S protein expression, while the inhibitory effect is markedly decreased in the elderly and diabetic patients. Moreover, three out of the four circulating miRNAs are significantly increased in the serum of healthy volunteers after 8-weeks' continuous physical exercise. Serum exosomes isolated from these volunteers also showed stronger inhibitory effects on S protein expression and SARS-CoV-2 replication. Our study demonstrates for the first time that circulating exosomal miRNAs can directly inhibit SARS-CoV-2 replication and may provide a possible explanation for the difference in response to COVID-19 between young people and the elderly or people with comorbidities.

Top 100 cited articles on diabetes mellitus and Covid-19: A bibliometric analysis.

AIMS: There is a lack of bibliometric analytical studies on Diabetes Mellitus in Covid-19. As diabetes mellitus is a common co-morbidity associated with poor outcomes in Covid-19, we undertook a bibliometric analysis of the top 100 publications relating to this subject. METHODS: The top 100 cited papers were searched on Pubmed. Information about authors, month and year of publication, name of the journal, country of the affiliating institute of the first author, affiliation, total citations, citation density, type of study, type of paper, nature of the study, collaborations, number of affiliations and erratum details were collected. RESULTS: The top 100 papers were published in 57 journals and were cited 53,374 times. Though most of the top 100 papers were written by first authors affiliated to institutes in the United States, the publication from China were the most influential. Two institutions from the United States had the highest number of affiliations of the first author. The Lancet was the most productive journal with the highest number of total citations (24,221). CONCLUSIONS: This study gives valuable information to academicians and researchers regarding trends in the publication of the most influential articles on diabetes mellitus and Covid-19 infection.

Diabetes, COVID 19 and mucormycosis: Clinical spectrum and outcome in a tertiary care medical center in Western India.

AIMS: Diabetes Mellitus predisposes patients to invasive fungal infections. There has been a recent surge of Mucormycosis with COVID 19 infection particularly in patients with diabetes. This study aims to study the clinical spectrum of CAM (COVID -associated Mucormycosis) with diabetes and subsequent outcomes. MATERIAL AND METHODS: This was a descriptive study conducted at a single COVID Care Centre in India in patients with COVID Associated Mucormycosis from April 12, 2021 to May 31, 2021. RESULTS: Among 953 hospitalized patients with COVID 19 infection, 32 patients had CAM with an incidence of 3.36%. In patients with CAM, 87.5% had Diabetes Mellitus as the most common co-morbidity. The majority of the patients had poor glycemic control with a mean HbA1c of 9.06%. Out of the total study population, 93% had prior exposure to high dose corticosteroids. During the study period, 12.5% patients of CAM did not survive. CONCLUSION: Mucormycosis is an angioinvasive fungal infection with high mortality. The disease has surged in COVID 19 pandemic due to uncontrolled diabetes and improper corticosteroid use.

Could Exogenous Insulin Ameliorate the Metabolic Dysfunction Induced by Glucocorticoids and COVID-19?

The finding that high-dose dexamethasone improves survival in those requiring critical care due to COVID-19 will mean much greater usage of glucocorticoids in the subsequent waves of coronavirus infection. Furthermore, the consistent finding of adverse outcomes from COVID-19 in individuals with obesity, hypertension and diabetes has focussed attention on the metabolic dysfunction that may arise with critical illness. The SARS coronavirus itself may promote relative insulin deficiency, ketogenesis and hyperglycaemia in susceptible individuals. In conjunction with prolonged critical care, these components will promote a catabolic state. Insulin infusion is the mainstay of therapy for treatment of hyperglycaemia in acute illness but what is the effect of insulin on the admixture of glucocorticoids and COVID-19? This article reviews the evidence for the effect of insulin on clinical outcomes and intermediary metabolism in critical illness.

COVID-19 and Diabetes: Understanding the Interrelationship and Risks for a Severe Course.

The relationship between COVID-19 and diabetes mellitus is complicated and bidirectional. On the one hand, diabetes mellitus is considered one of the most important risk factors for a severe course of COVID-19. Several factors that are often present in diabetes mellitus are likely to contribute to this risk, such as older age, a proinflammatory and hypercoagulable state, hyperglycemia and underlying comorbidities (hypertension, cardiovascular disease, chronic kidney disease and obesity). On the other hand, a severe COVID-19 infection, and its treatment with steroids, can have a specific negative impact on diabetes itself, leading to worsening of hyperglycemia through increased insulin resistance and reduced ß-cell secretory function. Worsening hyperglycemia can, in turn, adversely affect the course of COVID-19. Although more knowledge gradually surfaces as the pandemic progresses, challenges in understanding the interrelationship between COVID-19 and diabetes remain.

Correlation of Hemoglobin A1C and Outcomes in Patients Hospitalized With COVID-19.

OBJECTIVE: Diabetes is a known risk factor for severe coronavirus disease 2019 (COVID-19). We conducted this study to determine if there is a correlation between hemoglobin A1C (HbA1C) level and poor outcomes in hospitalized patients with diabetes and COVID-19. METHODS: This is a retrospective, single-center, observational study of patients with diabetes (defined by an HbA1C level of ≥6.5% or known medical history of diabetes) who had a confirmed case of COVID-19 and required hospitalization. All patients were admitted to our institution between March 3, 2020, and May 5, 2020. HbA1C results for each patient were divided into quartiles: 5.1% to 6.7% (32-50 mmol/mol), 6.8% to 7.5% (51-58 mmol/mol), 7.6% to 8.9% (60-74 mmol/mol), and >9% (>75 mmol/mol). The primary outcome was in-hospital mortality. Secondary outcomes included admission to an intensive care unit, invasive mechanical ventilation, acute kidney injury, acute thrombosis, and length of hospital stay. RESULTS: A total of 506 patients were included. The number of deaths within quartiles 1 through 4 were 30 (25%), 37 (27%), 34 (27%), and 24 (19%), respectively. There was no statistical difference in the primary or secondary outcomes among the quartiles, except that acute kidney injury was less frequent in quartile 4. CONCLUSION: There was no significant association between HbA1C level and adverse clinical outcomes in patients with diabetes who are hospitalized with COVID-19. HbA1C levels should not be used for risk stratification in these patients.

Wharton's Jelly Mesenchymal Stem Cell-Derived Extracellular Vesicles Reduce SARS-CoV2-Induced Inflammatory Cytokines Under High Glucose and Uremic Toxin Conditions.

Cytokine storm is recognized as one of the factors contributing to organ failures and mortality in patients with COVID-19. Due to chronic inflammation, COVID-19 patients with diabetes mellitus (DM) or renal disease (RD) have more severe symptoms and higher mortality. However, the factors that contribute to severe outcomes of COVID-19 patients with DM and RD have received little attention. In an effort to investigate potential treatments for COVID-19, recent research has focused on the immunomodulation functions of mesenchymal stem cells (MSCs). In this study, the correlation between DM and RD and the severity of COVID-19 was examined by a combined approach with a meta-analysis and experimental research. The results of a systematic review and meta-analysis suggested that the odd of mortality in patients with both DM and RD was increased in comparison to those with a single comorbidity. In addition, in the experimental research, the data showed that high glucose and uremic toxins contributed to the induction of cytokine storm in human lung adenocarcinoma epithelial cells (Calu-3 cells) in response to SARS-CoV Peptide Pools. Of note, the incorporation of Wharton's jelly MSC-derived extracellular vesicles (WJ-EVs) into SARS-CoV peptide-induced Calu-3 resulted in a significant decrease in nuclear NF-κB p65 and the downregulation of the cytokine storm under high concentrations of glucose and uremic toxins. This clearly suggests the potential for WJ-EVs to reduce cytokine storm reactions in patients with both chronic inflammation diseases and viral infection.

Predictors of COVID-19 related death in diabetes patients: A case-control study in Iran.

BACKGROUND: Identifying the predictors of COVID-19 related death in diabetes patients can assist physicians for detecting risk factors related to the worse outcome in these patients. In this study we investigated the predictors of the death in patients with diabetes compared with non-diabetic COVID-19 patients. METHODS: In the present case-control study, the case group were diabetic patients with COVID-19 and the control group included Non-diabetic COVID-19 patients. The data source regarding the demographic characteristics, clinical symptoms, laboratory, and radiological findings on admission as well as the complications, treatment, and outcomes during hospitalization were gathered from their medical record through two trained nurses. Adjusted and unadjusted odds ratios (OR) estimate were calculated using the simple and multiple logistic regression through backward model. RESULTS: The mean (SD) age of the case group was higher than that of the control group; [65.24 (12.40) years vs. 59.35 (17.34) years, respectively (P < 0.001)]. Results of the adjusted logistic regression model showed that, advanced age (+60 year) (OR = 5.13, P = 0.006), addiction (OR = 5.26, P = 0.033), high level of Blood urea nitrogen (OR = 5.85, P < 0.001), and high level of Alkaline Phosphatase (OR = 3.38, P = 0.012) in diabetic patients were significantly associated with increase the odds of death in COVID-19 patients. CONCLUSION: We found that in COVID-19 patients with diabetes; advanced age, addiction, high level of BUN and Alp and in non-diabetic COVID-19 patients advanced age, dyspnea, high level of BUN and SGOT were associated with increase risk of death in these patients.

Prevalence and impact of comorbidities on disease prognosis among patients with COVID-19 in Bangladesh: A nationwide study amid the second wave.

BACKGROUND: Socio-demographics and comorbidities are involved in determining the severity and fatality in patients with COVID-19 suggested by studies in various countries, but study in Bangladesh is insufficient. AIMS: We designed the study to evaluate the association of sociodemographic and comorbidities with the prognosis of adverse health outcomes in patients with COVID-19 in Bangladesh. METHODS: A multivariate retrospective cohort study was conducted on data from 966 RT-PCR positive patients from eight divisions during December 13, 2020, to February 13, 2021. Variables included sociodemographic, comorbidities, symptoms, Charlson comorbidity index (CCI) and access to health facilities. Major outcome was fatality. Secondary outcomes included hospitalization, duration of hospital stay, requirement of mechanical ventilation and severity. RESULTS: Male (65.8%, 636 of 966) was predominant and mean age was 39.8 ± 12.6 years. Fever (79%), dry cough (55%), and loss of test/smell (51%) were frequent and 74% patients had >3 symptoms. Fatality was recorded in 10.5% patients. Comorbidities were found in 44% patients. Hypertension (21.5%) diabetes (14.6%), and cardiovascular diseases (11.3%) were most prevalent. Age >60 years (OR: 4.83, 95% CI: 2.45-6.49), and CCI >3 (OR: 5.48, 95% CI: 3.95-7.24) were predictors of hospitalizations. CCI >4 (aOR: 3.41, 95% CI: 2.57-6.09) was predictor of severity. Age >60 years (aOR: 3.77, 95% CI: 1.07-6.34), >3 symptoms (aOR: 2.14, 95% CI: 0.97-4.91) and CCI >3 vs. CCI <3 (aOR: 5.23, 95% CI: 3.77-8.09) were independently associated with fatality. CONCLUSIONS: Increased age, >3 symptoms, increasing comorbidities, higher CCI were associated with increased hospitalization, severity and fatality in patients with COVID-19.

Effectiveness of diabetes education including insulin injection technique and dose adjustment through telemedicine in hospitalized patients with COVID-19.

AIMS: To study the feasibility of diabetes education through telemedicine in patients with diabetes mellitus (DM) hospitalized for coronavirus disease 2019 (COVID-19) management. METHODS: This was a prospective study of 100 patients with DM who were admitted in a COVID isolation ward for management of COVID-19. Patients managed with multiple subcutaneous insulin injections were eligible. During teleconsultation, diabetes education including insulin injection technique was given by a diabetes educator via a phone call (audio and video) during hospitalization. They were also re-assessed after 2 weeks of discharge from the hospital via teleconsultation or in-person. RESULTS: Out of 100 patients, 72.0% had prior history of diabetes while 28.0% were newly diagnosed. The median age of our cohort was 56 years and median duration of diabetes was 7.0 years. Telemedicine as a mode of consult for diabetes education was accepted by 96.0% of patients during hospitalization. At 2 weeks' follow-up, 77.0% patients were following insulin instructions correctly and were satisfied with this mode of consultation. CONCLUSION: Diabetes education using telemedicine as a technology is feasible, acceptable, and effective in the management of most patients with DM. Telemedicine appears to be an effective way to replace routine visits in special situations.

SARS-CoV-2 infects human pancreatic ß cells and elicits ß cell impairment.

Emerging evidence points toward an intricate relationship between the pandemic of coronavirus disease 2019 (COVID-19) and diabetes. While preexisting diabetes is associated with severe COVID-19, it is unclear whether COVID-19 severity is a cause or consequence of diabetes. To mechanistically link COVID-19 to diabetes, we tested whether insulin-producing pancreatic ß cells can be infected by SARS-CoV-2 and cause ß cell depletion. We found that the SARS-CoV-2 receptor, ACE2, and related entry factors (TMPRSS2, NRP1, and TRFC) are expressed in ß cells, with selectively high expression of NRP1. We discovered that SARS-CoV-2 infects human pancreatic ß cells in patients who succumbed to COVID-19 and selectively infects human islet ß cells in vitro. We demonstrated that SARS-CoV-2 infection attenuates pancreatic insulin levels and secretion and induces ß cell apoptosis, each rescued by NRP1 inhibition. Phosphoproteomic pathway analysis of infected islets indicates apoptotic ß cell signaling, similar to that observed in type 1 diabetes (T1D). In summary, our study shows SARS-CoV-2 can directly induce ß cell killing.