Chronic liraglutide therapy induces an enhanced endogenous glucagon‐like peptide‐1 secretory response in early type 2 diabetes

Sustained exogenous stimulation of a hormone‐specific receptor can affect endogenous hormonal regulation. In this context, little is known about the impact of chronic treatment with glucagon‐like peptide‐1 (GLP‐1) agonists on the endogenous GLP‐1 response. We therefore evaluated the impact of chronic liraglutide therapy on endogenous GLP‐1 and glucose‐dependent insulinotropic polypeptide (GIP) response to an oral glucose challenge. A total of 51 people with type 2 diabetes of 2.6 ± 1.9 years’ duration were randomized to daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with an oral glucose tolerance test (OGTT) every 12 weeks. GLP‐1 and GIP responses were assessed according to their respective area under the curve (AUC) from measurements taken at 0, 30, 60, 90 and 120 minutes during each OGTT. There were no differences in AUC_GIP between the groups. By contrast, although fasting GLP‐1 was unaffected, the liraglutide arm had ~2‐fold higher AUC_{GLP ‐1} at 12 weeks ( P < .001), 24 weeks ( P < .001), 36 weeks ( P = .03) and 48 weeks ( P = .03), as compared with placebo. Thus, chronic liraglutide therapy induces a previously unrecognized, robust and durable enhancement of the endogenous GLP‐1 response, highlighting the need for further study of the long‐term effects of incretin mimetics on L‐cell physiology.     

Effect of exercise combined with glucagon‐like peptide‐1 receptor agonist treatment on cardiac function: A randomized double‐blind placebo‐controlled clinical trial

In patients with type 2 diabetes, both supervised exercise and treatment with the glucagon‐like peptide‐1 (GLP‐1) receptor agonist (GLP‐1RA) liraglutide may improve cardiac function. We evaluated cardiac function before and after 16 weeks of treatment with the GLP‐1RA liraglutide or placebo, combined with supervised exercise, in 33 dysregulated patients with type 2 diabetes on diet and/or metformin. Early diastolic myocardial tissue velocity was improved by exercise in the placebo group (mean ± standard deviation [s.d.] ?7.1 ± 1.6 to ?7.7 ± 1.8 cm/s, P = .01), but not in the liraglutide group (?7.1 ± 1.4 to ?7.0 ± 1.4 cm/s, P = .60; between groups, P = .02). Similarly, the mean ± s.d. ratio of early and atrial mitral annular tissue velocities improved in the placebo group (1.0 ± 0.4 to 1.2 ± 0.4, P = .003), but not in the liraglutide group (1.0 ± 0.3 to 1.0 ± 0.3, P = .87; between groups, P = .03). We found no significant differences in heart rate, left ventricular (LV) structure or function within or between the groups. In conclusion, the addition of liraglutide to exercise in sedentary patients with dysregulated type 2 diabetes may blunt the suggested beneficial effect of exercise on LV diastolic function.     

利拉鲁肽对缺氧和高糖所致心肌细胞钙超载和细胞凋亡的影响

 目的 研究利拉鲁肽对缺氧和高糖所致心肌细胞钙超载和细胞凋亡的影响。方法 采用原代培养的乳鼠心肌细胞,建立缺氧和高糖模型。实验分为:正常对照组、利拉鲁肽对照组、缺氧和高糖模型组、利拉鲁肽处理组、胰高血糖素样肽-1 (glucagon like peptide-1, GLP-1)受体抑制剂组、高渗对照组6组。采用荧光分光光度法检测心肌细胞内钙离子变化,化学荧光法检测活性氧族(reactive oxygen species, ROS)水平、利用生化方法检测Ca²⁺-ATP 和Na⁺-K⁺-ATP酶活性、RT-PCR技术检测钙敏感的钙蛋白酶(μ-calpain)基因表达、流式细胞仪测定细胞凋亡率、ELISA法检测细胞caspase-3活性。结果 与正常对照组相比,缺氧高糖模型组细胞内ROS水平、μ-calpain mRNA表达量、caspase-3活性均显著升高(P<0.01);Ca²⁺-ATP 和Na⁺-K⁺-ATP酶活性显著降低(P<0.01);游离钙离子浓度由(117.19±15.04)nmol/L增加至(508.53±26.11)nmol/L,细胞凋亡率由(3.95±0.12)%增加至(31.03±4.30)%(P<0.01)。利拉鲁肽处理组细胞较缺氧高糖模型组上述参数均明显改善,游离钙离子浓度和细胞凋亡率显著降低(P<0.01);GLP-1R抑制剂exendin(9-39)可拮抗利拉鲁肽的上述作用(P<0.05)。结论 利拉鲁肽可明显抑制缺氧和高糖所致心肌细胞钙超载及μ-calpain基因的上调,降低caspase-3水平,减少心肌细胞凋亡,对心肌细胞具有保护作用。     

利拉鲁肽与艾塞那肽治疗2型糖尿病降低体质量指标的meta分析

目的：系统评价类胰高血糖素样肽1类似物利拉鲁肽与艾塞那肽治疗2型糖尿病降低体质量指标情况。方法计算机检索Cochrane图书馆、PubMed、EMBASE、CNKI、CBM、中国生物医学文献数据库、中国期刊全文数据库,对纳入的随机对照试验（RCT）进行质量评价,并用Stata11.0软件对提取的相关数据进行meta分析。结果共纳入31个RCT,共计7036例患者,对其体质量降低情况进行了meta分析。结果发现,利拉鲁肽与对照组相比,当注射剂量为1.8 mg时,能有效降低体质量（WMD=-0.45,95%CI：-0.59,-0.31）;与阳性对照相比,当注射剂量为1.2 mg和1.8 mg时,均能有效降低体质量（WMD=-0.91,95%CI：-1.07,-0.75;WMD=-0.78,95%CI：-1.02,-0.54）。艾塞那肽与对照组相比,当注射剂量为5μg和10μg时,均能有效降低体质量（WMD=-0.36,95%CI：-0.64,-0.09;WMD=-0.99,95%CI：-1.27,-0.72）;与阳性对照相比,当注射剂量为10μg时,能有效降低体质量（WMD=-1.14,95%CI：-1.46,-0.82）。结论利拉鲁肽和艾塞那肽作为新的肠促胰岛激素类似物,均能够减轻体质量,为2型糖尿病患者提供了新的降糖药选择。     

Liraglutide prevents high glucose level induced insulinoma cells apoptosis by targeting autophagy

Background  The pathophysiology of type 2 diabetes is progressive pancreatic beta cell failure with consequential reduced insulin secretion. Glucotoxicity results in the reduction of beta cell mass in type 2 diabetes by inducing apoptosis. Autophagy is essential for the maintenance of normal islet architecture and plays a crucial role in maintaining the intracellular insulin content by accelerating the insulin degradation rate in beta cells. Recently more attention has been paid to the effect of autophagy in type 2 diabetes. The regulatory pathway of autophagy in controlling pancreatic beta cells is still not clear. The aim of our study was to evaluate whether liraglutide can inhibit apoptosis and modulate autophagy in vitro in insulinoma cells (INS-1 cells).

Methods  INS-1 cells were incubated for 24 hours in the presence or absence of high levels of glucose, liraglutide (a long-acting human glucagon-like peptide-1 analogue), or 3-methyadenine (3-MA). Cell viability was measured using the Cell Counting Kit-8 (CCK8) viability assay. Autophagy of INS-1 cells was tested by monodansylcadaverine (MDC) staining, an autophagy fluorescent compound used for the labeling of autophagic vacuoles, and by Western blotting of microtubule-associated protein I light chain 3 (LC3), a biochemical markers of autophagic initiation.

Results  The viability of INS-1 cells was reduced after treatment with high levels of glucose. The viability of INS-1 cells was reduced and apoptosis was increased when autophagy was inhibited. The viability of INS-1 cells was significantly increased by adding liraglutide to supplement high glucose level medium compared with the cells treated with high glucose levels alone. 

Conclusions  Apoptosis and autophagy were increased in rat INS-1 cells when treated with high level of glucose, and the viability of INS-1 cells was significantly reduced by inhibiting autophagy. Liraglutide protected INS-1 cells from high glucose level-induced apoptosis that is accompanied by a significant increase of autophagy, suggesting that liraglutide plays a role in beta cell apoptosis by targeting autophagy. Thus, autophagy may be a new target for the prevention or treatment of diabetes.

     

胰高血糖素样肽1及其类似物治疗阿尔茨海默病作用机制研究进展

研究发现阿尔茨海默病(AD)的许多病理特征和认知功能下降可能与脑内胰岛素抵抗有关。对AD动物模型和轻度认知功能障碍患者的脑组织进行研究,结果表明应用胰高血糖素样肽1(GLP-1)类似物如利拉鲁肽、艾塞那肽治疗后,脑内胰岛素抵抗和许多病理特征减少或是逆转。这一研究结果为GLP-1类似物对AD的潜在治疗研究提供理论基础。对GLP-1及其类似物在AD中的潜在治疗作用做一综述。     

Effects of liraglutide on cardiovascular risk biomarkers in patients with type 2 diabetes and albuminuria: A sub‐analysis of a randomized,placebo‐controlled,double‐blind,crossover trial

We assessed the effects of liraglutide treatment on five cardiovascular risk biomarkers, reflecting different pathophysiology: tumour necrosis factor (TNF)‐α; soluble urokinase plasminogen activator receptor (suPAR); mid‐regional pro‐adrenomedullin (MR‐proADM); mid‐regional pro‐atrial natriuretic peptide (MR‐proANP); and copeptin, in people with type 2 diabetes with albuminuria. In a randomized, double‐blind, placebo‐controlled, crossover trial we enrolled people with type 2 diabetes and persistent albuminuria (urinary albumin‐to‐creatinine ratio [UACR] >30 mg/g) and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m². Participants received liraglutide (1.8 mg/d) and matched placebo for 12 weeks, in random order. The primary endpoint was change in albuminuria; this was a prespecified sub‐study. A total of 32 participants were randomized, of whom 27 completed the study. TNF‐α level was 12% (95% confidence interval [CI] 3; 20) lower after liraglutide treatment compared with placebo (P = .012); MR‐proADM level was 4% (95% CI 0; 8) lower after liraglutide treatment compared with placebo (P = .038), and MR‐proANP level was 13% (95% CI 4; 21) lower after liraglutide treatment compared with placebo (P = .006). In the present study, we showed anti‐inflammatory effects of liraglutide treatment, reflected in reductions in levels of TNF‐α and MR‐proADM, while the reduction in MR‐proANP levels may represent a clinically relevant benefit with regard to heart failure.