Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development

To discover new drugs to combat coronavirus disease 2019 (COVID-19), an understanding of the molecular basis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated and was positively correlated with disease course and severity in COVID-19 patients. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cell lines and human ACE2 transgenic mice, while CTSL overexpression, in turn, enhanced pseudovirus infection. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity and prevented SARS-CoV-2 pseudovirus infection. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.

Blood glucose is a representative of the clustered indicators of multi-organ injury for predicting mortality of COVID-19 in Wuhan, China

BackgroundConcomitance with diabetes is associated with high mortality in critical conditions. Patients with previous diabetes are more vulnerable to COVID-19. However, new-onset COVID-19-related diabetes (CRD) and its relevance have scarcely been reported. This study investigates new-onset CRD and its correlation with poor outcomes or death in patients with COVID-19. MethodsWe performed a single center, retrospective case series study in 120 patients with laboratory confirmed COVID-19 at a university hospital. Fasting blood glucose (FBG) [≥]7.0 mmol/L for two times during hospitalization and without a history of diabetes were defined as CRD. The Critical status was defined as admitted to intensive care unit (ICU) or death. ResultsAfter excluding patients with a history of diabetes, chronic heart, kidney, and liver disease, 69 patients with COVID-19 were included in the final analysis. Of the 69 patients, 23 were Moderate, 20 were Severe, and 26 were Critical (including 16 deceased patients). The prevalence of CRD in Critical and Moderate+Severe patients was 53.85% and 13.95%, respectively. Kaplan-Meier survival analysis revealed a significantly higher mortality rate in patients with CRD (P=0.0019). Multivariable analysis indicated that CRD was an independent predictor for death (HR = 3.75, 95% CI 1.26-11.15). Cluster analysis suggested that indicators for multi-organ injury were interdependent, and more proximities of FBG with indicators for multi-organ injury was present. ConclusionOur results suggest that new onset COVID-19-related diabetes is an indicator of multi-organ injury and predictor for poor outcomes and death in COVID- 19 patients. As it is easy to perform for clinical practices and even self-monitoring, glucose testing will be much helpful for predicting poor outcomes to facilitate appropriate intensive care in patients with COVID-19. FundingNational Key Research and Development Program of China; The Beijing Science and Technology Project. Significance of this studyO_ST_ABSEvidence before this studyC_ST_ABSConcomitance with diabetes is associated with high mortality in critical conditions. Patients with previous diabetes are more vulnerable to COVID-19. However, new-onset COVID-19-related diabetes (CRD) and its relevance have scarcely been reported. Recently, an international group of leading diabetes researchers participating in the CoviDIAB Project have established a global registry of patients with Covid-19-related diabetes (covidiab.e-dendrite.com). Added value of this study?New-onset diabetes in COVID-19 defined as CRD was investigated. Correlation between CRD and poor outcomes or death in patients with COVID-19 was found. About half of the Critical patients have new onset CRD. CRD is the representative of the clustered indicators of multi-organ injury and is the predictor for poor outcomes and death. How might these results change the focus of research or clinical practice?Our results suggest that new onset diabetes is an indicator of multi-organ injury and predictor for poor outcomes and death in COVID-19 patients. The study of CRD may also uncover novel mechanisms of disease.

Higher severity and mortality in male patients with COVID-19 independent of age and susceptibility

ImportanceThe recent outbreak of Novel Coronavirus (SARS-CoV-2) Disease (COVID-19) has put the world on alert, that is reminiscent of the SARS outbreak seventeen years ago. ObjectiveWe aim to compare the severity and mortality between male and female patients with both COVID-19 and SARS, to explore the most useful prognostic factors for individualized assessment. Design, Setting, and ParticipantsWe extracted the data from a case series of 43 hospitalized patients we treated, a public data set of the first 37 cases died of COVID-19 in Wuhan city and 1019 survived patients from six cities in China. We also analyzed the data of 524 patients with SARS, including 139 deaths, from Beijing city in early 2003. Main Outcomes and MeasuresSeverity and mortality. ResultsOlder age and high number of comorbidities were associated with higher severity and mortality in patients with both COVID-19 and SARS. The percentages of older age ([≥]65 years) were much higher in the deceased group than in the survived group in patients with both COVID-19 (83.8 vs. 13.2, P<0.001) and SARS (37.4 vs. 4.9, P<0.001). In the case series, men tend to be more serious than women (P=0.035), although age was comparable between men and women. In the public data set, age was also comparable between men and women in the deceased group or the survived group in patients with COVID-19. Meanwhile, gender distribution was exactly symmetrical in the 1019 survivors of COVID-19. However, the percentage of male were higher in the deceased group than in the survived group (70.3 vs. 50.0, P=0.015). The gender role in mortality was also observed in SARS patients. Survival analysis showed that men (hazard ratio [95% CI] 1.47 [1.05-2.06, P= 0.025) had a significantly higher mortality rate than women in patients with SARS. Conclusions and RelevanceOlder age and male gender are risk factors for worse outcome in patients with COVID. While men and women have the same susceptibility to both SARS-CoV-2 and SARS-CoV, men may be more prone to have higher severity and mortality independent of age and susceptibility. Key PointsO_ST_ABSQuestionC_ST_ABSAre men more susceptible to getting and dying from COVID-19? FindingsIn the case series, men tend to be more serious than women. In the public data set, the percentage of men were higher in the deceased group than in the survived group, although age was comparable between men and women. MeaningMale gender is a risk factor for worse outcome in patients with COVID independent of age and susceptibility.

Risk of silent myocardial ischemia detected by single photon emission computed tomography (SPECT) among asymptomatic Chinese patients with type 2 diabetes.

To explore the prevalence and risk factors of silent myocardial ischemia (SMI) detected by using single photon emission computed tomography (SPECT) in Chinese asymptomatic patients with type 2 diabetes (T2D).In this hospital-based retrospective study, 821 T2D patients who were screened for SMI detected by stress myocardial perfusion imaging using SPECT between June 2014 and July 2016 were investigated. Clinical indicators were compared between the patients with SMI and controls without SMI. Risk factors for SMI were evaluated by univariate and multivariate analysis.In this study, there were 131 patients with SMI in asymptomatic diabetes and the prevalence of SMI was 21.3% of 614 individuals. Logistic regression analysis indicated that diabetic retinopathy (OR = 1.474, 95%CI: 1.113-1.951, P = .007), male gender (OR = 1.805, 95%CI: 1.183-2.747, P = .006), and low-density lipoprotein (LDL) cholesterol (OR = 1.298, 95%CI: 1.042-1.615, P = .02) were risk factors associated with SMI. Besides, the prevalence of SMI increased in associated with the progression of retinopathy (P = .041). The percentage of SMI diagnosed in patients with no diabetic retinopathy (NDR), non-proliferative diabetic retinopathy (NPDR), and proliferative diabetic retinopathy (PDR) were 18.5% (75/405), 25.2% (37/147), and 30.6% (19/62), respectively. The percentage of SMI in male (24.5%, 85/347) was higher than that in female (17.2%, 46/267), P = .029.Physicians should be aware of these conditions when examining male patients with type 2 diabetes, especially with DR and/or high level of low-density lipoprotein cholesterol (LDL cholesterol), even if otherwise asymptomatic. A routine screening for SMI may thus be considered advisable in these patients.

Influence of insulin on growth hormone secretion, level and growth hormone signalling / 生理学报

Growth hormone (GH), as a vital hormone, has to experience a series of processes to fulfill its function including secretion, entering the circulation to reach target tissues (pre-receptor process), binding on the GH receptor (GHR) and triggering signaling inside cells (post-GHR process). Insulin can directly or indirectly influence part of these processes. GH secretion from pituitary somatotropes is regulated by GH-releasing hormone (GHRH) and somatostatin (SS) from hypothalamus. Insulin may exert positive or negative effects on the neurons expressing GHRH and SS and somatotropes under healthy and pathological conditions including obesity and diabetes. Glucose and lipid levels in circulation and dietary habits may influence the effect of insulin on GH secretion. Insulin may also affect GHR sensitivity and the level of insulin-like growth factor 1 (IGF-1), thus influence the level of GH. The GH signaling is also important for GH to play its role. GH signaling involves GHR/JAK2/STATs, GHR/JAK2/SHC/MAPK and GH/insulin receptor substrate (IRS)/PI3K/Akt pathways. These pathways may be shared by insulin, which is the basis for the interaction between insulin and GH, and insulin may attenuate or facilitate the GH signal by influencing molecules in the pathways. Many factors are related to the effect of insulin, among them the most important ones are duration of action and amount of insulin. The tendency of insulin-reduced GH signaling becomes obvious with increased dose and acting time of insulin. The participation of suppressor of cytokine signaling (SOCS), the interaction between JAK2 and IRS, and GHR sensitivity should also be considered when discovering GH signal. The involvement of SS in response to insulin is not clear yet. The details of how GH secretion, level and signaling change in response to time and dose of insulin treatment warrant further studies.

Efficacy and safety of avandamet or uptitrated metformin treatment in patients with type 2 diabetes inadequately controlled with metformin alone: a multicenter, randomized, controlled trial / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>At present, China has listed the compound tablet containing a fixed dose of rosiglitazone and metformin, Avandamet, which may improve patient compliance. The aim of this study was to evaluate the efficacy and safety of Avandamet or uptitrated metformin treatment in patients with type 2 diabetes inadequately controlled with metformin alone.</p><p><b>METHODS</b>This study was a 48-week, multicenter, randomized, open-labeled, active-controlled trial. Patients with inadequate glycaemic control (glycated hemoglobin [HbA1c] 7.5-9.5%) receiving a stable dose of metformin (≥1500 mg) were recruited from 21 centers in China (from 19 November, 2009 to 15 March, 2011). The primary objective was to compare the proportion of patients who reached the target of HbA1c ≤7% between Avandamet and metformin treatment.</p><p><b>RESULTS</b>At week 48, 83.33% of patients reached the target of HbA1c ≤7% in Avandamet treatment and 70.00% in uptitrated metformin treatment, with significantly difference between groups. The target of HbA1c ≤6.5% was reached in 66.03% of patients in Avandamet treatment and 46.88% in uptitrated metformin treatment. The target of fasting plasma glucose (FPG) ≤6.1 mmol/L was reached in 26.97% of patients in Avandamet treatment and 19.33% in uptitrated metformin treatment. The target of FPG ≤7.0 mmol/L was reached in 63.16% of patients in Avandamet treatment and 43.33% in uptitrated metformin treatment. Fasting insulin decreased 3.24 ± 0.98 μU/ml from baseline in Avandamet treatment and 0.72 ± 1.10 μU/ml in uptitrated metformin treatment. Overall adverse event (AE) rates and serious AE rates were similar between groups. Hypoglycaemia occurred rarely in both groups.</p><p><b>CONCLUSIONS</b>Compared with uptitrated metformin, Avandamet treatment provided significant improvements in key parameters of glycemic control and was generally well tolerated.</p><p><b>REGISTRATION NUMBER</b>ChiCTR-TRC-13003776.</p>

Lixisenatide treatment improves glycaemic control in Asian patients with type 2 diabetes mellitus inadequately controlled on metformin with or without sulfonylurea: a randomized, double-blind, placebo-controlled, 24-week trial (GetGoal-M-Asia).

BACKGROUND: This study assessed the efficacy and safety of the once-daily glucagon-like peptide-1 receptor agonist, lixisenatide, in Asian patients with type 2 diabetes mellitus inadequately controlled on metformin ± sulfonylurea. METHODS: In this 24-week, double-blind, placebo-controlled, multinational study, patients were randomized to lixisenatide 20 µg once daily or placebo. The primary endpoint was absolute change in glycated haemoglobin (HbA1c ) from baseline to week 24. RESULTS: A total of 391 patients were randomized. Lixisenatide significantly reduced HbA1c levels compared with placebo (LS mean difference: -0.36%, p = 0.0004). A significantly higher proportion of lixisenatide-treated patients achieved HbA1c targets of <7% (p = 0.003) and ≤6.5% (p = 0.001) versus placebo. Lixisenatide was associated with a statistically significant reduction in 2-h postprandial plasma glucose after a standardized breakfast versus placebo (LS mean difference: -4.28 mmol/L, p < 0.0001) and a significant reduction in fasting plasma glucose (p = 0.0109). There was no difference in weight loss versus placebo, with a modest reduction in body weight reported for both groups (lixisenatide: -1.50 kg, placebo: -1.24 kg; p = 0.296). The incidence of treatment-emergent adverse events (TEAEs) was 64.3% with lixisenatide versus 47.4% with placebo, with serious TEAEs reported in 1.5% versus 2.1% of patients, respectively. The most common TEAE in the lixisenatide group was nausea (16.3% vs 2.6% with placebo). The incidence of symptomatic hypoglycaemia was 5.6% with lixisenatide treatment and 2.6% with placebo (p = 0.1321), with no severe symptomatic hypoglycaemia events reported. CONCLUSIONS: In Asian patients with type 2 diabetes mellitus insufficiently controlled on metformin ± sulfonylurea, lixisenatide significantly improved glycaemic control and was well tolerated during the 24-week study.

Management status of type 2 diabetes mellitus in tertiary hospitals in Beijing: gap between guideline and reality / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Diabetes has become one of the most common chronic diseases and the third leading cause of death in China. Many programs have been initiated at national and local levels to address the illness. However, the effect of these programs in daily outpatient clinics is still unclear. The objective of this study was to investigate the management status of type 2 diabetes mellitus (T2DM) and factors associated with it in diabetes clinics of tertiary hospitals in Beijing.</p><p><b>METHODS</b>A cross-sectional survey was conducted in six tertiary hospitals in Beijing. Control criteria were defined based on 2007 China guideline for type 2 diabetes (CGT2D).</p><p><b>RESULTS</b>A sample of 1151 patients, age (60.8 ± 9.2) years, and with a median disease duration of 7.3 years was included. The hemoglobin A1c (HbA1c) mean level was (7.15 ± 1.50)%, the percentage of patients achieving the targets for HbA1c was 37.8%, blood pressure 65.6%, triglyceride (TG) 48.8%, high-density lipoprotein (HDL) 59.2%, low-density lipoprotein (LDL) 34.0%, and total cholesterol (TC) 42.0%. The factors independently associated with glycemic control were diabetes duration (odds ratio (OR) = 0.95; 95% confidence interval (CI): 0.919 - 0.982, P < 0.01), body mass index (BMI) (OR = 0.914, 95%CI: 0.854 - 0.979, P = 0.01) and smoking (OR = 0.391, 95%CI: 0.197 - 0.778, P < 0.01). The factors independently associated with blood pressure control were BMI (OR = 0.915, 95%CI: 0.872 - 0.960, P < 0.01) and male gender (OR = 0.624, 95%CI: 0.457 - 0.852, P < 0.01). The factor independently associated with LDL control was education level (OR = 1.429, 95%CI: 1.078 - 1.896, P = 0.013).</p><p><b>CONCLUSIONS</b>The management status of T2DM patients in tertiary hospitals in Beijing has improved remarkably. However, there is still room for further improvement to reach the guideline target. Long diabetes duration, high BMI, smoking, male gender and low education level were independently associated with poor metabolic control.</p>