达格列净联合利拉鲁肽对2型糖尿病患者相关代谢指标的影响

目的 分析达格列净联合利拉鲁肽对2型糖尿病患者相关代谢指标的影响,为临床治疗提供依据.方法 选取2018年3月至2020年9月我院收治的136例2型糖尿病患者作为研究对象,根据治疗方案的不同将其分为对照组和观察组,各68例.对照组在常规干预的基础上给予利拉鲁肽治疗,观察组在对照组基础上联合达格列净进行治疗.比较两组治疗前、后的血糖指标、胰岛功能指标、脂代谢指标、APN和氧化应激指标.结果 治疗后,两组的FPG、2 h PG水平及HbA1c均较治疗前明显降低,且观察组低于对照组,差异具有统计学意义(P<0.05).治疗后,两组的FINS、2 h INS、FCP、2 h CP水平及HOMA-β较治疗前升高,HOMA-IR较治疗前降低,且观察组优于对照组,差异具有统计学意义(P<0.05).治疗后,两组的TG、TC、LDL-C水平较治疗前降低,HDL-C水平较治疗前升高,且观察组优于对照组,差异具有统计学意义(P<0.05).治疗后,两组的APN、GSH-Px及SOD水平均较治疗前明显升高,且观察组高于对照组,差异具有统计学意义(P<0.05).结论 达格列净联合利拉鲁肽治疗2型糖尿病能有效控制血糖,提高胰岛功能,改善糖脂代谢水平及氧化应激指标.     

利拉鲁肽通过circ-sirt1/NF-κB信号通路抑制血管平滑肌细胞炎症的机制研究

目的 探究利拉鲁肽(liraglutide,LIR)对肿瘤坏死因子α(tumour necrosis factor-α,TNF-α）诱导的血管平滑肌细胞炎症反应的作用及其可能的分子机制。 方法 实验分为空白对照组(NC组)、TNF-α组(10 μg/L)和TNF-α+LIR组(10 μg/L TNF-α+100 nmol/L LIR)。酶联免疫吸附测定(enzyme-linked immunosorbent assay,ELISA)检测细胞培养基中的白细胞介素1β(interleukin-1β,IL-1β)和白细胞介素6(interleukin-6,IL-6)。实时荧光定量核酸扩增检测系统(real-time quantitative polymerase chain reaction detecting system,qPCR)检测circ-sirt1及细胞间黏附分子1(inter-cellular adhesion molecule 1,ICAM-1)、单核细胞趋化蛋白1(monocyte chemoattractant protein-1,MCP-1)、抑制性卡巴蛋白α(inhibitor kppa B-α,IκB-α）mRNA的表达。Western Blot检测细胞ICAM-1、MCP-1和IκB-α蛋白表达。免疫荧光检测核因子κB（nuclear factor kappa-B,NF-κB）p65蛋白分布。 结果 与NC组相比,TNF-α组细胞培养基中的IL-1β和IL-6含量显著升高,ICAM-1、MCP-1 mRNA及蛋白表达显著升高,IκB-α mRNA及蛋白表达显著减低,circ-sirt1表达显著降低,NF-κB p65蛋白主要定位在细胞核。与TNF-α组相比,TNF-α+LIR组IL-1β和IL-6含量显著减少,ICAM-1、MCP-1蛋白表达显著降低,IκB-α蛋白表达显著增加,circ-sirt1表达显著升高,NF-κB p65蛋白细胞核定位减少。 结论 利拉鲁肽能够抑制血管平滑肌细胞的炎性反应,可能是通过抑制炎症介质释放及circ-sirt1/NF-κB信号通路的激活发挥作用。     

利拉鲁肽注射剂治疗糖尿病的临床研究

目的观察利拉鲁肽治疗糖尿病的临床疗效与安全性。方法选取糖尿病患者86例,随机分为试验组(43例)和对照组(43例)。对照组进行常规治疗。在对照组基础上,试验组于每日早餐前,皮下注射利拉鲁肽0.6 mg,疗程均为24周。比较治疗后2组患者的临床疗效和药物不良反应(ADR),测定2组患者的血糖、脂联素和血管紧张素Ⅱ水平。结果治疗后,试验组总有效率(93.0%)显著高于对照组(76.7%),差异有统计学意义(P<0.05)。治疗后,试验组与对照组的空腹血糖分别为(5.93±0.80),(7.56±0.50)mmol·L^-1;这2组的餐后血糖分别为(7.74±0.76),(9.21±1.06)mmol·L^-1;这2组的糖化血红蛋白分别为(6.02±0.86)%,(8.42±0.50)%,试验组均明显低于对照组,差异均有统计学意义(均P<0.05)。试验组与对照组的脂联素分别为(7.89±0.74),(6.05±0.75)mg·L^-1;这2组的血管紧张素Ⅱ分别为(125.98±2.26),(117.49±4.17)ng·L^-1,试验组的上述指标均明显高于对照组,差异均有统计学意义(均P<0.05)。试验组和对照组ADR发生率分别为0和7.0%,组间差异有统计学意义(P<0.05)。结论利拉鲁肽治疗糖尿病可明显改善机体内各项指标,提高康复率,且安全性较好。     

利拉鲁肽对高脂喂养肥胖大鼠胰腺中核转录因子κB和蛋白酪氨酸磷酸酶1B的影响

目的研究利拉鲁肽对高脂喂养肥胖大鼠胰腺中核转录因子κB(NF-κB)和蛋白酪氨酸磷酸酶1B(PTP-1B)表达的影响。方法用高脂饮食诱导建立大鼠肥胖模型,并随机分组对照组和实验组,每组7只;另取7只正常大鼠作为空白组。实验组予以皮下注射利拉鲁肽注射液0.6 mg·kg^-1·d^-1,对照组和空白组均予以皮下注射同体积0.9%NaCl约2 mL。3组大鼠均干预2周。比较3组大鼠胰腺中NF-κB活性和PTP-1B蛋白表达量。结果干预2周后,实验组、对照组和空白组的NF-κB积分灰度值分别为69.2,150.5和70.4,PTP-1B蛋白表达量分别为(1.53±0.34),(1.79±0.12)和(1.32±0.34),实验组和空白组的上述指标比较,差异均无统计学意义(均P>0.05),对照组的上述指标与实验组、空白组比较,差异均有统计学意义(均P<0.05)。结论利拉鲁肽注射液可阻断高脂饮食对胰腺组织NF-κB的活化作用,同时可降低PTP-1B蛋白的表达。     

The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non‐human primate model of Alzheimer's disease

Alzheimer's disease (AD) is a devastating neurological disorder that still lacks an effective treatment, and this has stimulated an intense pursuit of disease‐modifying therapeutics. Given the increasingly recognized link between AD and defective brain insulin signaling, we investigated the actions of liraglutide, a glucagon‐like peptide‐1 (GLP‐1) analog marketed for treatment of type 2 diabetes, in experimental models of AD. Insulin receptor pathology is an important feature of AD brains that impairs the neuroprotective actions of central insulin signaling. Here, we show that liraglutide prevented the loss of brain insulin receptors and synapses, and reversed memory impairment induced by AD‐linked amyloid‐β oligomers (AβOs) in mice. Using hippocampal neuronal cultures, we determined that the mechanism of neuroprotection by liraglutide involves activation of the PKA signaling pathway. Infusion of AβOs into the lateral cerebral ventricle of non‐human primates (NHPs) led to marked loss of insulin receptors and synapses in brain regions related to memory. Systemic treatment of NHPs with liraglutide provided partial protection, decreasing AD‐related insulin receptor, synaptic, and tau pathology in specific brain regions. Synapse damage and elimination are amongst the earliest known pathological changes and the best correlates of memory impairment in AD. The results illuminate mechanisms of neuroprotection by liraglutide, and indicate that GLP‐1 receptor activation may be harnessed to protect brain insulin receptors and synapses in AD. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Liraglutide for type 2 diabetes mellitus

Introduction: Prevalence of type 2 diabetes mellitus (T2DM) is increasing. Management of this condition and minimizing the cardiovascular risks associated with it poses a significant burden on healthcare resources across the world. Currently available therapeutic agents are effective in glycemic management; however, the majority of these are associated with undesirable effects such as hypoglycemia and weight gain. Incretin-based therapies have been introduced over the last few years and are associated with less risk of hypoglycemia and weight gain.

Areas covered: This review includes current challenges in the management of T2DM, and an overview of glucagon-like peptide-1 (GLP-1)-based therapies, in particular the results of Phase III clinical studies of recently approved liraglutide. Apart from glycemic control, multifactorial interventions are needed to minimize the cardiovascular risks associated with T2DM. Liraglutide is effective in improving glycemic control measured by HbA1c and it is also shown to improve weight. Recently, the National Institute of Health and Clinical Excellence in the UK has approved liraglutide 1.2 mg dose in dual and triple therapy for T2DM.

Expert opinion: Liraglutide, a once-daily GLP-1 analog, has a definite role in selected patients with T2DM and the long-term cardiovascular safety is currently being ascertained in ongoing trials.     

Effects of liraglutide on postprandial insulin and glucagon responses in Japanese patients with type 2 diabetes

This study assessed the endocrine pancreatic responses to liraglutide (0.9 mg once a day) during normal living conditions in Japanese patients with type 2 diabetes. The study included 14 hospitalized patients with type 2 diabetes. Meal tests were performed after improvement of glycemic control achieved by two weeks of multiple insulin injection therapy and after approximately two weeks of liraglutide treatment. Continuous glucose monitoring was performed to compare daily variation in glycemic control between multiple insulin injection therapy and liraglutide treatment. Liraglutide reduced plasma glucose levels after the test meals (60–180 min; p<0.05), as a result of significant increases in insulin secretion (0–180 min; p<0.05) and decreases in the incremental ratio of plasma glucagon (15–60 min; p<0.05). Continuous glucose monitoring showed that liraglutide treatment was also associated with a decrease in glucose variability. We also demonstrated that optimal glycemic control seen as a reduction in 24-h mean glucose levels and variability was obtained only with liraglutide monotherapy. In conclusion, liraglutide treatment increases insulin secretion and suppresses glucagon secretion in Japanese patients with type 2 diabetes under normal living conditions. The main therapeutic advantages of liraglutide are its use as monotherapy and its ability to decrease glucose variability.     

Liraglutide changes postprandial responses of gut hormones involved in the regulation of gallbladder motility

Aim

Liraglutide treatment is associated with gallbladder-related disorders and has been shown to delay postprandial gallbladder refilling. The gut hormones cholecystokinin (CCK), fibroblast growth factor 19 (FGF19) and glucagon-like peptide 2 (GLP-2), are known to regulate gallbladder motility and may be implicated in gallbladder-related disorders associated with liraglutide treatment.

Materials and Methods

In a double-blind, 12-week trial, 52 participants [50% male, age 47.6 ± 10.0 years, body mass index 32.6 ± 3.4 kg/m² (mean ± standard deviation)] with obesity were randomized 1:1 to once-daily subcutaneous liraglutide (escalated from 0.6 mg to 3.0 mg once-daily) or placebo. During liquid meal tests performed at baseline, after the first dose and following 12 weeks of treatment, we evaluated postprandial gallbladder dynamics and plasma responses of CCK, FGF19 and GLP-2.

Results

Liraglutide reduced postprandial FGF19 after the first dose [area under the curve (AUC)_{0-240 min} 24.8 vs. 48.0 min × ng/ml, treatment ratio (TR) (95% confidence interval) 0.52 (0.39; 0.69)] and following 12 weeks of treatment [AUC_{0-240 min} 33.7 vs. 48.5 ng/ml × min, TR 0.69 (0.52; 0.93)]. Liraglutide also reduced postprandial GLP-2 responses (AUC_{0-240 min} 3650 vs. 4894 min × pmol/L, TR 0.75 (0.62; 0.90)] following the first dose as well as after 12 weeks [AUC_{0-240 min} 3760 vs. 4882 min × pmol/L, TR 0.77 (0.60; 0.99)]. Liraglutide increased postprandial responses of CCK after the first dose [AUC_{0-240 min} 762 vs. 670 min × pmol/L; TR 1.14 (0.97; 1.33)] and following 12 weeks of treatment [AUC_{0-240 min} 873 vs. 628 min × pmol/L; TR 1.39 (1.12; 1.73)].

Conclusion

Compared with placebo, treatment with liraglutide decreased postprandial FGF19 and GLP-2 concentrations and increased postprandial CCK concentrations, which may explain the delayed postprandial gallbladder refilling observed in individuals with obesity treated with liraglutide.     

Pharmacological management of type 2 diabetes: the potential of incretin-based therapies

Management guidelines recommend metformin as the first-line therapy for most patients with type 2 diabetes uncontrolled by diet and exercise. Efficacy with metformin therapy is usually of limited duration, which necessitates the early introduction of one or two additional oral agents or the initiation of injections, glucagon-like peptide-1 (GLP-1) agonists or insulin. Although safe and effective, metformin monotherapy has been associated with gastrointestinal side effects (≈20% of treated patients in randomized studies) and is contraindicated in patients with renal insufficiency or severe liver disease. Patients treated with a sulphonylurea are at increased risk for hypoglycaemia and moderate weight gain, whereas those receiving a thiazolidinedione are subject to an increased risk of weight gain, oedema, heart failure or fracture. Weight gain and hypoglycaemia are associated with insulin use. Thus, there is an unmet need for a safe and efficacious add-on agent after initial-therapy failure. Evidence suggests that incretin-based agents, such as GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, can successfully achieve glycaemic targets and potentially provide cardiovascular and β-cell-function benefits. This review will examine current approaches for treating type 2 diabetes and discuss the place of incretin therapies, mainly GLP-1 agonists, in the type 2 diabetes treatment spectrum.