GLP-1受体激动剂与二肽基肽酶4抑制剂治疗2型糖尿病的比较

随着对肠促胰素在维持葡萄糖稳定作用认识的日益增多,促进了针对2型糖尿病患者肠促胰素活性缺乏治疗药物的研发.根据肠促胰素治疗药物不同的作用机制,可分为以下2类:(1)胰升糖素样肽1(GLP-1)受体激动剂,包括利拉鲁肽(liraglutide)、艾塞那肽每日2次制剂和艾塞那肽每周1次制剂;(2)二肽基肽酶4(DPP-4)抑制剂,包括西格列汀(sitagliptin)、利拉利汀(linagliptin)、沙格列汀(saxagliptin)和维格列汀(vildagliptin),DPP-4抑制剂可限制内源性GLP-1的降解.这2类药物具有某些共性,如葡萄糖依赖性刺激胰岛素分泌,低血糖发生率低.然而这2类药物在疗效方面的表现却有所不同.本文综述了这2类基于肠促胰素治疗药物的药代动力学及其临床方面的疗效和安全性,阐明了此类药物在2型糖尿病治疗中的地位.     

基于肠促胰素治疗药物在中国或亚洲患者中的应用比较

目的随着对降糖药不良反应和降糖外保护效应的重视不断提高,基于肠促胰素治疗药物的临床应用不断增加。同样作为基于肠促胰素治疗药物——胰升血糖素样肽-1(GLP-1)受体激动剂与二肽基肽酶-4(DPP-4)抑制剂在药理学、疗效和安全性方面存在一些差异,且不同的GLP-1受体激动剂和DPP-4抑制剂间也各有优势和不足。本文将以在中国或亚洲患者中进行的研究为证据,对在我国上市的2种GLP-1受体激动剂和5种DPP-4抑制剂的降糖疗效、降糖外保护效应进行比较,旨在指导临床医生选择合理的降糖药物。     

肠促胰素类降糖药物对体重的作用

胰高血糖素样肽-1(GLP-1)受体激动剂和二肽基肽酶-4(DPP-4)抑制剂是新型的2型糖尿病治疗药物.普遍认为,GLP-1受体激动剂可显著减轻患者体重,DPP-4抑制剂对体重的作用为中性.然而,这两类药物与不同药物联用,患者体重可不同程度增加,尤其是与磺脲类或噻唑烷二酮类药物联用时.临床医师应了解GLP-1受体激动剂和DPP-4抑制剂对体重的影响,为2型糖尿病患者制定更合理、安全和有效的治疗方案.     

基于肠促胰素治疗对骨代谢的影响

糖尿病与骨代谢疾病密切相关,糖尿病患者易发生骨质疏松。基于肠促胰素治疗包括胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)受体激动剂和二肽基肽酶-4(dipeptidyl peptidase-4,DPP-4)抑制剂,这类药物不仅在调节体内葡萄糖稳态中起重要作用,而且对骨代谢有间接或直接的改善作用,有可能为骨质疏松的治疗提供新的思路,本文就上述热点问题作一综述。     

2型糖尿病胰岛功能障碍与基于肠促胰素的治疗

多项研究显示,胰岛细胞功能障碍(α细胞及β细胞)对2型糖尿病的发生发展起决定性作用.β细胞功能障碍主要表现为胰岛素分泌的缺陷,α细胞功能障碍则主要是进餐后胰升糖素的分泌未得到有效抑制.因此,胰岛功能障碍是2型糖尿病治疗的重要靶点.研究显示,基于肠促胰素的药物,包括胰升糖素样肽1( GLP-1)受体激动剂及二肽基肽酶4(DPP-4)抑制剂能恢复胰岛细胞对葡萄糖的敏感性,有效改善血糖控制.期待此类药物对胰岛功能改善的更多研究.     

从LIRA—DPP-4i研究看利拉鲁肽的早期临床应用

胰升血糖素样肽-1（GLP-1）受体激动剂（含GLP-1类似物）和二肽基肽酶-Ⅳ（DPP-Ⅳ）抑制剂是目前与肠促胰素有关的治疗T2DM的药物。LIRA-DPP-4i研究表明,利拉鲁肽与西格列汀相比,具有更有效降（HbA1c、FPG降幅更大）、更明显减轻体重和更显著改善β细胞功能的特点。利拉鲁肽还可降低糖尿病前期发病率,早期应用更早获益。     

GLP-1受体激动剂与DPP-4抑制剂对2型糖尿病的疗效对比

目的:比较胰高血糖素样肽1(GLP-1)受体激动剂与二肽基肽酶4(DPP-4)抑制剂治疗2型糖尿病(T2DM)的临床效果。方法:选择2015年1月~2016年1月我院收治的T2DM患者96例。根据随机数字表法,患者被随机均分为GLP-1受体激动剂组(GLP-1组,接受GLP-1受体激动剂利拉鲁肽治疗)和DPP-4抑制剂组(DPP-4组,接受DPP-4抑制剂西格列汀治疗),两组均治疗18周。测量比较两组治疗前后空腹血糖(FBG)、餐后2h血糖(2hPG)水平,以及不良反应发生情况。结果:与治疗前比较,治疗18周后两组FBG、2hPG水平均有显著降低(P0.05或0.01);与DPP-4组比较,GLP-1组治疗后FBG[(7.48±0.45)mmol/L比(6.64±0.28)mmol/L]和2hPG[(11.15±1.01)mmol/L比(9.26±1.82)mmol/L]水平降低更显著,P均0.05。GLP-1组与DPP-4组的总不良反应发生率(29.2%比33.3%)无显著差异,P=0.078。结论:与DPP-4抑制剂比较,GLP-1受体激动剂治疗2型糖尿病在控制血糖和减轻体重方面效果更好,值得推广。     

肠促胰素在糖尿病肾病作用的研究进展

糖尿病肾病（diabetic nephropathy,DN）是糖尿病常见的慢性并发症,也是发达国家终末期肾病的首要原因,但DN的预防和治疗仍然是当今一大难题.肠促胰素类新型降糖药物,包括模拟胰高血糖素样肽1（glucagon like peptide-1,GLP-1）作用或使GLP-1受体激活的GLP-1类似物/受体激动剂,以及抑制GLP-1降解的二肽基肽酶-4（dipeptidyl peptidase-Ⅳ,DPP-Ⅳ）抑制剂两类.     

肠促胰素胰腺外获益之心血管保护

2014年美国糖尿病学会（ADA）年会上,Banting奖获得者是肠促胰素研究领域的奠基人之一、加拿大多伦多大学的德鲁克教授（Daniel Drucker）,他的获奖演说“解码肠道代谢信息,推动治疗革新”再次把糖尿病领域的目光聚焦在肠促胰素上.心血管疾病是2型糖尿病的主要并发症,在血糖良好控制基础上,全面改善心血管危险因素,降低心血管疾病发病率和病死率是2型糖尿病治疗的主要目标.胰高糖素样肽1受体激动剂（GLP-1RA）和二肽基肽酶Ⅳ（DPP-4）抑制剂丰富了糖尿病治疗手段[1],而基于肠促胰素治疗的胰腺外作用也越来越受到关注,基础和临床研究帮助我们认识基于肠促胰素治疗的心血管保护作用.     

二肽基肽酶4抑制剂治疗2型糖尿病的研究进展

肠促胰素是一类由肠道分泌的葡萄糖依赖性的促胰岛素分泌因子，主要由胰高糖素样肽-1（GLP-1）和糖依赖性胰岛素释放肽（GIP）组成，其中GLP-1在2型糖尿病的发生、发展中发挥重要作用。二肽基肽酶4（DPP-4）是灭活GLP-1的关键酶，其抑制剂是一种新型的口服降糖药，可以提高血液中内源性GLP-1和GIP水平，有效降低血糖并有良好的耐受性。本文就DPP-4抑制剂治疗2型糖尿病的进展作一综述。     

胰岛素瘤的解剖分布特点分析

目的胰岛素瘤是最常见的胰腺神经内分泌肿瘤，因其临床表现多样，导致诊断困难。影像学诊断尤其是超声内镜(EUS)在胰岛素瘤的诊断中起着重要作用，拥有较高的敏感性和特异性。本研究拟通过明确胰岛素瘤的解剖分布特点，以期有助于提高影像学的诊断准确率和降低漏诊率，尤其是在教育和培训实践中对于EUS的学习者更具有指导价值。 方法回顾性分析解放军总医院第一医学中心病案资料数据库1993年1月至2019年11月经外科手术、病理确诊为胰岛素瘤的患者的临床资料，检索方法采取搜索术后病理诊断为"胰岛素瘤"的病例，通过查阅病例的方法，提取出胰岛素瘤的大小和解剖分布等数据，进一步分析其特点。 结果共检索到确诊为胰岛素瘤的患者116例，其中，男45例、女71例，年龄13～76岁，平均年龄(44.4±14.85)岁。胰岛素瘤单发110例(94.8%)、多发6例(5.2%)。位置分布：头颈部46例(39.7%)，单发45例、多发1例；体尾部68例(58.6%)，单发65例、多发3例；全胰腺多发2例(1.7%)。病变大小特点：最大径0.4～3.4 cm，平均大小(1.53±0.58)cm。≤1 cm 29例、>1 cm而≤1.5 cm41例、>1.5 cm而≤2.0 cm28例，≤3 cm 15例，>3 cm 3例。年龄与肿瘤的大小相关，≤44岁患者肿瘤平均大小为(1.36±0.51)cm、>44岁患者肿瘤平均大小为(1.70±0.60)cm，P<0.05。头颈部的肿瘤大于体尾部的肿瘤，头颈部肿瘤平均大小(1.66±0.63)cm，体尾部(1.42±0.52)cm，P<0.05。 结论胰岛素瘤在胰腺体尾部较头颈部更好发；绝大多数单发，但可以全胰腺多发；多数小于1.5 cm，肿瘤的大小与患者年龄和肿瘤的解剖分布相关。     

Pathogenesis of carcinoma of the papilla of Vater

Most adenomas and carcinomas of the small intestine and extrahepatic bile ducts arise in the region of the papilla of Vater. In familial adenomatous polyposis (FAP) it is the main location for carcinomas after proctocolectomy. In many cases symptoms due to stenosis lead to diagnosis at an early tumor stage. In about 80%, curative intended resection is possible. Operability is the most relevant prognostic factor. Most ampullary carcinomas resp. carcinomas of the papilla of Vater develop from adenomatous or flat dysplastic precursor lesions. They can be sited in the ampulloduodenal part of the papilla of Vater, which is lined by intestinal mucosa. They also can develop in deeper parts of the ampulla, which are lined by pancreaticobiliary duct mucosa. Intestinal-type adenocarcinoma and pancreaticobiliary-type adenocarcinoma represent the main histological types of ampullary carcinoma. Furthermore, there exist unusual types and undifferentiated carcinomas. Many carcinomas of intestinal type express the immunohistochemical marker profile of intestinal mucosa (keratin 7?, keratin 20+, MUC2+). Carcinomas of pancreaticobiliary type usually show the immunohistochemical profile of pancreaticobiliary duct mucosa (keratin 7+, keratin 20?, MUC2?). Even poorly differentiated carcinomas, as well as unusual histological types, may conserve the marker profile of the mucosa they developed from. These findings underline the concept of histogenetically different carcinomas of the papilla of Vater which develop either from intestinal- or from pancreaticobiliary-type mucosa of the papilla of Vater. Molecular alterations in ampullary carcinomas are similar to those of colorectal as well as pancreatic carcinomas, although they appear at different frequencies. In future studies, molecular alterations in ampullary carcinomas should be correlated closely with the different histologic tumor types. Consequently, the histologic classification should reflect the histogenesis of ampullary tumors from the two different types of papillary mucosa.     

Lack of correlation of degree of villous atrophy with severity of clinical presentation of coeliac disease

BACKGROUND AND AIM: Both the clinical presentation and the degree of mucosal damage in coeliac disease vary greatly. In view of conflicting information as to whether the mode of presentation correlates with the degree of villous atrophy, we reviewed a large cohort of patients with coeliac disease. PATIENTS AND METHODS: We correlated mode of presentation (classical, diarrhoea predominant or atypical/silent) with histology of duodenal biopsies and examined their trends over time. RESULTS: The cohort consisted of 499 adults, mean age 44.1 years, 68% females. The majority had silent coeliac disease (56%) and total villous atrophy (65%). There was no correlation of mode of presentation with the degree of villous atrophy (p=0.25). Sixty-eight percent of females and 58% of males had a severe villous atrophy (p=0.052). There was a significant trend over time for a greater proportion of patients presenting as atypical/silent coeliac disease and having partial villous atrophy, though the majority still had total villous atrophy. CONCLUSIONS: Among our patients the degree of villous atrophy in duodenal biopsies did not correlate with the mode of presentation, indicating that factors other than the degree of villous atrophy must account for diarrhoea in coeliac disease.     

Demonstration of the mechanism of action of biguanides

Summary Palmitic acid oxidation in rat diaphragm homogenate is depressed by biguanide concentrations that are still incapable of inhibiting oxidative phosphorylation. Glucose oxidation is not directly effected by the same biguanide concentrations: however, the inhibitory effect of palmitic acid on glucose oxidation is partly removed by biguanides. Inhibition of fatty acid oxidation, which accounts for most of the metabolic effects caused by these drugs, can be regarded as the fundamental mechanism of action of biguanides. There is some evidence suggesting that these drugs might interact with carnitine, thus preventing long-chain fatty acids from being transported across the mitochondrial membrane to the site of oxidation. Traduzione a cura degli AA.     

血吸虫童虫生长发育及其机制的研究进展

血吸虫童虫是宿主免疫系统攻击的重要靶标,包括皮肤型、肺型和肝门型童虫。宿主分子对童虫生长发育具有重要作用。童虫生长发育机制包括免疫调节、信号转导、性别发育及凋亡等。肌动蛋白、组织蛋白酶、烯醇化酶和葡萄糖基转移酶等分子为血吸虫童虫生长发育的重要分子。本文对血吸虫童虫生长发育及其机制的研究进展做一综述。     

124例耐多药结核分枝杆菌基因突变特征分析

目的对临床分离的耐多药结核分枝杆菌相关基因的突变特征进行分析。方法对124例耐多药结核分枝杆菌以及50株敏感株的耐药相关基因(包括异烟肼inh A、kat G、oxyR-ahp C间隔区以及利福平rpo B)进行序列测定,分析其基因突变情况。结果异烟肼耐药inh A基因突变率为14.5%;kat G基因突变率为70.2%(87/124),主要位于315位;oxyR-ahp C间隔区突变率为15.3%;inh A、kat G两种基因同时突变率75.0%,三种基因同时突变率为89.5%。利福平rpo B基因突变的检出率高达95.2%,突变主要发生在531、526、516位点。结论我省耐多药菌异烟肼耐药相关基因最常见突变为kat G 315、inh A C-T(-15)、axyR-ahp C间隔区(-10)C-T,利福平为rpo B531、526、516。结合MDR-TB耐药相关基因的特征分析,可以建立一种快速、准确、特异的适合于我省的检测结核菌耐多药性的新方法。     

Assessment of quality of life of parents of children with juvenile chronic arthritis

The aim of the study was to assess the quality of life (QOL) and the psychological status of parents of children with juvenile chronic arthritis (JCA). The QOL, anxiety and depression of the parents of 28 children with JCA were evaluated and compared to those of the parents of 28 healthy children. Mothers of JCA children and mothers of healthy children reported similar QOL. The reported anxiety and depression levels were similar for mothers and fathers in both groups. The parents of children with pauciarticular-type JCA reported lower QOL and higher levels of anxiety and depression than the parents of children with other types, namely polyarticular and systemic JCA. These findings may be explained by the fact that the pauciarticular patients had shorter disease duration and were less frequently seen in the outpatient clinic. The QOL of mothers of children with JCA was found to be slightly impaired in the group of children with pauciarticular JCA. Future larger studies are needed to confirm these results, as the number of subjects in the three groups was rather low. Received: 26 September 2001 / Accepted: 8 February 2002     

氯硝柳胺悬浮剂的毒性评价

目的评价氯硝柳胺悬浮剂的毒性，为现场大规模应用灭螺提供依据。方法按照中华人民共和国国家标准GB 15670-1995《农药登记毒理学试验方法》和鱼类毒性试验方法进行。结果经口、经皮肤的LDso雌、雄性大鼠均>5 000 mg/kg，经呼吸道的LCso雌、雄性大鼠均>5 000mg/m3，该药经口、经皮肤、经呼吸道毒性均属微毒类药物；兔眼用药后，观察期内无不良反应，对眼无刺激性；皮肤用药后对皮肤无刺激性。与氯硝柳胺原药、氯硝柳胺乙醇胺盐原药和氯硝柳胺乙醇胺盐可湿性粉剂相比，氯硝柳胺悬浮剂对鱼急性毒性最低。结论氯硝柳胺悬浮剂属微毒类药物，对鱼的毒性低于其乙醇胺盐可湿性粉剂，适合于现场应用。     

Numerical Simulation of the Effect of Rate of Change of Glucose on Measurement Error of Continuous Glucose Monitors

Background

A 5-day in-patient study designed to assess the accuracy of the FreeStyle Navigator® Continuous Glucose Monitoring System revealed that the level of accuracy of the continuous sensor measurements was dependent on the rate of glucose change. When the absolute rate of change was less than 1 mg•dl⁻¹•min⁻¹ (75% of the time), the median absolute relative difference (ARD) was 8.5%, with 85% of all points falling within the A zone of the Clarke error grid. When the absolute rate of change was greater than 2 mg•dl⁻¹•min⁻¹ (8% of the time), the median ARD was 17.5%, with 59% of all points falling within the Clarke A zone.

Method

Numerical simulations were performed to investigate effects of the rate of change of glucose on sensor measurement error. This approach enabled physiologically relevant distributions of glucose values to be reordered to explore the effect of different glucose rate-of-change distributions on apparent sensor accuracy.

Results

The physiological lag between blood and interstitial fluid glucose levels is sufficient to account for the observed difference in sensor accuracy between periods of stable glucose and periods of rapidly changing glucose.

Conclusions

The role of physiological lag on the apparent decrease in sensor accuracy at high glucose rates of change has implications for clinical study design, regulatory review of continuous glucose sensors, and development of performance standards for this new technology. This work demonstrates the difficulty in comparing accuracy measures between different clinical studies and highlights the need for studies to include both relevant glucose distributions and relevant glucose rate-of-change distributions.     

Study of constancy of hydrogen-consuming flora of human colon

The constancy of the hydrogen consuming flora of the human colon was studied in 15 healthy subjects via two measurements obtained 18 to 36 months apart. Hydrogen disappearance rate and the major products of H₂-consuming bacteria, methane and sulfide, were measured during incubation of fecal homogenates with excess hydrogen and sulfate. In 11/15, the hydrogen consumption rate and the predominant hydrogen-consuming pathway (methanogenesis, sulfate reduction, or neither) remained constant. However, major shifts in these pathways were observed in four subjects, with two losing and two gaining the ability to produce methane. Methanogenesis was associated with the highest hydrogen consumption rate. This study demonstrates that clinically unrecognizable, major alterations of the colonic flora occur in healthy subjects. Understanding of the factors responsible for these alterations might allow for therapeutic manipulation of the colonic flora.Supported in part by the Department of Veterans Affairs and NIDDKD RO1 DK 13309-25.