Intestinal glucagon-like peptide-1:A new regulator of impaired counterregulatory responses to hypoglycemia in type 1 diabetes mellitus

In this article,we review the study by Jin et al,which examined the role of intestinal glucagon-like peptide-1(GLP-1)in counterregulatory responses to hypoglycemia in patients with type 1 diabetes mellitus(T1DM).With the global rise of T1DM,there is an increased burden on society and healthcare systems.Due to insulin therapy and islet dysfunction,T1DM patients are highly vulnerable to severe hypoglycemia,a leading cause of mortality.In healthy individuals,counterregulatory mechanisms restore blood glucose during hypoglycemia,but repeated episodes impair these responses.Jin et al demonstrated that overexpression of GLP-1 attenuates the sympathetic-adrenal reflex and disrupts the secretion of counterregulatory hormones such as glucagon during hypoglycemia,leading to counterregulatory dysfunction.These findings highlight the critical role of GLP-1 in the impaired counterregulatory response to hypoglycemia in T1DM patients and provide new insights into the potential application of GLP-1-related therapies in T1DM patients.

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.

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.

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.

三黄煎对Ⅱ型糖尿病大鼠胰岛素分泌等功能的影响

观察中药三黄煎对 型糖尿病大鼠胰岛素分泌、胰岛素敏感性及胰升糖素分泌的影响。以小剂量链脲佐菌素加高能量饲料制成 型糖尿病大鼠模型 ,随机分为治疗组、造模组和正常组 ,治疗组予中药三黄煎治疗 6周。结果 : 型糖尿病大鼠与正常组大鼠相比存在明显的胰岛素分泌缺陷、胰岛素抵抗和胰升糖素分泌异常 ,治疗组经 6周的治疗胰岛素敏感性增加 ,其胰岛素分泌亦有所改善 ,胰升糖素的不适当分泌也受到抑制。结论 :中药三黄煎可能通过调节胰岛素抵抗与胰岛素分泌之间、胰岛素与胰升糖素之间的反馈平衡关系而起到一定的治疗作用。

预防性应用类高血糖素多肽-Ⅱ对缺血-再灌注肠黏膜屏障的影响

目的:观察类高血糖素多肽Ⅱ(GLP Ⅱ)对缺血再灌注所致的肠黏膜屏障损害的预防保护作用。 方法:采用夹闭肠系膜上动脉20min所致肠道缺血再灌注损伤小鼠模型,将30只小鼠随机分为正常(N)组、对照(C)组和GLP Ⅱ预处理(P)组。观察缺血再灌注后1天,肠黏膜形态、肠道细菌移位率、血浆内毒素水平和肠道IgA浓度的变化,并进行相关分析。 结果:缺血再灌注后,C组肠黏膜受到明显损伤,P组肠黏膜增生明显,C组和P组小鼠的肠道细菌移位率和血浆内毒素水平均明显高于N组(P<0. 01),肠道IgA浓度则明显降低(P<0. 01)。与C组相比,P组的细菌移位率和内毒素水平要低于C组(P=0. 005),IgA浓度要高于C组(P<0. 01)。 结论:缺血再灌注严重损害了肠黏膜屏障,经GLP Ⅱ预处理可以有效地减轻肠黏膜屏障的损伤。

类高血糖素多肽-Ⅱ对短肠大鼠残留小肠葡萄糖吸收的影响

目的:研究类高血糖素多肽 Ⅱ(GLP Ⅱ)对短肠大鼠残留小肠葡萄糖吸收的影响。 方法: 75%小肠切除大鼠随机分成空白对照组(SB组)、类高血糖素多肽 Ⅱ组 (SB/GLP Ⅱ组),另设一组正常进食大鼠作为SB组的对照组。术后第 1天起进食标准大鼠饲料,术后第 6天进行体内小肠循环灌流实验,测定大鼠回肠的单位长度及单位重量的葡萄糖吸收数据。 结果:灌洗段回肠长度各组无差异,SB组湿重 /长度比值显著高于正常组,但显著低于SB/GLP Ⅱ组。灌洗段回肠每厘米 45min葡萄糖吸收量正常组和SB组无差异,SB/GLP Ⅱ组显著高于SB组(P<0. 05)。正常组灌洗段回肠每克湿重葡萄糖吸收率显著高于SB组,但SB组和SB/GLP Ⅱ组无差异 (P>0. 05)。 结论:GLP Ⅱ能显著促进短肠大鼠残留小肠单位长度的葡萄糖吸收。

中老年Ⅱ型糖尿病患者血清胃动素和生长抑素的水平及意义

目的探讨中老年Ⅱ型糖尿病患者内分泌和代谢的特征。方法Ⅱ型糖尿病３５例，无糖尿病的对照组３７例。用放射免疫法测定血清胃动素，生长抑素，胰高血糖素及胰岛素。结果与正常对照组比较，中老年Ⅱ型糖尿病患者血清胃动素无明显变化（Ｐ＞０．０５）；生长抑素明显升高（Ｐ＜０．０１）；胰高血糖素升高（Ｐ＜０．０１）；胰岛素降低（Ｐ＜０．０１）。结论中老年人Ⅱ型糖尿病患者血清胃动素变化不明显，但血清生长抑素、胰高血糖素明显升高，胰岛素降低，这为研究Ⅱ型中老年糖尿病的治疗及其并发症（如胃轻瘫）的治疗可能有一定临床意义。

Ⅱ型糖尿病代谢相关信号转导分子机制研究进展

糖尿病是一种以高血糖为特征的代谢性疾病,主要分为Ⅰ型糖尿病、Ⅱ型糖尿病和妊娠糖尿病等3类。Ⅱ型糖尿病患者众多,占糖尿病患者总数的90%~95%,因而成为研究热点。同时,Ⅱ型糖尿病也因其发病因素多、发病过程复杂而成为研究的难点。我们从代谢相关酶与血糖调节相关信号通路2个方面,回顾了近年来在Ⅱ型糖尿病发病机制与治疗领域的研究进展,为探讨Ⅱ型糖尿病的发病机制及治疗靶点提供一些理论依据。

Mimicking natural cholesterol assimilation to elevate the oral delivery of liraglutide for type Ⅱ diabetes therapy

Glucagon-like peptide-1 receptor agonists(GLP-1 RA)are a series of polypeptides broadly applied in the long-term treatment of typeⅡdiabetes.However,administration of GLP-RA is mainly through repetitive subcutaneous injection,which may seriously decrease the compliance and safety.Herein,a bio-inspired oral delivery system was designed to enhance the oral absorption of liraglutide(Lira),a kind of GLP-1 RA,by mimicking the natural cholesterol assimilation.25-hydroxycholesterol(25HC),a cholesterol derivative,was modified on the surfaced of Lira-loaded PLGA nanoparticles(Lira 25HC NPs)and functioned as a“top-down”actuator to facilitate unidirectional transcytosis across the intestinal epithelium.After oral delivery,Lira 25HC NPs displayed improved therapeutic effect as compared with oral free Lira on typeⅡdiabetes db/db mice,as evidenced by multiple relieved diabetic symptoms including the enhanced glucose tolerance,repressed weight growth,improved liver glucose metabolism,decreased fasting blood glucose,HbA 1c,serum lipid,and increasedβcells activity.Surprisingly,the fasting blood glucose,liver glucose metabolism,and HbA1c of oral Lira-loaded 25HC NPs were comparable to subcutaneous injection of free Lira.Further mechanisms revealed that 25HC ligand could mediate the nanoparticles to mimic natural cholesterol absorption by exerting high affinity towards apical Niemann-Pick C1 Like 1(NPC1L1)and then basolateral ATP binding cassette transporter A1(ABCA1)overexpressed on the opposite side of intestinal epithelium.This cholesterol assimilation-mimicking strategy achieve the unidirectional transport across the intestinal epithelium,thus improving the oral absorption of liraglutide.In general,this study established a cholesterol simulated platform and provide promising insight for the oral delivery of GLP-1 RA.

sGLP-1对Ⅱ型糖尿病大鼠治疗效果的研究

目的研究人工合成胰高血糖素样截短肽(sGLP-1)对Ⅱ型糖尿病大鼠的治疗效果。方法Ⅱ型糖尿病GK大鼠随机分为三组,以合成的GLP-1为阳性对照,观察sGLP-1对Ⅱ型糖尿病GK大鼠血糖水平、胰岛素分泌以及糖耐量的影响,通过MTT法测定sGLP-1对胰岛β细胞系β-TC3增殖作用。结果与GLP-1相比sGLP-1能够长效控制的血糖水平,明显改善糖尿病大鼠的糖耐量(P<0.01)。同时sGLP-1能促进胰岛素分泌和胰岛β-TC3细胞的增殖,使得胰岛体积增大,数量增多。结论sGLP-1控制血糖的长效能力优于GLP-1,可能从刺激胰岛素分泌和促进胰岛β细胞增殖两个方面对Ⅱ型糖尿病具有治疗作用。

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.

新型胰高血糖素样肽-1类似物依西纳肽的药理与临床评价

依西纳肽是一种与胰高血糖素样肽-1(GLP-1)结构相似的新型多肽类药物,其特点是可与胰脏GLP- 1受体结合刺激胰岛素分泌,改变胰岛β-细胞功能进行性衰退,并从多种其他途径调节2型糖尿病患者的血糖水平。临床上可用于二甲双胍、磺酰脲类及其两者并用无效的2型糖尿病的治疗,降血糖作用强,不良反应少,耐受性好。现通过文献检索综述了依西纳肽的药理作用、药动学及临床评价。

RFLP和DGGE技术探讨胰高糖素受体基因第二外显子与中国人NIDDM的关系

目的 探讨胰高糖素受体 ( GCG- R)基因第二外显子与中国人 型糖尿病是否存在关联。方法 运用聚合酶链反应—限制性片段长度多态性 ( PCR- RFLP)和聚合酶链反应—变性梯度凝胶电泳 ( PCR-DGGE)分析方法在 2 0 0例无亲缘关系之中国云南昆明地区汉族人 ( 型糖尿病患者 1 2 0例 ,健康对照者80例 )中对 GCG- R基因第二外显子进行检测。结果 所有研究对象中无论是 型糖尿病患者还是健康对照者在 GCG- R基因第二外显子上均无一例存在突变 ,其 GCG- R基因 40号密码子的基因型均表现为Gly40 /Gly40之纯合子。结论 提示在中国云南昆明地区的汉族人中 ,GCG- R基因 Gly40 Ser突变与 型糖尿病不存在任何关联。

GFP荧光标记GLP-1受体细胞系的建立

为建立胰高血糖素样肽1受体(glucagon-like peptide 1 receptor,GLP-1R)药物筛选模型,真核表达载体pCMV6/GFP/GLP-1R构建好后,转染至U2OS细胞,转染后的细胞经G418筛选获得单克隆细胞株。该细胞株经Western-blot和GLP-1类似物检测,结果表明GLP-1R在该细胞株高表达并对GLP-1类似物有着高灵敏度与特异性的反应,可以用于GLP-1受体激动剂的筛选。

营养不良新生大鼠胰岛素与胰高血糖素及IGF-Ⅱ基因表达的变化

目的 探讨营养不良对胚胎胰岛细胞功能的影响。方法 限制妊娠晚期（１４ ～２１ 天）雌性大鼠摄食量（ 低于正常５０ ％ ） 以制备营养不良新生大鼠模型，利用 Ｎｏｒｔｈｅｒｎ 印迹法分析胰腺胰岛素、胰高血糖素的基因表达，以及胰腺和肝脏胰岛素样生长因子Ⅱ（ Ｉ Ｇ ＦⅡ） 基因表达。结果 营养不良新生大鼠胰腺胰岛素ｍ Ｒ Ｎ Ａ 含量明显低于正常对照组（ Ｐ＜ ０ ．０５） ，而胰高血糖素ｍ Ｒ Ｎ Ａ 含量无明显变化；营养不良新生大鼠胰腺和肝脏 Ｉ Ｇ ＦⅡｍ Ｒ Ｎ Ａ 含量与正常对照比较无明显变化。结论 胚胎期营养不良可抑制胰岛素基因表达，而对胰高血糖素和 Ｉ Ｇ ＦⅡ基因表达影响不明显。

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.