Brexpiprazole caused glycolipid metabolic disorder by inhibiting GLP1/GLP1R signaling in rats

Brexpiprazole (Bre) is a new multi-target antipsychotic drug (APD) approved by the US FDA in 2015, and shows good therapeutic potential. But it lacks assessments on the metabolic side effects, which obstructs the treatment of schizophrenia. Glucagon-like peptide 1 (GLP1), an incretin associated with insulin action and metabolism, is involved in the metabolic syndrome (MS) caused by most APDs. In this study, we examined the adverse effects of Bre on glycolipid metabolism in rats and determined whether GLP1 was involved in Bre-caused MS. In the first part of experiments, rats were orally administered Bre (0.5 mg· kg⁻¹· d⁻¹) for 28 days with aripiprazole (1.0 mg· kg⁻¹· d⁻¹) or olanzapine (1.0 mg· kg⁻¹· d⁻¹) as the controls. Compared to vehicle, Bre administration significantly increased the weight gain, serum lipid (TG, TC, LDL, FFA), and blood glucose levels accompanied by the hormonal (insulin, glucagon, GLP1) imbalance, and the impaired glucose tolerance and insulin sensitivity. Moreover, we demonstrated that Bre administration significantly decreased the protein and mRNA levels of GLP1 in pancreas and small intestine by suppressing CaMKIIα, AMPK, and β-catenin; Bre administration also caused islet dysfunction with decreased GLP1R, PI3K, IRβ expression in pancreas, and the interference of IRS1, PI3K, p-AKT, and GLUT4 expression in the liver and skeletal muscle that represented the insulin resistance. In the second part of experiments, rats were orally administered Bre (0.5 mg· kg⁻¹· d⁻¹) for 42 days. We showed that co-administration with the GLP1 receptor (GLP1R) agonist liraglutide (0.125 mg· kg⁻¹· d⁻¹, ip) could ameliorate Bre-caused metabolic abnormalities. Our results demonstrate that GLP1/GLP1R signaling is involved in Bre-induced glycolipid metabolic disorders and co-treatment with liraglutide is an effective intervention against those abnormal metabolisms.     

达格列净联合利拉鲁肽对肥胖2型糖尿病患者糖脂代谢、脂肪分布及胰岛功能的影响

目的 观察达格列净联合利拉鲁肽对肥胖2型糖尿病患者糖脂代谢、脂肪分布及胰岛功能的影响。方法 选取2019年1月至2020年6月我院收治的90例肥胖2型糖尿病患者为研究对象,将其随机分为对照组和观察组,各45例。两组均接受二甲双胍基础治疗,在此基础上,对照组采用利拉鲁肽进行治疗,观察组在对照组基础上采用达格列净进行治疗。比较两组的糖脂代谢、脂肪分布、胰岛功能指标及不良反应发生情况。结果 治疗前,两组患者的HbA1c、FPG、TC、TG水平比较,差异无统计学意义（P>0.05）;治疗后,两组患者的HbA1c、FPG、TC、TG水平均较治疗前降低,且观察组低于对照组,差异具有统计学意义（P<0.05）。治疗前,两组患者的SFA、VFA、EAT、BF%比较,差异无统计学意义（P>0.05）;治疗后,两组患者的SFA、VFA、EAT、BF%均较治疗前降低,且观察组低于对照组,差异具有统计学意义（P<0.05）。治疗前,两组患者的2 h INS、FCP水平及HOMA-IR、ISI比较,差异无统计学意义（P>0.05）;治疗后,两组患者的2 h INS、FCP水平均较治...     

利拉鲁肽对糖尿病前期大鼠胰岛海马胆碱能神经刺激肽前体蛋白的影响

目的明确利拉鲁肽对糖尿病前期OLETF大鼠的阻抑作用,观察对胰腺海马胆碱能神经刺激肽前体蛋白(hippocampal cholinergicneurostimulating peptide precursor protein,HCNP-pp)的影响。方法检测空腹及餐后2小时血糖,将处于糖耐量减低阶段12～14周龄OLETF大鼠随机分为3组,安慰剂组(PBO组)、100μg/kg利拉鲁肽处理组(L-100组)、200μg/kg利拉鲁肽处理组(L-200组),LETO大鼠为阴性对照组(LETO组)。12周后检测大鼠体重、空腹血糖、餐后2 h血糖和胰岛素,以免疫组织化学染色分析胰岛细胞形态学变化,应用蛋白印迹技术检测HCNP-pp及胰高血糖素样多肽-1受体(GLP-1R)蛋白含量;应用实时定量PCR检测HCNP-pp和LGP-1R、胆碱乙酰转移酶(ChAT)、3型毒蕈碱样受体(M3R)基因表达水平。结果PBO组OLETF大鼠空腹、餐后2 h血糖符合糖尿病诊断标准,而L-100组、L-200组及LETO组大鼠均未进展为糖尿病状态。PBO组OLETF大鼠体重及空腹胰岛素均明显高于L-100组、L-200组和LETO组(P<0.01)。与PBO组相比,L-200组、LETO组大鼠胰腺胰岛素阳性细胞表达密度明显增多(P<0.01),而与L-100组差别无统计学意义(P>0.05);L-100组、L-200组及LEITO组大鼠胰腺HCNP-pp蛋白相对含量明显减少(P<0.05或P<0.01);L-100组、L-200组及LEITO组大鼠胰腺GLP-1R蛋白相对含量明显增多(P<0.01);L-100组、L-200组和LETO组大鼠胰腺HCNP-pp mRNA水平明显下降(P<0.01);L-200组和LETO组大鼠胰GLP-1R,ChAT、M3R mRNA水平均明显增多(P<0.01);L-100组大鼠GLP-1R和ChAT mRNA水平均明显增多(P<0.01),而M3R mRNA水平则无变化(P>0.05)。结论利拉鲁肽可阻抑糖尿病前期进展,可能与胰腺HCNP-pp表达下降、GLP-1R表达增高及胰岛β细胞密度增加相关。利拉鲁肽改善胰岛素分泌状态,可能与胰腺HCNP增多、ChAT和M3R表达增高相关。     

Neuroprotective and neurotrophic actions of glucagon-like peptide-1: an emerging opportunity to treat neurodegenerative and cerebrovascular disorders

Like type-2 diabetes mellitus (T2DM), neurodegenerative disorders and stroke are an ever increasing, health, social and economic burden for developed Westernized countries. Age is an important risk factor in all of these; due to the rapidly increasing rise in the elderly population T2DM and neurodegenerative disorders, both represent a looming threat to healthcare systems. Whereas several efficacious drugs are currently available to ameliorate T2DM, effective treatments to counteract pathogenic processes of neurodegenerative disorders are lacking and represent a major scientific and pharmaceutical challenge. Epidemiological data indicate an association between T2DM and most major neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Likewise, there is an association between T2DM and stroke incidence. Studies have revealed that common pathophysiological features, including oxidative stress, insulin resistance, abnormal protein processing and cognitive decline, occur across these. Based on the presence of shared mechanisms and signalling pathways in these seemingly distinct diseases, one could hypothesize that an effective treatment for one disorder could prove beneficial in the others. Glucagon-like peptide-1 (GLP-1)-based anti-diabetic drugs have drawn particular attention as an effective new strategy to not only regulate blood glucose but also to reduce apoptotic cell death of pancreatic beta cells in T2DM. Evidence supports a neurotrophic and neuroprotective role of GLP-1 receptor (R) stimulation in an increasing array of cellular and animal neurodegeneration models as well as in neurogenesis. Herein, we review the physiological role of GLP-1 in the nervous system, focused towards the potential benefit of GLP-1R stimulation as an immediately translatable treatment strategy for acute and chronic neurological disorders.     

A comparison of currently available GLP-1 receptor agonists for the treatment of type 2 diabetes

Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists are a valuable addition to the type 2 diabetes armamentarium. They increase insulin secretion and reduce glucagon secretion in a glucose-dependent manner, posing a relatively low hypoglycemia risk. GLP-1 receptor agonists also offer weight-loss benefits. Because GLP-1 receptor agonists are relatively new agents, there is limited direction on their use.

Areas covered: This article aims to provide guidance to physicians when considering GLP-1 receptor agonist use in individual patients. It examines the clinical profiles of the currently available GLP-1 receptor agonists: exenatide twice-daily (BID), liraglutide once daily and exenatide extended release (ER) once weekly. Phase III clinical trial data on efficacy, safety and patient satisfaction are compared, with a primary focus on head-to-head trials.

Expert opinion: Liraglutide seems to be the most effective GLP-1 receptor agonist in terms of HbA_1c reduction and weight loss. Exenatide BID may offer an advantage where postprandial glucose control is a primary concern. Exenatide ER generally outperforms exenatide BID and is a good option for patients who struggle to adhere to more frequent regimens. The future may hold interesting developments in terms of reduced dosing frequency, oral formulations and alternative therapeutic uses.