Effects of dapagliflozin compared with glimepiride on body composition in Asian patients with type 2 diabetes inadequately controlled with metformin: The BEYOND study

Aims

To evaluate the effect of dapagliflozin on body composition such as total body fat (BF) mass, abdominal visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) areas compared with glimepiride in Korean patients with type 2 diabetes.

Materials and Methods

This was a 52-week, multicentre, randomized, parallel-group, open-label, Phase IV (NCT02564926) study. Patients with inadequate glycaemic control (glycated haemoglobin ≥7.0% and <10.0%) on metformin monotherapy (≥1000 mg/day) were randomized 1:1 to receive dapagliflozin 10 mg/day or glimepiride 1-2 mg/day for 12 months as an add-on to metformin. Baseline and end of study body composition evaluations included dual-energy X-ray absorptiometry and abdominal computed tomography scans.

Results

Of 124 enrolled patients from 14 centres, 121 received study treatment (dapagliflozin: 60; glimepiride: 61) and 106 (85.5%) completed the study. Over 52 weeks, the dapagliflozin group showed the following differences versus the glimepiride group: −2.59 kg BF mass, −1.94% BF%, −17.55 cm² VAT area, −18.39 cm² SAT area, −0.46% glycated haemoglobin, −18.25 mg/dl fasting blood glucose, −3.7 kg weight, −2.21 cm waist circumference, −1.37 kg/m² body mass index, −6.81 mmHg systolic blood pressure and +657.71 ng/ml in adiponectin; all were statistically significant. Both groups had similar incidences of adverse events; however, hypoglycaemic events were mainly (12 of 15) reported in the glimepiride group.

Conclusion

Dapagliflozin reduced total BF mass, abdominal VAT and SAT areas, and showed better glycaemic control than glimepiride. Being safe and well-tolerated, dapagliflozin appears to be a more favourable alternative to sulphonylureas as add-on therapy after metformin monotherapy failure in Korean patients with type 2 diabetes.     

Skp2与肺癌关系的研究进展

Skp2是新发现的Skp1-Cullin-F-box(SCF)多功能E3酶复合体中的一种F-box蛋白,能通过泛素化依赖的蛋白水解途径调控细胞周期相关蛋白,从而影响细胞周期相关蛋白的表达水平,众多研究发现其与肺癌发生、发展和预后密切相关。本文就Skp2基因结构特征,作用机制及其与肺癌的关系作一综述。     

Baseline factors associated with glycaemic response to treatment with once‐weekly dulaglutide in patients with type 2 diabetes

Dulaglutide glycaemic efficacy has been demonstrated in the AWARD clinical trial programme. The objective of the present analysis was to determine the major baseline factors associated with the reduction in glycated haemoglobin (HbA1c) in response to dulaglutide. Baseline covariates from patients receiving dulaglutide in six phase III studies (n = 2806) were analysed using a gradient‐boosting method to assess their relative influence on the change in HbA1c after 26 weeks of treatment. Influential variables (relative influence >5%) were further evaluated in univariate and multivariable modelling. The gradient‐boosting analysis showed that the top influential baseline factors associated with HbA1c reduction were: HbA1c (48.8%), age (9.1%), fasting serum glucose (FSG; 8.2%), fasting serum insulin (FSI; 6.7%) and estimated glomerular filtration rate (eGFR; 5.4%). Multivariable regression showed that higher baseline HbA1c was the major factor associated with greater HbA1c reduction [coefficient estimates: ?0.6% (?6.6 mmol/mol); p < 0.0001]. Age ≤65 years, lower FSG level, FSI level ≤55 pmol/L and eGFR ≤100 mL/min/1.73 m² were associated with greater decreases in HbA1c, but the effect was very small [coefficient estimates: ?0.05% to ?0.2% (?0.6 to ?2.2 mmol/mol)]. These data indicate that higher baseline HbA1c, reflecting poor glycaemic status, is the major factor associated with greater reduction in HbA1c in response to dulaglutide treatment.     

急性心肌梗死患者血脂与前列环素、血栓素相关性的研究

目的 本试验观察了140例正常人及80例急性心肌梗死(AMI)患者的血脂水平和PGI2(前列环素)、TXA2(血栓素)的稳定代谢产物6-Keto-PGFla、TXB2及T/P水平的变化,并对AMI患者中血脂各项和6-Keto-PGFla、TXB2及T/P进行相关分析,结果显示:AMI患者的TC、TG、LDL、APOB、6-Keto-PGFla、TXB2水平高于正常人,而HDL、APOAI、T/P水平低于正常人(P<0.05),单因素相关分析表明:AMI患者的6-Keto-PGFla与TC、LDL显著相关(P<0.05)、6-Keto-PGFla、TXB2与LP(a)显著相关(P<0.05)。提示:AMI患者的血脂、PGI2、TXB2之间有一定的相关关系,表明冠心病、急性心梗的发病机制的两大学说——血脂沉积学说和血小板聚集血栓形成学说之间可能有些内在联系。     

Higher levels of circulating ANGPTL2 are associated with macular edema in patients with type 2 diabetes

Macular edema (ME) is an inflammatory disease characterized by increased microvascular permeability. Here, we proposed that plasma angiopoietin-like protein 2 (ANGPTL2) level may be related to the severity of ME patients with type 2 diabetes mellitus (T2DM). In this cross-sectional study, 172 T2DM patients were recruited and divided into clinically significant macular edema (CSME), non-CSME (nCSME), and control groups. Serum ANGPTL2 level was quantified by ELISA and best corrected vision acuity (BCVA) was detected. After adjust age, sex, body mass index (BMI), and duration of diabetes variables, ANGPTL2 performed statistics difference among CSME-, nCSME-groups, and control group (4.46 [3.97, 4.96, 95%CI] ng/mL in CSME group, 3.80 [3.42, 4.18, 95%CI] ng/mL in nCSME-group, 3.33 [3.03, 3.63, 95%CI] ng/mL in control, P < .01). After adjustment of confounding factors, high levels of circulating ANGPTL2 were related with the diagnosis of ME, BCVA, and C reactive protein (CRP) through univariate regression analysis (P < .05). Meanwhile, in the multiple regression model, ANGPTL2 took the mainly effect proportion for the diagnosis of diabetic macular edema (DME), with a LogWorth value 3.559 (P < .001). Our study suggested that elevated circulating ANGPTL2 may be associated with the development of DME and the severity of visual impairment in patients with type 2 diabetes.     

Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to be a serious global public health threat. The 3C-like protease (3CLpro) is a virus protease encoded by SARS-CoV-2, which is essential for virus replication. We have previously reported a series of small-molecule 3CLpro inhibitors effective for inhibiting replication of human coronaviruses including SARS-CoV-2 in cell culture and in animal models. Here we generated a series of deuterated variants of a 3CLpro inhibitor, GC376, and evaluated the antiviral effect against SARS-CoV-2. The deuterated GC376 displayed potent inhibitory activity against SARS-CoV-2 in the enzyme- and the cell-based assays. The K18-hACE2 mice develop mild to lethal infection commensurate with SARS-CoV-2 challenge doses and were proposed as a model for efficacy testing of antiviral agents. We treated lethally infected mice with a deuterated derivative of GC376. Treatment of K18-hACE2 mice at 24 h postinfection with a derivative (compound 2) resulted in increased survival of mice compared to vehicle-treated mice. Lung virus titers were decreased, and histopathological changes were ameliorated in compound 2–treated mice compared to vehicle-treated mice. Structural investigation using high-resolution crystallography illuminated binding interactions of 3CLpro of SARS-CoV-2 and SARS-CoV with deuterated variants of GC376. Taken together, deuterated GC376 variants have excellent potential as antiviral agents against SARS-CoV-2.

Coronaviruses are a large group of viruses that can cause a wide variety of diseases in humans and animals (1). They are single-stranded, positive-sense RNA viruses that belong to four genera, designated α, β, γ, and δ coronaviruses, in the Coronaviridae family (1). Human coronaviruses (229E, NL63, OC43, and HKU1) generally cause mild upper respiratory infections. However, global outbreaks of new human coronavirus infections with severe respiratory disease have periodically emerged from animals, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and, most recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 (2). SARS-CoV-2 emerged in China in December 2019 and subsequently spread throughout the world. Ominously, the diversity of coronavirus strains in potential animal reservoirs suggests that emerging and reemerging pathogenic coronaviruses will continue to pose a significant threat to public health. Currently, vaccines using different platforms have been developed or under development, and three vaccines just became available in the United States for COVID-19 licensed for emergency use, with more others expected to be available soon. The specific therapeutic interventions that are currently licensed or given emergency use authorizations include remdesivir (Veklury), a combination of remdesivir and a JAK inhibitor, baricitinib, and a single monoclonal antibody or a mixture of monoclonal antibodies.Although additional clinical trial results will be needed to fully understand the efficacy of these treatments, the currently available clinical data on these treatments showed limited effects of these treatments in reducing disease progression or facilitating recovery (3). Clinical presentation of COVID-19 patients varies from being asymptomatic to several respiratory disease that may lead to death. Viral replication in the respiratory tract peaks during the first week of infection and decline, and in severe COVID-19 cases extensive inflammatory responses in the lungs initiated by viral replication dominate in the late stage, being the main culprit for lethality (4). Therefore, a combination of antiviral agents and immune modulators such as dexamethasone has been suggested to improve clinical outcome in advanced diseases (3). Currently, only the nucleoside analog remdesivir is available for COVID-19 patients as a Food and Drug Administration (FDA)-approved drug, and additional potent direct-acting antiviral agents, such as protease inhibitors, are urgently required to enrich the drug arsenal against SARS-CoV-2 infection.The SARS-CoV-2 genome encodes two polyproteins which are processed by a 3C-like protease (3CLpro) and a papain-like protease. These viral proteases are essential for viral replication, making them attractive targets for drug development (5–7). It is furthermore acknowledged that, in addition to the development of effective vaccines, the concurrent identification of FDA-approved drugs that can be repurposed for use against SARS-CoV-2 may accelerate the development and implementation of effective countermeasures against the virus (reviewed in ref. 8). We previously described a series of 3CLpro inhibitors (including GC376) with activities against multiple coronaviruses, including SARS-CoV (9), MERS-CoV (6, 10), and SARS-CoV-2 (10). GC376 was recently demonstrated in clinical trials to have efficacy against a fatal feline coronavirus infection, feline infectious peritonitis (FIP) (11, 12), and is currently in clinical development for treating FIP in cats.Some mice that express human ACE2 or hamsters develop weight loss and lung histopathology but they have no or little mortality following human SARS-CoV-2 infection (13–15). Thus, they serve as good models for asymptomatic, mild, and moderate SARS-CoV-2 infection and for studies of viral transmission. Currently only a few fatal infection animal models are available that can recapitulate the key features of severe pathogenesis in humans with COVID-19. Transgenic hACE2-HFH4 mice (16) and K18-hACE2 mice (17–19), which express human angiotensin I-converting enzyme 2 (ACE2) receptor under HFH4 or K18 promoter, or a mouse-adapted SARS-CoV-2 MA10 strain (7) can lead to fatality dependent upon virus challenge doses. Neural invasion of the brain variably occurs in hACE2 transgenic mice and is associated with a fatal outcome. In the absence of brain infection, however, the respiratory infection is still lethal, depending on initial virus inoculum. Although there is evidence of neurological complications, such as encephalopathy and encephalitis, in COVID-19 patients (20), the relevance of brain infection in these animal models in human neurological disease needs further clarification. The fatal infection models are useful models for efficacy testing of antiviral agents as they show viral replication in the lungs with inflammation and virus-induced histopathological changes that resemble severe COVID-19 infection in humans. In the K18-hACE2 model, pre- and postinfection treatment efficacy of human convalescent plasma from a recovered COVID-19 patient was previously studied (18), and antiviral agents such as GC376 (7, 21) were tested. We report herein the results of our studies related to the synthesis and evaluation of deuterated GC376 variants which have enhanced antiviral activity and display efficacy in a fatal mouse model (K18-hACE2 mice) of SARS-CoV-2.     

对氧磷酶2基因多态性与阿尔茨海默病的相关性研究

目的 探讨对氧磷酶2（paraoxonase 2,PON2）基因多态性（148Ala/Gly;311Cys/Ser）与Alzheimer病（AD）之间的关系.方法 用PCR-RFLP分析技术对132例AD患者和186例年龄匹配的健康对照者进行PON2 148Ala/Gly及311Cys/Ser基因多态性的分析.结果 PON2基因148、311位点存在多态性,其基因型频率和等位基因频率在AD患者和正常对照者间差异无显著性.结论 PON2基因多态性与AD未发现显著相关性.     

Defective immunological functions associated with abnormal lymphokine-activated killer activity in patients with hepatocellular carcinoma

The in vitro lymphokine-activated killer (LAK) activity of peripheral blood mononuclear cells (PBMC) from 36 patients with hepatocellular carcinoma was investigated. The activity was greatly diminished in 13 patients and enhanced in seven patients. A flow cytometric study showed that the percentage of OKM1+, Leu-7+-11b+, and Leu-7-11b+ fractions in PBMC was decreased and the percentage of OKT8+ and Leu7+11- fractions was increased significantly in the 13 patients with lower LAK activity, compared with the values of the seven higher LAK activity patients. Furthermore, the response of PBMC to interleukin-2 (IL-2) was deficient in the lower activity group. However, there was no significant difference in IL-2 production by PBMC, IL-2 receptor (p55) expression of PBMC and mitogen (Con-A, PHA) response of PBMC between the two groups. These findings indicate the possibility that diminished LAK activity in hepatoma patients is due to a decreased number of LAK precursor cells and a defective response of LAK precursor cells to IL-2.     

BCL-2家族与细胞凋亡及肺纤维化

目前已经发现的BCL-2蛋白家族按功能可分为2类,一类具有抑制凋亡作用(如BCL-2),而另一类具有促进凋亡作用(如Bax).BCL-2家族调节细胞凋亡机制目前仍不清楚,大多认为与BCL-2调节细胞的氧化应激及调节钙离子的跨膜运动有关.近几年研究证明,BCL-2家族蛋白主要直接控制线粒体外膜通透性的改变而引起细胞凋亡,除此之外,尚存在BCL-2不敏感的凋亡途径;细胞凋亡在肺纤维化中发挥重要的作用,包括上皮细胞的凋亡过度和成纤维细胞的凋亡不足;BCL-2家族蛋白在肺纤维化中发挥着启动和调节线粒体途径引起的细胞凋亡开关作用.     

茶多酚对H_2O_2诱导HL-60细胞癌基因表达的影响

目的　观察茶多酚对 H2 O2 诱导 HL- 60细胞癌基因表达的影响 ,同时观察细胞 DNA片段化程度的变化。方法　用二苯胺法对小片段 DNA进行分析 ,流式细胞仪观察癌基因表达变化。结果　 H2 O2 打断 DNA的能力与其作用浓度及时间有关 ,H2 O2 可使细胞 c- fos,c- jun,c- myc,bcl- 2 ,p53表达发生变化 ,茶多酚可以影响 H2 O2 诱导的 DNA损伤及癌基因表达。结论　茶多酚在一定浓度下 ,可以抑制 H2 O2 诱导的 DNA氧化损伤 ,并抑制癌基因表达的变化。高浓度茶多酚可以增强 H2 O2 的效应     

血管生成素及其Tie-2受体与2型糖尿病视网膜病变的相关性研究

2型糖尿病增殖性视网膜病变(PDR)组血清血管生成素(Ang)2水平明显高于非增殖性视网膜病变组(NPDR)和2型糖尿病无视网膜病变组[分别为5.80(3.83～8.00)、4.42(2.56～5.55)和2.75(1.40～4.64)ng/m1,P＜0.01],NPDR组高于2型糖尿病无视网膜病变组(P＜0.01);Ang-1在NPDR组高于2型糖尿病无视网膜病变组[10.57(8.99～12.05)对9.21(7.71～11.2)ng/m1,P＜0.05];Tie-2受体在3组间差异无显著性(P＞0.05).提示血清Ang-2水平可能与2型糖尿病视网膜病变的严重程度相关.

Abstract：

Angiopoietin-2 levels were 5. 80 ( 3. 83-8. 00 ) , 4. 42 ( 2. 56-5. 55 ) , and 2. 75 ( l. 40-4. 64 )ng/ml in type 2 diabetic patients with proliferative retinopathy, patients with non-proliferative retinopathy, and patients without retinopathy, respectively. Statistical significances existed between any two groups (all P ＜0. 01 ). Angiopoietin-1 level in patients with non-proliferative retinopathy was higher than that in patients without retinopathy [10. 57 ( 8. 99-12. 05 ) vs 9. 21 (7. 71-11.2 ) ng/ml, P＜0. 05]. No difference in receptor Tie-2 was found among the 3 groups (P＞0. 05 ). The results suggested that serum angiopoietin-2 level might be associated with the severity of retinopathy in type 2 diabetic patients.     

Impact of empagliflozin in patients with diabetes and heart failure

Heart failure (HF) is a common disease with increased risk for mortality and morbidity among patients with type 2 diabetes mellitus (T2DM). Optimal glycemic control in this patient population is challenging as many available therapies can potentially exacerbate symptoms of HF. Empagliflozin is one in a novel class of agents, the sodium glucose co-transporter 2 (SGLT2) inhibitors, that lowers blood glucose by increasing urinary glucose excretion and improves glycemic control and lowers body weight and blood pressure. In the recent EMPA-REG OUTCOME trial, empagliflozin was shown to improve cardiovascular outcomes in patients with T2DM and established cardiovascular risk where it reduced HF hospitalizations and cardiovascular death, with a consistent benefit among patients both with and without baseline HF. Here, we review the empagliflozin data on HF outcomes and discuss potential mechanisms for its benefits in HF with a focus on the potentially significant impact that empagliflozin may have on the care of patients with T2DM and HF in the future.     

EGCG联合不同剂量放疗对人肝癌细胞系HepG2中hTERT表达的影响

目的:研究相同剂量表没食子儿茶素没食子酸酯(EGCG)联合不同剂量放疗对HepG2中hTERT基因表达的影响, 探讨EGCG成为放疗增敏剂的作用.方法:用MTT比色法检测EGCG对HepG2细胞增殖的影响, 用荧光显微镜检测EGCG诱导HepG2的细胞凋亡, 从而找到合适的EGCG(25μmol/L)剂量用于观察其放射效果的实验; 采用实时荧光定量PCR检测不同剂量放疗(0、2、4、6 Gy)联合EGCG和不联合EGCG治疗后, HepG2中hTERT基因的表达. 放疗用直线加速器6MVX线.结果:EGCG具有抑制HepG2细胞增殖并诱导HepG2细胞凋亡的作用. 同时, 不同剂量放疗联合EGCG和不联合EGCG治疗后HepG2中hTERT基因的表达比较, 空白组无显著差异; 2Gy组、4 Gy组、6 Gy组均有显著差异(hTERT基因表达的扩增倍数: 0.477±0.025 vs 0.973±0.024; 1.110±0.083 vs 1.382±0.051; 1.174±0.128 vs 1.452±0.109, P <0.01或0.05), 并以2 Gy组最为显著.结论:EGCG具有抑制HepG2细胞增殖并诱导其凋亡的作用; EGCG联合不同剂量放疗可能下调HepG2中hTERT基因水平, 从而抑制端粒酶活性, 以放射剂量为2 Gy时显著, 因此,EGCG有可能成为放疗增敏剂.     

老年2型糖尿病肾功能异常的相关影响因素分析

目的探讨老年2型糖尿病（T2DM）肾功能异常的相关影响因素及临床意义。方法回顾性分析1997-2006年在解放军总医院住院治疗的老年T2DM患者临床资料,根据其肾小球滤过率（GFR）水平分为：GFR≥90（A组）、60～90（B组）、〈60（C组,肾功能异常组）ml/（min.1.73m^2）。对各组临床及实验室指标进行比较。结果共收集老年T2DM病例525例,A组159例（30.3%）,B组239例（45.5%）,C组127例（24.2%）。临床诊断糖尿病肾病（DN）者占13.7%,合并高血压者占71.05%;肾功能异常组中,DN仅占29.9%。在老年T2DM中,高血压病程、收缩压（SBP）、舒张压（DBP）、餐后2h血糖（2hPBG）、血清总胆固醇（TC）、血尿酸（BUa）为肾功能异常的独立相关影响因素,且高血压对其肾功能的影响更为显著。随血压水平增高、DM病程延长、尿白蛋白/肌酐比值（Alb/Cr）增加,GFR下降,肾功能异常发生率增加。血压〈130/80mmHg、≥130/80mmHg者,肾功能异常发生率分别为4.09%、41.72%;DM病程〈5年、5～10年、〉10年者,肾功能异常发生率依次为18.64%、26.09%和28.90%;尿Alb/Cr〈30、30～299、≥300mg/g者,肾功能异常发生率分别为10.53%、40.38%和75%。结论老年T2DM肾功能异常的影响因素较多,高血压病程、SBP、DBP、2hPBG、TC、BUa与之独立相关,高血压对其影响更为显著。血压、血糖控制良好为保护因素,针对上述影响因素的综合治疗对预防及延缓肾功能异常的发生、发展有重要的临床意义。     

Chronic Enteropathy Associated with SLCO2A1 with Pachydermoperiostosis

A 49-year-old man complained of chronic palpitation and shortness of breath, which had recently become exacerbated. A blood examination indicated severe refractory anemia and hypoproteinemia. Physical examinations revealed anemia, a systolic murmur, and spoon nails. Multiple nonspecific ileal ulcers were observed. A pathological examination indicated a small granuloma with CD68-positive histiocytes. He had a deeply wrinkled forehead, chiseled face, and clubbed fingers. Radiography revealed periostosis of the fingers and long bones in the limb. He was diagnosed with pachydermoperiostosis. SLCO2A1 demonstrated a c.1807C>T homo-mutation. He was also diagnosed with SLCO2A1-associated chronic enteropathy and thus was treated with 5-aminosalicylic acid, which temporarily improved the ileal ulcers, anemia, and hypoalbuminemia.     

The older patient with diabetes: a practical approach

Type 2 diabetes mellitus is very prevalent among persons aged 60–80 years old. This population is expected to increase in number and is characterized by the presence of comorbidities, long standing diabetes, frailty, high rate of cognitive impairment and limited life expectancy. These characteristics have a significant impact on diabetes and treatment among the elderly, much as diabetes predisposes to these conditions. In this article we will describe mechanisms that may lead to insulin resistance and diabetes among the elderly and also how these conditions contribute to the development of frailty and cognitive impairment. Hypoglycemia and it's consequences are important considerations when planning the treatment of diabetes. Treatment options in light of new goals and the danger of hypoglycemia will be detailed. Copyright © 2013 John Wiley & Sons, Ltd.     

环氧化酶-2在急性胰腺炎大鼠肺组织中的表达

目的探讨环氧化酶-2(COX-2)在大鼠急性胰腺炎肺损伤中的作用.方法大鼠胰胆管逆行注射3.5%牛磺胆酸钠,制作大鼠重症急性胰腺炎并发肺损伤模型.将实验大鼠分为正常对照组、胰腺炎1、4、8、12、24小时组.分别对胰腺损伤、肺损伤程度进行病理评分,酶显色法测定血清脂肪酶水平,并测定肺组织湿/干比;逆转录聚合酶链反应技术检测各组鼠肺组织COX-2的表达.结果造模后1小时,大鼠即出现较明显的胰腺损伤,伴有血清脂肪酶升高,随着时间的延长,胰腺损伤逐渐加重,以12小时为重.造模后1小时,肺损伤评分即有升高,但肺组织湿/于比无明显变化,此后,肺损伤程度逐渐增加,以24小时为重,光镜下主要表现为肺组织炎性细胞浸润、肺泡间隔增宽、肺泡腔内渗出液、肺泡腔塌陷等.正常大鼠肺组织内COX-2 mRNA呈低水平表达,造模4小时后,大鼠肺组织内COX-2 mRNA表达明显增加,至24小时达最高水平;大鼠肺组织内COX-2 mRNA表达与胰腺损伤程度、肺损伤程度成正相关.结论大鼠肺组织内COX-2参与了胰腺炎肺损伤的过程,抑制肺组织内COX-2的表达可能有助于胰腺炎和胰腺炎肺损伤的治疗.