用于治疗肥胖和糖尿病的二酰甘油酰基转移酶抑制剂研究进展

人体内的二酰甘油酰基转移酶是催化三酰甘油最终合成的关键酶,其基因缺失或酶活受抑时,机体不会因高脂饮食而发生肥胖,且对胰岛素的敏感性增强,因此该酶可作为肥胖和糖尿病治疗药物的靶点。综述二酰甘油酰基转移酶的功能研究以及天然来源和合成的二酰甘油酰基转移酶抑制剂的药理活性和构效关系。     

新一代广谱抗生素药物筛选靶点肽脱甲酰基酶的研究进展

肽脱甲酰基酶(peptide deformylase，PDF)存在于所有原核生物中，是其生长、代谢、繁殖必不可少的关键酶，但不存在于人类与其他哺乳动物细胞内，因而被视为新一代广谱抗生素药物筛选的理想靶点。现介绍PDF的结构、功能、理化性质以及作为药物筛选靶点的优良特点，此外，还简单介绍该酶与其抑制剂相互作用机制和以该酶为靶点新药研究进展。     

蕲蛇酶治疗肥胖2型糖尿病5年追踪疗效观察

目的观察蕲蛇酶对于肥胖的发病早期的2型糖尿病患者的远期疗效。方法BMI≥30、病史不超过2年的2型糖尿病患者32例,给予蕲蛇酶0.75U静滴,1日1次,共10d。在专科医师指导下进行糖尿病饮食和运动,追踪随访期间实验对象每年减体重〉5kg,使体重控制在BMI24-28,观察治疗前和治疗后每年的体重指数（BMI）、空腹血糖（FPG）、空腹胰岛素（FINS）、餐后血糖（FBG）、餐后胰岛素（PINS）、糖化血红蛋白（HbA1c）,治疗前与治疗后第五年检测值进行比较。结果治疗前和治疗后第五年BMI、FPG、FINS、FBG、PINS、HbA1c差异有显著性意义P〈0.01。结论蕲蛇酶治疗肥胖、发病早期的2型糖尿病患者可获得良好的降糖疗效,血糖、HbA1c在5年内持续达标,不引发低血糖,不加重肥胖,达到长期缓解的目标。     

一例2型糖尿病肥胖患者的治疗方案优化

2型糖尿病肥胖患者多伴有高胰岛素血症和胰岛素抵抗,二甲双胍是这类人群用药的首选方案.本文通过对一例2型糖尿病肥胖病例进行分析,明确这类患者血糖的管理目标、药物治疗方案制订和生活方式调整建议.     

小剂量蕲蛇酶联合足量胰岛素治疗肥胖中青年的2型糖尿病

目的探讨改善微循环药物联合足量胰岛素注射,恢复和/或增强胰岛素敏感性的方法以及治疗肥胖中青年2型糖尿病的疗效。方法接受小剂量蕲蛇酶联合足量胰岛素注射为试验组,口服二甲双胍联合小剂量胰岛素注射为对照组。比较两组患者治疗前后的11项临床指标。结果试验组治疗后与胰岛素敏感性有关的7项指标和4项伴随表现指标与对照组比较有显著性差异(P<0.01)。试验组44例缓解,对照组6例缓解。结论改善微循环药物联合足量胰岛素注射的作用能够恢复肥胖中青年2型糖尿病患者胰岛素敏感性,多数患者(44/51)可得到缓解。     

利拉鲁肽治疗新诊断肥胖2型糖尿病的疗效观察

目的观察利拉鲁肽在新诊断肥胖2型糖尿病中的疗效。方法选择50例新诊断的肥胖2型糖尿病患者用利拉鲁肽治疗12周,比较治疗前后血糖、BMI、血脂及胰岛素水平变化情况。结果利拉鲁肽治疗后,BMI及糖化血红蛋、白血糖、血脂明显降低,胰岛功能明显改善。结论肥胖2型糖尿病用利拉鲁肽治疗能有效控制血糖,减轻体质量,增加胰岛素敏感性,改善脂质代谢,是肥胖2型糖尿病的理想选择。     

肥胖糖尿病患者降糖药物的选择

随着人们生活水平的不断提高,高热量、高脂肪、高蛋白、低纤维饮食的摄入越来越多,肥胖症增加的同时,肥胖的2型糖尿病患者也越来越多,因而该类人群的治疗与管理已成为目前临床上的一个难点。肥胖2型糖尿病患者体质指数(body mass index,BMI)较高,胰岛素抵抗严重,而且多合并高血脂、高血压等多种疾病,具有发展快,血糖达标难,并发症出现早等主要特点。本文就肥胖与2型糖尿病的关系、肥胖2型糖尿病患者的药物选择,以及目前针对肥胖2型糖尿病治疗的展望做一个综述。     

以大肠埃希氏菌肽脱甲酰基酶为靶点的高通量筛选模型的建立

本文用PCR法从大肠埃希氏菌K-12中克隆出肽脱甲酰基酶(peptide deformylase，PDF)基因，通过测序确证与文献报道的pdf基因序列完全一致。将pdf连接到原核蛋白表达载体pET-30-a( )上，并转化到大肠埃希氏菌BL21(DE3)菌株中，IPTG诱导表达。过量表达的PDF酶用QSepharoseHP离子交换柱和Superdex75纯化得到高纯度Ni—PDF。应用荧光测试仪Polar Fluostar检测PDF对底物For—Met—Ala—Ser的水解活性，PDF酶的已知抑制剂放线酰胺素(actinonin)为阳性对照，通过优化酶反应条件，建立了以PDF为靶点的高通量药物筛选模型。     

利拉鲁肽治疗新诊断肥胖2型糖尿病疗效分析

肥胖已成为全球范围内危害公共健康的严重疾病,约80％的2型糖尿病患者存在不同程度的超重或肥胖,对于肥胖的糖尿病患者,治疗的关键是减轻体重。胰高血糖素样肽1（ GLP-1）类似物利拉鲁肽在降糖的同时,控制体重效果显著。本文应用利拉鲁肽治疗新诊断肥胖2型糖尿病患者,观察其降糖疗效。报告如下。     

新抗菌靶点肽去甲酰基酶抑制剂的研究进展

综述新抗菌靶点肽去甲酰基酶在细菌蛋白合成中的作用、三维结构及其抑制剂的设计、发现与开发和耐药菌的产生。随着细菌耐药性的广泛发生以及多药耐药菌的出现,临床上急需对耐药菌有效的新型抗菌药,而寻找新型抗菌靶点为抗耐药菌药物的研究提供了新思路。     

A < 1.7 cM interval is responsible for Dmo1 obesity phenotypes in OLETF rats

1. Dmo1 (Diabetes Mellitus OLETF type I) is a major quantitative trait locus for dyslipidaemia, obesity and diabetes phenotypes of male Otsuka Long Evans Tokushima Fatty (OLETF) rats. 2. Our congenic lines, produced by transferring Dmo1 chromosomal segments from the non-diabetic Brown Norway (BN) rat into the OLETF strain, have confirmed the strong, wide-range therapeutic effects of Dmo1 on dyslipidaemia, obesity and diabetes in the fourth (BC4) and fifth (BC5) generations of congenic animals. Analysis of a relatively small number of BC5 rats (n = 71) suggested that the critical Dmo1 interval lies within a < 4.9 cM region between D1Rat461 and D1Rat459. 3. To confirm the assignment of the Dmo1 critical interval, we intercrossed BC5 animals to produce a larger study population (BC5:F1 males; n = 406). For the present study, we used bodyweight at 18 weeks of age as an index of obesity; this phenotype is representative of the closely associated dyslipidaemia and hyperglycaemia phenotypes. 4. Interval mapping assigned logarithm of odds (LOD) peaks at the D1Rat90 marker (LOD = 9.11). One LOD support interval lies within the < 1.7 cM region between D1Rat461 and D1Rat459. 5. This large intercross study confirms that Dmo1 is likely localized within the interval.     

Mutated G-protein-coupled receptor GPR10 is responsible for the hyperphagia/dyslipidaemia/obesity locus of Dmo1 in the OLETF rat

1. We have confirmed the Diabetes Mellitus OLETF type I (Dmo1) effect on hyperphagia, dyslipidaemia and obesity in the Otsuka Long-Evans Tokushima Fatty (OLETF) strain. The critical interval was narrowed down to 570 kb between D1Got258 to p162CA1 by segregation analyses using congenic lines. 2. Within the critical 570 kb region of the Dmo1 locus, we identified the G-protein-coupled receptor gene GPR10 as the causative gene mutated in the OLETF strain. The ATG translation initiation codon of GPR10 is changed into ATA in this strain and, so, is unavailable for the initiation of translation. 3. The GPR10 protein has a cognate ligand, namely prolactin-releasing peptide (PrRP). Centrally administered PrRP suppressed the food intake of congenic rats that have a Brown Norway derived Dmo1 region (i.e. with wild-type GPR10), but did not suppress that of the OLETF strain, indicating that GPR10 is without function and could explain hyperphagia in the OLETF strain. 4. Moreover, when restricted in food volume to the same level consumed by the congenic strain, OLETF rats showed few differences in the parameters of dyslipidaemia and obesity compared with congenic strains. 5. Taken together, these results demonstrate that the mutated GPR10 receptor is responsible for the hyperphagia leading to obesity and dyslipidaemia in the obese diabetic strain rat.     

Long-term use of diethylpropion in obesity

Summary

Diethylpropion (‘Tenuate Dospan’) was found to be an acceptable therapy when given on a long-term basis to 20 very overweight patients who had failed to lose weight on diet alone. There were remarkably few untoward side-effects and no indication of the development of tolerance to the drug. An interesting feature of the trial was a correlation between fall in blood pressure with loss of weight.     

外泌体在肥胖症中的研究进展

外泌体是细胞分泌的一种囊泡样小体,可通过受体与配体间的相互作用刺激靶细胞,或通过向靶细胞转移各种生物活性分子如膜受体、蛋白质、mRNA和miRNA等方式在细胞间通讯中扮演重要角色,其中研究最多的是miRNAs。最近研究表明,外泌体中特定的miRNAs通过调控脂肪的形成、经典棕色脂肪组织功能和白色脂肪组织褐变过程,以及参与脂肪组织巨噬细胞的活化状态,在肥胖症的病理过程中发挥关键作用。     

Sibutramine for obesity in adolescents

In adolescents, there is an epidemic of being overweight or obese. Sibutramine has been shown to cause sustained loss of weight in adults. In a study based in Mexico City, adolescents with a BMI of 35/36 kg/m², who were put on a hypocaloric diet and undertook physical activity, lost 4.3 kg in 6 months, and this loss was increased to 7.3 kg by sibutramine. Similarly, in a study based in the US, there was a loss of 1.9 kg in the placebo group of obese adolescents with a hypocaloric diet and increased physical activity at the end of 12 months, and this was increased to 6.5 kg in the sibutramine group. Sibutramine has a slight tendency to increase blood pressure and heart rate, and seems to be more effective than orlistat in causing weight loss in adolescents. However, orlistat does not have negative effects on blood pressure. Long-term follow-up studies of sibutramine in adolescents are needed to determine whether the weight loss is maintained, and whether the weight loss translates into better clinical outcomes.     

Antisense and small-molecule modulation of diacylglycerol acyltransferase

Diacylglycerol acyltransferase 1 and diacylglycerol acyltransferase 2 each catalyze the synthesis of triacylglycerol from diacylglycerol and acyl-CoA. As altered triacylglycerol metabolism is associated with a variety of human diseases, methods to modulate the activity of these enzymes have garnered considerable interest. Genetic validation for targeting the diacylglycerol acyltransferases has emerged from mouse knockout models as well as antisense oligonucleotide therapy in rodents. Small molecule inhibitors of the diacylglycerol acyltransferases, especially diacylglycerol acyltransferase 1, have been the subject of intense activity in the patent literature.     

Pharmacological management of obesity

Obesity is a major chronic health problem in adults. It is a complex, multifactorial disorder characterised by excess accumulation of adipose tissue. It is associated with a number of complications including cardiovascular disease, hypertension, type 2 diabetes, dyslipidaemia and cancer. A weight loss in the order of 5 – 10% is associated with clinically meaningful reductions with respect to all comorbidities. Diet and exercise has been the cornerstone of weight management therapy, but this approach has limitations, especially for weight maintenance. Previous drugs used in obesity had serious side effects including valvular heart disease. However, recent drugs like orlistat and sibutramine have been rigorously tested and proven safe. Orlistat, a lipase inhibitor, inhibits absorption of dietary fat by ～ 30%. Taken with a hypocaloric diet, it produces and maintains clinically meaningful weight loss. Sibutramine is a centrally-acting agent which enhances satiety and thermogenesis by inhibiting serotonin and noradrenaline re-uptake. It is appropriate for patients who are unable to lose weight by lifestyle modification.     

马吲哚与芬氟拉明治疗单纯性肥胖的比较

目的：比较马吲哚与芬氟拉明对单纯性肥胖的疗效。方法：单纯性肥胖２６０例，随机分为２组，马吲哚组１３０例（男性４５例，女性８５例；年龄４１±ｓ９ａ）用马吲哚１ｍｇｐｏ，ｂｉｄ；芬氟拉明组１３０例（男性４９例，女性８１例；年龄４３±１１ａ）用芬氟拉明２０ｍｇ，ｐｏ，ｔｉｄ。２组治疗均８ｗｋ。结果：马吲哚组体重下降５．２±２．０ｋｇ，有效率为８２．３％，芬氟拉明组下降４．７±１．８ｋｇ，有效率为７３．１％；２组均有总胆固醇、舒张压、胰岛素及生长激素降低及超氧化物歧化酶－铜－锌升高，其程度马吲哚组优于芬氟拉明组（Ｐ均＜０．０１）。马吲哚组尚能克服嗜睡，对胃肠道不良反应少。结论：马吲哚可作为一种有效的减肥药。     

学龄前儿童肥胖的综合干预研究

目的：了解辖区学龄前儿童单纯性肥胖发生情况,评估综合干预对减少肥胖发生的有效方法。方法：选择8所二类幼儿园2012年和2013年入园的1618名儿童进行体重和身高测量,对所有肥胖儿童采取合理饮食、适当运动和健康教育综合干预1年,对干预前后肥胖的检出率和肥胖程度的变化进行比较。结果：入园儿童单纯性肥胖的检出率为6.86%,、干预1年后,相应的单纯性肥胖检出率为4.76%,儿童肥胖检出率差异有统计学意义（P＜0.05）。肥胖儿童的肥胖程度有所减轻。结论：合理饮食、适当运动和健康教育综合干预措施是预防和控制学龄前儿童肥胖的有效方法。