利拉鲁肽对新疆维吾尔族2型糖尿病肥胖患者的疗效研究

目的探讨利拉鲁肽治疗新疆维吾尔族2型糖尿病(T2DM)肥胖患者的疗效。方法纳入67例单用二甲双胍后血糖控制不理想的肥胖T2DM患者,将其随机分为二甲双胍组(单用二甲双胍)和二甲双胍+利拉鲁肽组(联合应用二甲双胍和利拉鲁肽),治疗周期为12周。分别在基线、治疗12周后检测2组患者腹部内脏脂肪面积(VA)、体脂百分比(PBF)、体脂肪量,同时测量一氧化氮(NO)、空腹血糖(FBG)、糖化血红蛋白(HbA1c)、游离脂肪酸(FFA)等相关指标,计算体质量指数(BMI)、腰臀比(WHR),采取病例对照的试验方法进行分析。结果治疗12周后,二甲双胍+利拉鲁肽组较二甲双胍组,患者体质量(W)、WHR、腰围(WC)、空腹血糖(FBG)、体脂肪量和腹内脂肪(VA)均明显下降,差异有统计学意义(P0.05)。结论接受利拉鲁肽治疗的T2DM肥胖患者在血糖、血脂得到控制的同时,能获得降低W、改善血管内皮功能、减少内脏脂肪的收益。     

Safety and tolerability of new-generation anti-obesity medications: a narrative review

The prevalence of obesity and associated comorbidities is rising. Despite their weight-loss efficacy, new generation anti-obesity medications are only prescribed to a minority of adults with obesity, possibly, which in part may be due to safety concerns. This review presents detailed safety profiles for orlistat, phentermine/topiramate, lorcaserin, naltrexone/bupropion and liraglutide 3.0 mg, and discusses the associated risk–benefit profiles. Two anti-obesity medications presented safety issues that warranted further discussion; phentermine/topiramate (fetal toxicity) and liraglutide 3.0 mg (risk of gallstone disease and mild, acute pancreatitis), whereas the adverse events associated with orlistat, lorcaserin, and naltrexone/bupropion were mostly transient tolerability issues. The difficulties surrounding the objective determination of risk–benefit for anti-obesity medications is discussed. The need for more long-term data, thorough patient assessment, individualization of pharmacological interventions and adherence to stopping rules to maximize risk–benefit are highlighted. Overall, the majority of new generation anti-obesity medications present encouraging tolerability profiles; however, in some cases a lack of long-term clinical trials confounds the accurate determination of risk–benefit.     

利拉鲁肽对高血脂小鼠血脂的影响

目的 研究利拉鲁肽对高血脂小鼠体质量和血清中总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白(LDL-C)及高密度脂蛋白(HDL-C)的影响。方法 将40只小鼠,随机分为对照组、模型组、阳性组及利拉鲁肽低、高剂量组。对照组饲喂基础饲料,其余4组均饲喂高脂饲料。对照组和模型组均ip生理盐水,阳性组ig辛伐他汀,利拉鲁肽低、高剂量组每日分别ip 200、400μg/kg利拉鲁肽1次,连续4周。实验结束处死小鼠,称质量,检测各组小鼠给药前后血清中TC、TG、LDL-C、HDL-C水平,并计算动脉粥样硬化指数(AI)和抗动脉粥样硬化指数(AAI)。结果 与对照组相比,模型组小鼠体质量及血脂指标明显升高;与模型组相比,阳性组、利拉鲁肽低、高剂量组小鼠体质量及血脂指标明显降低,且利拉鲁肽的效果明显优于辛伐他汀;与模型组相比,利拉鲁肽低剂量组的AI显著性降低,利拉鲁肽高剂量组的AAI显著升高。结论 利拉鲁肽能具有很好的调血脂、抑制动脉粥样硬化的功效,在预防心血管疾病方面具有很好的应用前景。     

利拉鲁肽对高脂喂养大鼠胰腺β细胞ATF4/CHOP通路的影响

目的 观察利拉鲁肽对高脂喂养大鼠胰腺GRP78、转录活化因子4(ATF4)、CCAAT区/增强子结合蛋白同源蛋白(CHOP)、TRB3蛋白和mRNA表达情况,探讨利拉鲁肽对高脂喂养大鼠胰腺ATF4/CHOP通路的影响.方法 将雄性Wistar大鼠44只分为对照组、高脂组、干预组1、干预组2,每组11只,对照组给予普通饮食,其余3组给予高脂饮食喂养8周后,干预组1给予利拉鲁肽100 μg·kg-1·d-1皮下注射;干预组2给予利拉鲁肽200 μg·kg-1·d-1皮下注射.药物干预2周后处死,每组取5只大鼠行清醒状态下高胰岛素-正葡萄糖钳夹试验计算葡萄糖输注率(GIR),测定其余大鼠空腹血糖(FBG)、空腹胰岛素(FINS)、血清游离脂肪酸(FFA)、总胆田醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)和高密度脂蛋白胆固醇(HDL-C),计算胰岛β细胞功能指数(HOMA-β),Western blot和Realtime-PCR技术检测胰腺GRP78、ATF4、CHOP和TRB3蛋白及mRNA的表达.结果 与对照组相比,高脂组FBG、FFA、TC、FINS、TG、LDL-C水平显著升高,HDL-C、GIR和HOMA-β明显下降(P＜0.05或P＜0.01),与高脂组相比,干预组2 HDL-C、GIR和HOMA-β升高(P＜0.05或P＜0.01),其余指标明显下降;与干预组1相比,干预组2的血FGB、FFA、TC下降,GIR和HOMA-β升高(P＜0.05).与对照组相比,高脂组GRP78、ATF4、CHOP和TRB3蛋白及mRNA的表达明显升高;与高脂组相比,干预组1与干预组2随利拉鲁肽浓度升高,GRP78、ATF4、CHOP和TRB3蛋白及mRNA表达逐渐下降.结论 利拉鲁肽可呈浓度依赖性改善高脂喂养大鼠胰岛素抵抗及保护胰岛β细胞,其作用机制可能涉及胰腺内质网ATF4/CHOP通路.     

Effects of liraglutide and ischemic postconditioning on myocardial salvage after I/R injury in pigs*

Objectives. Acute STEMI is routinely treated by acute PCI. This treatment may itself damage the tissue (reperfusion injury). Conditioning with GLP-1 analogs has been shown to reduce reperfusion injury. Likewise, ischemic postconditioning provides cardioprotection following STEMI. We tested if combined conditioning with the GLP-1 analog liraglutide and ischemic postconditioning offered additive cardioprotective effect after reperfusion of 45?min coronary occlusion of left anterior descending artery (LAD). Design. Fifty-eight non-diabetic female Danish Landrace pigs (60?±?10kg) were randomly assigned to four groups. Myocardial infarction (MI) was induced by occluding the LAD for 45?min. Group 1 (n?=?14) was treated with i.v. liraglutide after 15?min of ischemia. Group 2 (n?=?17) received liraglutide treatment concomitant with ischemic postconditioning, after 45?min of ischemia. Group 3 (n?=?15) recieved ischemic postconditioning and group 4 (n?=?12) was kept as controls. Results. No intergroup differences in relative infarct size were detected (overall mean 57?±?3%; p?=?0.68). Overall mortality was 34% (CI 25–41%) including 26% post-intervention, with no intergroup differences (p?=?0.99). Occurrence of ventricular fibrillation (VF) was 59% (CI 25–80%) including 39% postintervention with no intergroup differences (p?=?0.65). Conclusions. In our closed-chest pig-model, we were unable to detect any cardioprotective effect of liraglutide or ischemic postconditioning either alone or combined.     

Newer therapeutic options for children with diabetes mellitus: theoretical and practical considerations

Recent studies in adult patients with type 1 diabetes mellitus (T1DM) and T2DM have examined the potential utility, benefits, and side effects of agents that augment insulin secretion after oral ingestion of nutrients in comparison with intravenous nutrient delivery, the so-called incretins. Two families of incretin-like substances are now approved for use in adults. Glucagon-like peptide-1 (GLP-1) or agents that bind to its receptor (exenatide, Byetta) or agents that inhibit its destruction [dipeptidyl peptidase-IV (DPP-IV) inhibitors, Vildagliptin] improve insulin secretion, delay gastric emptying, and suppress glucagon secretion while decreasing food intake without increasing hypoglycemia. Pramlintide, a synthetic amylin analog, also decreases glucagon secretion and delays gastric emptying, improves hemoglobin A1c (HbA1C), and facilitates weight reduction without causing hypoglycemia. We review the historical discovery of these agents, their physiology [corrected] and their current applications. Remarkably, only one or two studies have been reported in children. Pediatricians caring for children with T1DM and T2DM should become familiar with these agents and investigate their applicability, as they seem likely to enhance our therapeutic armamentarium to treat children with diabetes mellitus.     

Management of Type 2 diabetes: the role of incretin mimetics

Type 2 diabetes is characterised by insulin resistance and progressive β-cell dysfunction (which leads to hyperglycaemia), the risk of progressive worsening of glycaemic control and an increased risk of both macrovascular and microvascular complications. Existing treatment strategies target deficient insulin secretion and insulin resistance, but do not generally address the underlying progressive β-cell dysfunction that is common to Type 2 diabetes. Traditionally, Type 2 diabetes is first treated with medical nutrition therapy (reduced food intake and increased physical activity), followed by stepwise addition of oral antidiabetes therapies and, ultimately, exogenous insulin, as required. Unfortunately, these approaches have not been shown to delay the need for additional therapies, nor do they generally prevent or delay the inexorable decline in β-cell function. Patients with Type 2 diabetes commonly experience deterioration in glycaemic control, and may have substantial weight gain due to the diabetes therapies that contribute to worsening obesity. In addition, insulin-providing therapies, such as sulfonylureas and exogenous insulin, carry the risk of hypoglycaemia, and cannot fully address the complex hormonal irregularities that characterise Type 2 diabetes, including the role of glucagon hypersecretion. New therapeutic approaches are being developed that couple durable glycaemic control with improved control of body weight. These approaches include development of the incretin mimetics, which are a novel class of agents that share several of the glucoregulatory effects of incretin hormones, such as glucagon-like hormone-1. Deficiency of glucagon-like hormone-1 secretion is known to be present in those with abnormal glucose tolerance. Agents that manipulate the physiological actions of incretin hormones, such as glucagon-like hormone-1, may significantly benefit patients with Type 2 diabetes.