Glucagon-like peptide-1 agonists:Role of the gut in hypoglycemia unawareness,and the rationale in type 1 diabetes

Type 1 diabetes is increasing and the majority of patients have poor glycemic control.Although advanced technology and nanoparticle use have greatly enhanced insulin delivery and glucose monitoring,weight gain and hypoglycemia remain major challenges and a constant source of concern for patients with type 1 diabetes.Type 1 diabetes shares some pathophysiology with type 2 diabetes,and an overlap has been reported.The above observation created great interest in glucagon-like peptide-1 receptor agonists(GLP-1)as adjuvants for type 1 diabetes.Previous trials confirmed the positive influence of GLP-1 agonists onβcell function.However,hypoglycemia unawareness and dysregulated glucagon response have been previously reported in patients with recurrent hypoglycemia using GLP-1 agonists.Jin et al found that the source of glucagon dysregulation due to GLP-1 agonists resides in the gut.Plausible explanations could be gut nervous system dysregulation or gut microbiota disruption.This review evaluates the potential of GLP-1 agonists in managing type 1 diabetes,particularly focusing on their impact on glycemic control,weight management,and glucagon dysregulation.We provide a broader insight into the problem of type 1 diabetes mellitus management in the light of recent findings and provide future research directions.

Glucagon-like peptide-1 analogue prevents nonalcoholic steatohepatitis in non-obese mice

AIM: To investigate whether a glucagon-like peptide-1(GLP-1) analogue inhibits nonalcoholic steatohepatitis(NASH), which is being increasingly recognized in Asia, in non-obese mice. METHODS: A methionine-choline-deficient diet(MCD) along with exendin-4(20 μg/kg per day, ip), a GLP-1 analogue, or saline was administered to male db/db mice(non-obese NASH model). Four or eight weeks after commencement of the diet, the mice were sacrificed and their livers were excised. The excised livers were examined by histochemistry for evidence of hepatic steatosis and inflammation. Hepatic triglyceride(TG) and free fatty acid(FFA) content was measured, and the expression of hepatic fat metabolism- and inflammation-related genes was evaluated. Oxidative stress-related parameters and macrophage recruitment were also examined using immunohistochemistry.RESULTS: Four weeks of MCD feeding induced hepatic steatosis and inflammation and increased the hepatic TG and FFA content. The expression of fattyacid transport protein 4(FATP4), a hepatic FFA influxrelated gene; macrophage recruitment; and the level of malondialdehyde(MDA), an oxidative stress marker, were significantly augmented by a 4-wk MCD. The levels of hepatic sterol regulatory element-binding protein-1c(SREBP-1c) m RNA(lipogenesis-related gene) and acyl-coenzyme A oxidase 1(ACOX1) m RNA(β-oxidation-related gene) had decreased at 4 wk and further decreased at 8 wk. However, the level of microsomal triglyceride transfer protein m RNA(a lipid excretion-related gene) remained unchanged. The administration of exendin-4 significantly attenuated the MCD-induced increase in hepatic steatosis, hepatic TG and FFA content, and FATP4 expression as well as the MCD-induced augmentation of hepatic inflammation, macrophage recruitment, and MDA levels. Additionally, it further decreased the hepatic SREBP-1c level and alleviated the MCD-mediated inhibition of the ACOX1 m RNA level. CONCLUSION: These results suggest that GLP-1 inhibits hepatic steatosis and inflammation through the inhibition of hepatic FFA influx and oxidative stress in a non-obese NASH model.

Coagonist of glucagon-like peptide-1 and glucagon receptors ameliorates kidney injury in murine models of obesity and diabetes mellitus

AIM To investigate the role of glucagon-like peptide-1(GLP-1)/glucagon receptors coagonist on renal dysfunction associated with diabetes and obesity. METHODS Chronic high-fat diet fed C57 BL/6 J mice, streptozotocintreated high-fat diet fed C57 BL/6 J mice and diabeticC57 BLKS/J db/db mice were used as models of diabetes-induced renal dysfunction. The streptozotocintreated high-fat diet fed mice and db/db mice were treated with the GLP-1 and glucagon receptors coagonist(Aib2 C24 Chimera2, 150 μg/kg, sc) for twelve weeks, while in chronic high-fat diet fed mice, coagonist(Aib2 C24 Chimera2, 150 μg/kg, sc) treatment was continued for forty weeks. Kidney function, histology, fibrosis, inflammation, and plasma biochemistry were assessed at the end of the treatment. RESULTS Coagonist treatment decreased body weight, plasma lipids, insulin resistance, creatinine, blood urea nitrogen, urinary albumin excretion rate and renal lipids. In kidney, expression of lipogenic genes(SREBP-1 C, FAS, and SCD-1) was decreased, and expression of genes involved in β-oxidation(CPT-1 and PPAR-α) was increased due to coagonist treatment. In plasma, coagonist treatment increased adiponectin and FGF21 and decreased IL-6 and TNF-?. Coagonist treatment reduced expression of inflammatory(TNF-α, MCP-1, and MMP-9) and pro-fibrotic(TGF-β, COL1 A1, and α-SMA) genes and also improved histological derangement in renal tissue.CONCLUSION Coagonist of GLP-1 and glucagon receptors alleviated diabetes and obesity-induced renal dysfunction by reducing glucose intolerance, obesity, and hyperlipidemia.

Glycated haemoglobin reduction and fixed ratio combinations of analogue basal insulin and glucagon-like peptide-1 receptor agonists:A systematic review

BACKGROUND Fixed ratio combinations(FRCs)of analogue basal insulin and glucagon-like peptide-1 receptor agonists are a newer addition to the therapeutic armamentarium for the management of type 2 diabetes mellitus.They reduce treatment complexity by combining two injectables in a single daily injectable,thus potentially improving adherence and persistence.Clinicians wanting to use FRCs would need to choose between members of the class.AIM To describe and contrast the glycated haemoglobin reduction of two FRCs of analogue basal insulin and glucagon like peptide-1 receptor agonist in adults with type 2 diabetes mellitus.METHODS The following Population,Intervention,Comparison,Outcome question was used for the primary analysis:Among adult patients with type 2 diabetes mellitus[P],what is the effect of iGlarLixi[I]compared to IDegLira[C]for bringing about glycaemic control(as measured by reduction in glycosylated haemoglobin)[O]?The Prisma Statement was used as a guideline for framing this systematic review.We searched PubMed,EMBASE and Cochrane library databases and Clinicaltrials.gov using various keywords and medical search headings related to type 2 diabetes mellitus,iGlarlixi,IDegLira and glycated haemoglobin A1c.RESULTS All 14 studies identified by the systematic search met the primary efficacy endpoint of reduction in glycated haemoglobin.There were no head-to-head studies between the FRCs of iGlarlixi and IDegLira,and we therefore did an indirect comparison based on a common comparator of insulin glargine U100.Both iGlarLixi and IDegLira effectively reduce glycated haemoglobin when compared to insulin glargine U100.However,using indirect comparisons,IDegLira had a greater haemoglobin A1c reducing ability(0.6%vs 0.3%).The indirect comparison is limited by the differences between the studies;the fasting blood glucose targets were slightly higher for iGlarLixi studies when compared to the IDegLira studies(4.0-5.0 mmol/L and 4.4-5.6 mmol/L),and the IDegLira study used a greater average dose of insulin glargine when compared to the iGlarLixi studies(66 U/d vs 40 U/d).CONCLUSION Both iGlarLixi and IDegLira effectively reduce glycated haemoglobin.Indirect comparisons,using insulin glargine as the common comparator,suggest that IDegLira reduces glycated haemoglobin to a greater extent than iGlarLixi.However,given the limitations of indirect comparisons,robust head to head studies and real-world data would better inform clinician choice and clinical practice guidelines.

Glucagon peptide-like 1 receptor (GLP-1R) expression per se: a new insight into neurodegenerative disease?

Glucagon peptide-like 1（GLP-1）and GLP-1 receptor（GLP-1R）：GLP-1 is an incretin hormone secreted from gut L cells.GLP-1 exerts its action through binding to its specific receptor,GLP-1R,which is a member of the G protein-coupled receptor superfamily.GLP-1R is reportedly expressed in various organs,such as the liver,kidney,and peripheral tissues.

Role of incretins and glucagon receptor agonists in metabolic dysfunction-associated steatotic liver disease:Opportunities and challenges

Metabolic dysfunction-associated steatotic liver disease(MASLD)has become the most common chronic liver disease worldwide,paralleling the rising pandemic of obesity and type 2 diabetes.Due to the growing global health burden and com-plex pathogenesis of MASLD,a multifaceted and innovative therapeutic approach is needed.Incretin receptor agonists,which were initially developed for diabetes management,have emerged as promising candidates for MASLD treatment.This review describes the pathophysiological mechanisms and action sites of three major classes of incretin/glucagon receptor agonists:glucagon-like peptide-1 receptor agonists,glucose-dependent insulinotropic polypeptide receptor agonists,and glucagon receptor agonists.Incretins and glucagon directly or indirectly impact various organs,including the liver,brain,pancreas,gastro-intestinal tract,and adipose tissue.Thus,these agents significantly improve glycemic control and weight management and mitigate MASLD pathogenesis.Importantly,this study provides a summary of clinical trials analyzing the effect-iveness and safety of incretin receptor agonists in MASLD management and provides an in-depth analysis highlighting their beneficial effects on improving liver function,hepatic steatosis,and intrahepatic inflammation.There are emerging challenges associated with the use of these medications in the real world,particularly adverse events,drug-drug interactions,and barriers to access,which are discussed in detail.Additionally,this review highlights the evolving role of incretin receptor agonists in MASLD management and suggests future research directions.

Influence of glucagon-like peptide 1 on the expression of ACAT1,CD36 gene and cholesterol metabolism in macrophages

Objective:To investigate whether glucagon like peptide-1(GLP-1)can reduce the cholesterol in foam cells derived from macrophages by affecting the expression of CD36 and acyl-CoA1(ACAT1)The content.Methods:Macrophages were obtained from mice,and after corresponding treatment,they were divided into 4 groups:blank control group,experimental group,GLP-1 agitation group,GLP-1 inhibition group,and the expression of CD36,ACAT1 mRNA and protein in cells of each group was detected.Expression and levels of total cholesterol(TC),free cholesterol(FC)and cholesterol ester(CE).Results:Compared with the blank control group,the content of TC,FC,CE and the expression of CD36,ACAT1 mRNA and protein in the experimental group were significantly increased(P<0.05);compared with the experimental group,the content and content of TC,FC,CE in the GLP-1 excited group The expressions of CD36 and ACAT1 mRNA and protein were significantly decreased(P<0.05);compared with the GLP-1 agitation group,the contents of TC,FC and CE and the expression of CD36,ACAT1 mRNA and protein were significantly increased in the GLP-1 inhibition group(P<0.05).Conclusion:The expression levels of CD36 and ACAT1 can be suppressed by GLP-1,and under the indirect influence of GPL-1,the level of intracellular cholesterol will also be reduced,so that the process of macrophages to foam cells is suppressed Thereby slowing down the development of atherosclerosis.

Role of intestinal glucagon-like peptide-1 in impaired counterregulatory responses to hypoglycemia

Patients with type 1 diabetes mellitus(T1DM)experience multiple episodes of hypoglycemia,resulting in dysfunctional counter-regulatory responses with time.The recent experimental study by Jin et al explored the role of intestinal glucagon-like peptide-1(GLP-1)in impaired counter-regulatory responses to hypoglycemia.They identified intestinal GLP-1 along with GLP-1 receptor(GLP-1R)as the new key players linked with impaired counter-regulatory responses to hypoglycemia in type 1 diabetic mice.They also demonstrated that excessive expression of GLP-1 and GLP-1R was associated with attenuated sympathoadrenal responses and decreased glucagon secretion.The study has enormous clinical relevance as de-fective counter regulation and hypoglycemia unawareness negatively impacts the intensive glycemic management approach in this group of patients.However,the physiological processes must be validated in dedicated human studies to compre-hensively understand the pathophysiology of this complex relationship,and to clarify the true extent of impaired hypoglycemia counter regulation by intestinal GLP-1.For now,following the results of the index study and other similar studies,GLP-1 analogues usage in T1DM must be carefully monitored,as there is an inherent risk of worsening the already impaired counter-regulatory responses in these patients.Further studies in the future could identify other key players in-volved in this clinically relevant interaction.

Xenopus GLP-1-based glycopeptides as dual glucagon-like peptide 1 receptor/glucagon receptor agonists with improved in vivo stability for treating diabetes and obesity

Peptide dual agonists toward both glucagon-like peptide 1 receptor(GLP-1R)and glucagon receptor(GCGR)are emerging as novel therapeutics for the treatment of type 2 diabetes mellitus(T2DM)patients with obesity.Our previous work identified a Xenopus GLP-1-based dual GLP-1R/GCGR agonist termed xGLP/GCG-13,which showed decent hypoglycemic and body weight lowering activity.However,the clinical utility of xGLP/GCG-13 is limited due to its short in vivo half-life.Inspired by the fact that O-GlcNAcylation of intracellular proteins leads to increased stability of secreted proteins,we rationally designed a panel of O-GlcNAcylated xGLP/GCG-13 analogs as potential long-acting GLP-1R/GCGR dual agonists.One of the synthesized glycopeptides 1f was found to be equipotent to xGLP/GCG-13 in cell-based receptor activation assays.As expected,O-GlcNAcylation effectively improved the stability of xGLP/GCG-13 in vivo.Importantly,chronic administration of 1f potently induced body weight loss and hypoglycemic effects,improved glucose tolerance,and normalized lipid metabolism and adiposity in both db/db and diet induced obesity(DIO)mice models.These results supported the hypothesis that glycosylation is a useful strategy for improving the in vivo stability of GLP-1-based peptides and promoted the development of dual GLP-1R/GCGR agonists as antidiabetic/antiobesity drugs.

Boc5对脑缺血再灌注小鼠血脑屏障损伤的保护作用

目的探讨胰高血糖素样1受体(GLP-1R)小分子激动剂Boc5对脑缺血再灌注损伤(CIRI)后血脑屏障损伤的作用及机制。方法将C57BL/6J小鼠随机分为假手术组、模型组和Boc5高、中、低剂量组。模型组以及Boc5高、中、低剂量组行大脑中动脉栓塞再灌注(MCAO/R)损伤,Boc5高、中、低剂量组在MCAO/R损伤前连续给药7 d不同剂量的Boc5,假手术组及模型组每日给予等体积生理盐水。神经功能评分、足误实验和转棒实验评价小鼠行为学损伤;检测血清超氧化物歧化酶(SOD)、丙二醛(MDA)和过氧化氢酶(CAT)水平;评价小鼠血液生化指标变化;2,3,5-三苯基氯化四氮唑(TTC)染色法检测缺血梗死面积;分光光度法检测脑组织伊文氏蓝含量;Western Blot法检测缺血半暗区闭合蛋白、紧密连接蛋白-5表达;免疫荧光法检测缺血半暗区星形胶质细胞标志物GFAP表达;酶联免疫吸附(ELISA)法检测星形胶质细胞氧糖剥夺损伤/复氧(OGD/R)后炎性因子水平。结果实验结果表明,Boc5能显著改善行为学缺陷,可降低MCAO/R损伤后SOD、MDA和CAT水平,显著减小梗死面积,显著减轻MCAO/R所致血脑屏障损伤,显著降低星形胶质细胞增生及活化水平及星形胶质细胞OGD/R损伤后的炎性因子水平。结论Boc5可减轻MCAO/R损伤所致小鼠血脑屏障损伤,其机制可能是通过减轻星形胶质细胞炎症。

全球抗糖尿病药物研发现状及市场分析

目的:为开发新一代抗糖尿病药物提供新的思路。方法:利用文献调研、网络调研、专家咨询等方法,系统整理和归纳了抗糖尿病药物的在研数量、抗2型糖尿病药物的主要研发公司及研发药物数量和2006-2010年抗糖尿病药物的市场销售额,分析目前全球抗糖尿病药物的研发现状及不同种类药物的市场表现。结果与结论:截至2012年3月,共有400多种抗2型糖尿病药物处于临床试验阶段,默克公司研发的药物数量较多,其次为辉瑞、葛兰素史克、罗氏、礼来、诺和诺德等公司。2010年抗糖尿病药物全球销售额达344.29亿美元,比2009年304.06亿元的销售额增长了12.2%,比2006年213.10亿美元的销售额增长了68.2%。胰岛素和胰岛素类似物所占市场份额最高,且保持了逐年增长的趋势;口服药物中促胰岛素分泌剂市场保持了较高的增长势头;同时随着二肽基肽酶Ⅳ(DPP-Ⅳ)抑制剂、胰高血糖素样肽1(GLP-1)类似物等疗效更佳、副作用更小的新型口服促胰岛素分泌剂的上市,格列奈类药物的市场份额正在逐渐减小。DPP-Ⅳ抑制剂、GLP-1类似物、胰高血糖素受体拮抗药、钠-葡萄糖协同转运蛋白2抑制剂等为当下新一代抗2型糖尿病药物研究的重点。