利拉鲁肽对 2 型糖尿病大鼠降血压、利水盐的作用机制探讨

目的 通过观察胰高血糖素样肽-1（GLP-1）类似物利拉鲁肽对 2 型糖尿病大鼠肾脏内髓一氧化氮合酶（NOS）、环加氧酶 2（COX2）表达的影响, 探讨利拉鲁肽降血压和利水盐的作用机制。 方法 30 只雄性 SD 大鼠给予高糖高脂饲料喂养, 自由摄水, 8 周后空腹注射链脲佐菌素（STZ）, 成功建立 2 型糖尿病大鼠模型 18 只, 选取 12 只随机分为利拉鲁肽处理 2 型糖尿病模型（DMT）组和 2 型糖尿病模型（DM）组, 另取 12 只正常大鼠随机分为利拉鲁肽处理野生型大鼠（WTT）组和野生型大鼠对照（WT）组,每组 6 只。 DMT 和 WTT 组每天予以利拉鲁肽（200 μg/kg 体质量）皮下注射, DM 和 WT 组每天予以等量生理盐水皮下注射, 各组分别在给药后 0、2、4、6 周检测血糖和血压, 给药后 6 周收集尿液检测 K、Na、Cl 离子浓度, 然后处死大鼠, 收集血液检测血 K、Na、Cl 离子浓度, 取肾组织通过 Real-time PCR 和 Western blot 检测肾脏内髓 NOS 和 COX2 的 mRNA 和蛋白表达水平。 结果 利拉鲁肽干预后, DMT 组大鼠血糖（F=5.933, P < 0.05）及血压（F=22.070, P < 0.05）随时间变化逐渐降低。 在干预 6 周后, DMT 组大鼠血糖（mmol/ L： 12.78±3.82 vs. 18.75±1.68）和血压（mmHg： 119.98±4.43 vs. 136.42±4.48）较 DM 组均明显降低（P < 0.05）, 血液中 K、 Na、Cl 离子浓度与 DM 组相比无明显差异, 但尿液中 K（mmol/L： 46.55±6.43 vs. 33.13±9.71）、Na（mmol/L： 56.33±8.83 vs. 41.20±7.25）、Cl（mmol/L： 159.81±25.06 vs. 71.44±12.99）离子浓度高于 DM 组大鼠（P < 0.05）, 且肾脏内髓 NOS、 COX2 的 mRNA 和蛋白表达均高于 DM 组大鼠（P < 0.05）。 结论 利拉鲁肽可能通过 NOS 诱导 COX2 的表达增强,发挥利水盐、降血压的作用。     

The effect of baseline characteristics on clinical efficacy of liraglutide in patients treated with high‐dose insulin

In patients requiring high‐dose insulin treatment, a randomized, double‐blind, placebo‐controlled study showed that liraglutide improved glycaemic control and treatment satisfaction while promoting weight loss. We performed a post hoc analysis to evaluate if patients’ baseline characteristics impact the efficacy of liraglutide, and which outcomes correlate with treatment satisfaction. We used regression analysis to model the change in HbA1c and weight, with treatment assignment and baseline characteristics [HbA1c, age, body mass index (BMI), total daily dose (TDD) of insulin, duration of insulin treatment, and type of insulin regimen] as independent variables. Improvement in HbA1c was best predicted by treatment with liraglutide, followed by higher baseline HbA1c, BMI and age. Changes in weight were only associated with liraglutide treatment, independent of all baseline characteristics. Improvement in HbA1c was the only significant predictor of improvement in treatment satisfaction, while weight loss, change in TDD of insulin and rate of hypoglycaemia did not influence treatment satisfaction. In patients treated with high‐dose insulin, liraglutide significantly improved glycaemic control and led to weight loss regardless of patients’ baseline characteristics. Improvement in HbA1c was the most important predictor of patients’ treatment satisfaction.     

Liraglutide Protects Neurite Outgrowth of Cortical Neurons Under Oxidative Stress though Activating the Wnt Pathway

Background

Neurogenesis including neurite outgrowth is important for brain plasticity under physiological conditions and in brain repair after injury. Liraglutide has been found to have neuroprotective action in the risk of central nervous system disease. However, the effect and the potential mechanism of liraglutide-induced neurite outgrowth in primary cortical neurons under oxidative stress remain poorly documented.

羟苯磺酸钙联合GLP-1类似物治疗糖尿病视网膜病变的临床意义

目的：探讨在2型糖尿病视网膜病变非增殖期的治疗阶段使用羟苯磺酸钙联合GLP-1类似物的临床效果与作用机制。方法：收集某院眼科收治的双眼非增殖性Ⅱ期、Ⅰ期轻度2型糖尿病视网膜病变患者60名使用平均随机的方法分成治疗组与对照组,治疗组患者采用口服羟苯磺酸钙50 mg联合皮下注射利拉鲁肽0.6 mg的方法进行治疗,对照组患者采用口服羟苯磺酸钙联合皮下注射生理盐水的方法进行治疗,在治疗之前对2组患者的眼底照相情况、外周血C肽水平、空腹血糖水平进行测量,在治疗6个月之后对患者进行随访,随后对患者眼底照相情况、外周血C肽水平、空腹血糖水平进行测量。结果：在6个月治疗之后治疗组患者视网膜病变程度要轻于对照组,治疗组外周血C肽水平高于对照组、空腹血糖水平要低于对照组。结论：羟苯磺酸钙联合GLP-1类似物的方法能够有效遏制2型糖尿病视网膜病变患者的进展。     

Glucagon‐like peptide‐1 analog,liraglutide, improves visceral sensation and gut permeability in rats

Background and Aim

A glucagon‐like peptide‐1 analog, liraglutide, has been reported to block inflammatory somatic pain. We hypothesized that liraglutide attenuates lipopolysaccharide (LPS)‐induced and repeated water avoidance stress (WAS)‐induced visceral hypersensitivity and tested the hypothesis in rats.

Methods

The threshold of the visceromotor response induced by colonic balloon distention was measured to assess visceral sensation. Colonic permeability was determined in vivo by quantifying the absorbed Evans blue spectrophotometrically, which was instilled in the proximal colon for 15 min. The interleukin‐6 level in colonic mucosa was also quantified using ELISA.

Results

Subcutaneously injected LPS (1 mg/kg) reduced the visceromotor response threshold after 3 h. Liraglutide (300 μg/kg subcutaneously) at 15 h and 30 min before injecting LPS eliminated LPS‐induced allodynia. It also blocked the allodynia induced by repeated water avoidance stress for 1 h for three consecutive days. Neither vagotomy nor naloxone altered the antinociceptive effect of liraglutide, but N^G‐nitro‐L‐arginine methyl ester, a nitric oxide synthesis inhibitor, blocked it. LPS increased colonic permeability and the interleukin‐6 level, and the analog significantly inhibited these responses.

Conclusions

This study suggests that liraglutide blocked LPS‐induced visceral allodynia, which may be a nitric oxide‐dependent response, and was probably mediated by inhibiting pro‐inflammatory cytokine production and attenuating the increased gut permeability. Because the LPS‐cytokine system is considered to contribute to altered visceral sensation in irritable bowel syndrome, these results indicate the possibility that liraglutide can be useful for treating this disease.     

基于ROS-NLRP3炎症小体介导的细胞焦亡探究利拉鲁肽对糖尿病肾病大鼠肾损伤的保护作用

目的 探究利拉鲁肽对糖尿病肾病大鼠的作用及其调控机制。方法 采取多次小剂量ip链脲佐菌素40 mg/kg构建糖尿病肾病大鼠模型，分为模型组、利拉鲁肽组、活性氧簇（ROS）抑制剂（NAC）组、利拉鲁肽+NAC组，另设置对照组，每组10只。利拉鲁肽组大鼠sc 200 μg/（kg·d）的利拉鲁肽；NAC组大鼠ip 20 mg/（kg·d）的NAC；利拉鲁肽+NAC组大鼠sc 200 μg/（kg·d）的利拉鲁肽的同时ip 20 mg/（kg·d）的NAC；对照组和模型组大鼠sc等量的生理盐水，1次/d，连续治疗4周。全自动分析仪检测24 h尿微量蛋白排泄率（MAER）；血糖仪测定空腹血糖（FBG）；试剂盒检测血清肌酐（Scr）、尿素氮（BUN）水平；HE染色、Masson染色观察肾组织病理变化；二氢乙锭（DHE）荧光探针检测肾组织活性氧（ROS）水平；化学比色法检测肾组织丙二醛（MDA）含量、谷胱甘肽过氧化物酶（GSH）和超氧化物歧化酶（SOD）活性；Western blotting检测肾组织NOD样受体蛋白3（NLRP3）炎症小体和焦亡相关蛋白表达。结果 与模型组相比，利拉鲁肽组和NAC组大鼠MAER、Scr、BUN、FBG均显著降低（P<0.05）；肾组织ROS、MDA含量显著降低，GSH、SOD活性升高（P<0.05）；NLRP3炎症小体相关蛋白[NLRP3、凋亡相关斑点样蛋白（ASC）、Caspase-1]和焦亡相关蛋白[cleaved-Caspase-1、GSDMD-N、白细胞介素（IL）-1β、IL-18]表达均显著降低（P<0.05、0.01）。与利拉鲁肽组相比，利拉鲁肽+NAC组上述指标均得到进一步改善，肾组织病理损伤进一步减轻。结论 利拉鲁肽能够通过ROS-NLRP3炎症小体途径抑制肾组织氧化应激介导的NLRP3炎症小体活化，从而抑制细胞焦亡，并最终发挥抗糖尿病肾病肾损伤作用。