利拉鲁肽治疗肥胖研究进展

肥胖是代谢性疾病以及各种肿瘤的危险因子,治疗肥胖包括生活方式干预、药物治疗、外科手术,如果生活干预的效果不理想,则需要加用药物治疗.2014年12月,利拉鲁肽被美国食品药品管理局(FDA)批准用于治疗肥胖,本文就利拉鲁肽利拉鲁肽相关基础研究以及临床应用做一综述.     

Liraglutide decreases energy expenditure and does not affect the fat fraction of supraclavicular brown adipose tissue in patients with type 2 diabetes

Background and aimsSeveral studies have shown that glucagon-like peptide-1 (GLP-1) analogues can affect resting energy expenditure, and preclinical studies suggest that they may activate brown adipose tissue (BAT). The aim of the present study was to investigate the effect of treatment with liraglutide on energy metabolism and BAT fat fraction in patients with type 2 diabetes.Methods and resultsIn a 26-week double-blind, placebo-controlled trial, 50 patients with type 2 diabetes were randomized to treatment with liraglutide (1.8 mg/day) or placebo added to standard care. At baseline and after treatment for 4, 12 and 26 weeks, we assessed resting energy expenditure (REE) by indirect calorimetry. Furthermore, at baseline and after 26 weeks, we determined the fat fraction in the supraclavicular BAT depot using chemical-shift water-fat MRI at 3T. Liraglutide reduced REE after 4 weeks, which persisted after 12 weeks and tended to be present after 26 weeks (week 26 vs baseline: liraglutide −52 ± 128 kcal/day; P = 0.071, placebo +44 ± 144 kcal/day; P = 0.153, between group P = 0.057). Treatment with liraglutide for 26 weeks did not decrease the fat fraction in supraclavicular BAT (−0.4 ± 1.7%; P = 0.447) compared to placebo (−0.4 ± 1.4%; P = 0.420; between group P = 0.911).ConclusionTreatment with liraglutide decreases REE in the first 12 weeks and tends to decrease this after 26 weeks without affecting the fat fraction in the supraclavicular BAT depot. These findings suggest reduction in energy intake rather than an increase in REE to contribute to the liraglutide-induced weight loss.Trial registry numberNCT01761318.     

消糖灵胶囊联合利拉鲁肽治疗肥胖2型糖尿病的临床研究

目的 探讨消糖灵胶囊联合利拉鲁肽治疗肥胖2型糖尿病的临床疗效。方法 选择2019年12月—2021年6月在河北中石油中心医院治疗的120例肥胖2型糖尿病患者，随机分为对照组和治疗组，每组各60例。对照组早餐前皮下注射利拉鲁肽注射液，0.6 mg/次，1次/d。治疗组在对照组的基础上口服消糖灵胶囊，3片/次，2次/d。两组患者连续用药15周。观察两组患者临床疗效，比较治疗前后两组患者症状缓解时间，血糖指标空腹血糖（FPG）、餐后2 h血糖（2 h PBG）、糖化血红蛋白（HbA1c）和空腹血清胰岛素（FINS）水平，血清因子肿瘤坏死因子-α（TNF-α）、可溶性血管细胞黏附因子-1（Svcam-1）、白细胞介素-6（IL-6）和超敏C反应蛋白（hs-CRP）水平，及不良反应。结果 治疗后，治疗组总有效率为98.33%，明显高于对照组的83.33%（P<0.05）。治疗后，治疗组多饮、多食、多尿、口干缓解时间均明显早于对照组（P<0.05）。治疗后，两组患者FPG、2 h FPG、HbA1c、FINS指标和血清因子TNF-α、Svcam-1、IL-6、hs-CRP水平均明显下降（P<0.05），且治疗后治疗组这些指标明显低于对照组（P<0.05）。治疗期间，治疗组不良反应发生率为6.67%，明显低于对照组的13.33%（P<0.05）。结论 消糖灵胶囊联合利拉鲁肽治疗肥胖2型糖尿病效果确切，症状缓解明显，并能有效控制患者血糖，降低机体炎症反应。     

Liraglutide prevents β-cell apoptosis via inactivation of NOX2 and its related signaling pathway

Aims

High glucose (HG)-induced pancreatic β-cell apoptosis may be a major contributor to the progression of diabetes mellitus (DM). NADPH oxidase (NOX2) has been considered a crucial regulator in β-cell apoptosis. This study was designed to evaluate the impact of GLP-1 receptor agonist (GLP-1Ra) liraglutide on pancreatic β-cell apoptosis in diabetes and the underlying mechanisms involved.

Protective effects of liraglutide on glomerular podocytes in obese mice by inhibiting the inflammatory factor TNF-α-mediated NF-κB and MAPK pathway

ObjectiveTo evaluate the protective effects of Glucagon-like peptide-1(GLP-1) receptor agonist (liraglutide) on glomerular podocytes of obese mice, and explore the possible underlying mechanism.MethodsTwelve of the thirty-four healthy and clean male mice were randomly selected as the normal control group. The remaining twenty-two mice were included in the high-fat diet (HFD) feeding group. After twelve weeks of high-fat diet and normal diet, two mice each from the HFD feeding group and the normal control group were randomly selected and sacrificed to suggested that the modeling was successful in the HFD feeding group. Then, twenty mice were randomly divided into HFD + liraglutide group (liraglutide group, n = 10) and HFD group (n = 10). The morphology and the structure of glomerular podocytes were observed using electron microscopy. Podocyte foot process diameter, glomerular basement membrane thickness were measured. ELISA was performed to determine the serum tumor necrosis factor α (TNF-α) level. The expression levels of TNF-α protein and nuclear factor-kappa B (NF-κB) in kidney tissues, extracellularsignal regulating kinase(ERK), c-Jun N-terminal kinase (JNK) and p38MAPK in the mitogenactivated protein kinases(MAPK) pathway were detected by western blotting.ResultsHFD-feeding caused significant renal injury, podocyte pathological changes, podocyte foot process diameter and glomerular basement membrane thickness were significantly increased compared with the control group. Liraglutide injection significantly alleviated HFD-induced effects on renal functions and podocyte morphology, as 24 h urine protein, urinary albumin and podocyte histomorphology. Moreover, HFD-induced Inflammatory reaction were obviously attenuated by Liraglutide administration, so did the HFD-induced activation of TNF-α-mediated NF-κB and MAPK pathways.ConclusionLiraglutide reduced urinary albumin excretion in obesity-related glomerulopathy model mice, and improved podocyte morphology and structural damage. The mechanism may be partly related to the inhibition of TNF-α-mediated NF-κB and MAPK pathways.     

利拉鲁肽对血糖控制不佳的2型糖尿病患者胰岛β细胞功能及血糖波动的影响

目的 观察应用胰岛素联合口服降糖药物(OADs)治疗血糖控制不佳的T2DM患者加用利拉鲁肽后,胰岛β细胞功能及血糖波动的变化. 方法 40例T2DM患者(HbA1 c＞7.0％)在胰岛素联用OADs的基础上加用利拉鲁肽治疗12周,观察治疗前后血糖、HbA1c、胰岛β细胞功能指数(HO-MA-β)及血糖波动的变化. 结果 加用利拉鲁肽治疗12周后,HbA1c[(8.21±2.65)％ vs(7.16±0.8)％]、平均血糖波动幅度(MAGE) [(3.98±0.52) vs(1.52±0.27) mmol/L]、日间血糖平均绝对差(MODD)[(1.29±0.34)vs(0.45±0.13) mmol/L]下降(P＜0.05);FC-P[(1.16±0.75) vs(2.87±1.02)ng/ml]、2 hC-P[(2.28±1.23)vs(4.16±0.98) ng/ml]及HOMA-β[(3.6±0.7)vs(4.8±0.9)]升高(P＜0.05). 结论 对于胰岛素联合OADs血糖控制不佳的T2DM患者,加用利拉鲁肽可有效降糖、平稳降糖,改善胰岛β细胞功能.     

利拉鲁肽对多囊卵巢综合征合并糖耐量异常及肥胖患者的代谢及受孕的影响

目的：探讨利拉鲁肽对多囊卵巢综合征（PCOS）合并糖耐量异常及肥胖患者中的代谢和受孕情况的影响。方法选取2011年3月至2014年3月就诊的PCOS合并肥胖及不孕患者177例,按随机数字表法分为利拉鲁肽治疗组[年龄（28±7）岁]和对照组[（27±7）岁]。对照组给予口服二甲双胍（0.5 g、3次/d）,治疗组在二甲双胍的基础上加用利拉鲁肽（1.2~1.8 mg/d）。于用药前、用药12周、24周后分别测定患者的体重、血液生化及性激素水平。组间差异采用独立样本t检验,计数资料比较采用卡方检验。结果（1）用药12、24周后两组体重、腰围、体质指数（BMI）均下降,而利拉鲁肽组低于对照组（t=10.11~19.97,均P<0.01）。（2）24周时利拉鲁肽组餐后2 h血糖（2 hPG）、糖化血红蛋白（HbA1c）较对照组降低[（7.5±1.2）比（8.0±1.1）mmol/L、（5.5±0.8）%比（6.0±0.3）%,t=31.61、21.93,均P<0.05]。（3）用药24周时两组间比较总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白胆固醇（LDL?C）之间差别有统计学意义（t=13.44~21.56,均P<0.05）。（4）用药12周、24周两组均出现血清性激素水平降低,利拉鲁肽组较对照组下降明显[24周时促卵泡生成素（4.2±0.4）比（5.0±0.6）U/L,促黄体生成素（6.1±1.4）比（8.2±1.2）U/L,t=13.72、204.30,均P<0.05]。（5）用药12周、24周后两组均出现空腹胰岛素（FINS）、胰岛素抵抗指数（HOMA?IR）水平降低,胰岛细胞功能指数（HOMA?β）升高,利拉鲁肽组高于对照组（t=20.75~35.78,均P<0.05）。（6）利拉鲁肽组月经周期规律变化率、排卵率、自然受孕率明显优于对照组[分别为86.2%（75/87）比70.5%（60/85）,78.1%（68/87）比50.5%（43/85）,42.5%（37/87）比22.3%（19/85）],差异有统计学意义（χ2=10.769、14.281、7.97,均P<0.05）。结论利拉鲁肽联合二甲双胍能有效减轻体重,改善糖、脂代谢和性激素水平,提高自然受孕率。     

Liraglutide protects against amyloid-β protein-induced impairment of spatial learning and memory in rats

Type 2 diabetes mellitus is a risk factor of Alzheimer's disease (AD), most likely linked to an impairment of insulin signaling in the brain. Liraglutide, a novel long-lasting glucagon-like peptide 1 (GLP-1) analog, facilitates insulin signaling and shows neuroprotective properties. In the present study, we analyzed the effects of liraglutide on the impairment of learning and memory formation induced by amyloid-β protein (Aβ), and the probable underlying electrophysiological and molecular mechanisms. We found that (1) bilateral intrahippocampal injection of Aβ_25–35 resulted in a significant decline of spatial learning and memory of rats in water maze tests, together with a serious depression of in vivo hippocampal late-phase long-term potentiation (L-LTP) in CA1 region of rats; (2) pretreatment with liraglutide effectively and dose-dependently protected against the Aβ_25–35-induced impairment of spatial memory and deficit of L-LTP; (3) liraglutide injection also activated cAMP signal pathway in the brain, with a nearly doubled increase in the cAMP contents compared with control. These results strongly suggest that upregulation of GLP-1 signaling in the brain, such as application of liraglutide, may be a novel and promising strategy to ameliorate the learning and memory impairment seen in AD.