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.

Rikkunshito increases peripheral incretin-hormone levels in humans and rats

BACKGROUND It was reported that rikkunshito(TJ-43)improved the cisplatin-induced decreases in the active form of ghrelin in plasma;however,other effects on gastrointestinal hormones have not been investigated.AIM To investigate the effects of TJ-43 on peripheral levels of incretin hormones,including gastric inhibitory polypeptide(GIP)and glucagon-like polypeptide-1(GLP-1),in humans and rats.METHODS Patients were divided into two groups,namely patients who received TJ-43 immediately following surgery[TJ-43(+)group]and those who received TJ-43 on postoperative day 21[TJ-43(-)group],and the plasma levels of active GIP and active GLP-1 were assessed.In animal experiments,rats were treated with TJ-43[rat(r)TJ-43(+)group]or without[rTJ-43(−)group]by gavage for 4 wk,and the plasma active GIP and active GLP-1 levels were measured.The expression of incretin hormones in the gastrointestinal tract and insulin in the pancreas were investigated by immunohistochemistry.Furthermore,the cyclic adenosine monophosphate activities were assessed in pancreatic tissues from rats treated with or without TJ-43 in vivo,and the blood glucose levels and plasma insulin levels were measured in rats treated with or without TJ-43 in oral glucose tolerance tests.RESULTS In humans,the active incretin hormone levels increased,and values were significantly greater in the TJ-43(+)group compared those in the TJ-43(-)group.In rats,the plasma active incretin levels significantly increased in the rTJ-43(+)group compared with those in the rTJ-43(-)group.GIP and GLP-1 expressions were enhanced by TJ-43 treatment.Moreover,plasma insulin levels increased and blood glucose levels were blunted in the rTJ-43(+)group.CONCLUSION The results show that TJ-43 may be beneficial for patients who undergo pancreatic surgery.

Diabetes and fatty liver:Involvement of incretin and its benefit for fatty liver management

Fatty liver disease is defined as liver condition characterized by hepatic steatosis,closely related to pathological conditions in type 2 diabetes and obesity.The high prevalence of fatty liver disease in obese patients with type 2 diabetes reached 70%,reflecting the importance of these conditions with fatty liver.Although the exact pathological mechanism of fatty liver disease,specifically non-alcoholic fatty liver disease(NAFLD)remains not completely revealed,insulin resistance is suggested as the major mechanism that bridged the development of NAFLD.Indeed,loss of the incretin effect leads to insulin resistance.Since incretin is closely related to insulin resistance and the resistance of insulin associated with the development of fatty liver disease,this pathway suggested a potential mechanism that explains the association between type 2 diabetes and NAFLD.Furthermore,recent studies indicated that NAFLD is associated with impaired glucagon-like peptide-1,resulting in decreased incretin effect.Nevertheless,improving the incretin effect becomes a reasonable approach to manage fatty liver disease.This review elucidates the involvement of incretin in fatty liver disease and recent studies of incretin as the management for fatty liver disease.

Rikkunshito increases appetite by enhancing gastrointestinal and incretin hormone levels in patients who underwent pyloruspreserving pancreaticoduodenectomy: A retrospective study

BACKGROUND Rikkunshito(TJ-43)relieves gastrointestinal disturbance by increases in the levels of acylated ghrelin.AIM To investigate the effects of TJ-43 in patients undergoing pancreatic surgery.METHODS Forty-one patients undergoing pylorus-preserving pancreaticoduodenectomy(PpPD)were divided into two groups;patients took daily doses of TJ-43 after surgery or after postoperative day(POD)21.The plasma levels of acylated and desacylated ghrelin,cholecystokinin(CCK),peptide YY(PYY),gastric inhibitory peptide(GIP),and active glucagon-like peptide(GLP)-1 were evaluated.Oral calorie intake was assessed at POD 21 in both groups.The primary endpoint of this study was the total food intake after PpPD.RESULTS The levels of acylated ghrelin were significantly greater in patients treated with TJ-43 than those in patients without TJ-43 administration at POD 21,and oral intake was significantly increased in patients treated with TJ-43.The CCK and PYY levels were significantly greater in patients treated with TJ-43 than those in patients without TJ-43 treatment.Furthermore,the GIP and active GLP-1 levels increased and values at POD 21 were significantly greater in patients treated with TJ-43 than those in patients without TJ-43 administration.Insulin secretion tended to increase in patients treated with TJ-43.CONCLUSION TJ-43 may have advantages for oral food intake in patients in the early phase after pancreatic surgery.Further investigation is needed to clarify the effects of TJ-43 on incretin hormones.

Incretin manipulation in diabetes management

Incretin-based therapies have revolutionized the medical management of type 2 diabetes mellitus(T2DM) in the 21 st century. Glucagon-like peptide-1(GLP-1) suppresses appetite and gastric motility, and has trophic effects on pancreas, cardio-protective and renal effects. GLP-1 analogues and dipeptidyl peptidase-4 inhibitors form the incretin-based therapies. Significant reduction of hemoglobin A1 c when used as monotherapy and in combination regimens, favorable effects on body weight, and low risk of hypoglycemia are their unique therapeutic benefits. Their safety and tolerability are comparable to other anti-diabetic medications. Concern about elevated risk of pancreatitis has been discarded by two recent meta-analyses. This article discusses the therapeutic manipulation of incretin system for the management of T2 DM.

Down-regulation of pancreatic transcription factors and incretin receptors in type 2 diabetes

Type 2 diabetes is one of the most prevalent and serious metabolic diseases.Under diabetic conditions,chronic hyperglycemia and subsequent induction of oxidative stress deteriorate pancreaticβ-cell function,which leads to the aggravation of type 2 diabetes.Although such phenomena are well known as glucose toxicity,its molecular mechanism remains unclear.In this review article,we describe the possible molecular mechanism forβ-cell dysfunction found in type 2 diabetes,focusing on(1)oxidative stress,(2)pancreatic transcription factors(PDX-1 and MafA)and(3)incretin receptors(GLP-1 and GIP receptors).Under such conditions,nuclear expression levels of PDX-1 and MafA are decreased,which leads to suppression of insulin biosynthesis and secretion.In addition,expression levels of GLP-1 and GIP receptors are decreased,which likely contributes to the impaired incretin effects found in diabetes.Taken together,it is likely that downregulation of pancreatic transcription factors(PDX-1and MafA)and down-regulation of incretin receptors(GLP-1 and GIP receptors)explain,at least in part,the molecular mechanism forβ-cell dysfunction found in type 2 diabetes.

Insulin plus incretin:A glucose-lowering strategy for type 2-diabetes

There are many advantages of combining incretin therapy[glucagon-like peptide-1(GLP-1)receptor agonists and dipeptidyl peptidase-4(DPP-4)inhibitors]with insulin therapy as a glucose-lowering strategy in type2 diabetes.One important advantage is the complementary mode of the mechanistic action of incretin and insulin therapy.Another advantage is the reduction in risk of hypoglycemia and weight gain when adding incretin therapy to insulin.Several clinical trials have studied the addition of GLP-1 receptor agonists[exenatide BID(twice daily),lixisenatide,albiglutide]or DPP-4inhibitors(vildagliptin,sitagliptin,saxagliptin,alogliptin,linagliptin)to ongoing insulin therapy or adding insulin to ongoing therapy with a GLP-1 receptor agonist(liraglutide).These studies show improved glycemia in the presence of limited risk for hypoglycemia and weight gain with the combination of incretin therapy with insulin.This article reviews the background and clinical studies on this combination.

Incretins and selective renal sodium-glucose co-transporter 2 inhibitors in hypertension and coronary heart disease

Hyperglycemia is associated with an increased risk of cardiovascular disease,and the consequences ofintensive therapy may depend on the mechanism of the anti-diabetic agent(s)used to achieve a tight control.In animal models,stable analogues of glucagon-like peptide-1(GLP-1)were able to reduce body weight and blood pressure and also had favorable effects on ischemia following coronary reperfusion.In a similar way,dipeptidyl peptidase IV(DPPIV)showed to have favorable effects in animal models of ischemia/reperfusion.This could be due to the fact that DPPIV inhibitors were able to prevent the breakdown of GLP-1 and glucose-dependent insulinotropic polypeptide,but they also decreased the degradation of several vasoactive peptides.Preclinical data for GLP-1,its derivatives and inhibitors of the DPPIV enzyme degradation suggests that these agents may be able to,besides controlling glycaemia,induce cardio-protective and vasodilator effects.Notwithstanding the many favorable cardiovascular effects of GLP-1/incretins reported in different studies,many questions remain unanswered due the limited number of studies in human beings that aim to examine the effects of GLP-1 on cardiovascular endpoints.For this reason,long-term trials searching for positive cardiovascular effects are now in process,such as the CAROLINA and CARMELINA trials,which are supported by small pilot studies performed in humans(and many more animal studies)with incretin-based therapies.On the other hand,selective renal sodium-glucose co-transporter 2 inhibitors were also evaluated in the prevention of cardiovascular outcomes in type 2 diabetes.However,it is quite early to draw conclusions,since data on cardiovascular outcomes and cardiovascular death are limited and long-term studies are still ongoing.In this review,we will analyze the mechanisms underlying the cardiovascular effects of incretins and,at the same time,we will present a critical position about the real value of these compounds in the cardiovascular system and its protection.

New perspectives on exploitation of incretin peptides for the treatment of diabetes and related disorders

The applicability of stable gut hormones for the treatment of obesity-related diabetes is now undisputable. This is based predominantly on prominent and sustained glucoselowering actions, plus evidence that these peptides can augment insulin secretion and pancreatic islet function over time. This review highlights the therapeutic potential of glucagon-like peptide-1(GLP-1), glucose-dependent insulinotropic polypeptide(GIP), oxyntomodulin(OXM) and cholecystokinin(CCK) for obesity-related diabetes.Stable GLP-1 mimetics have already been successfully adopted into the diabetic clinic, whereas GIP, CCK and OXM molecules offer promise as potential new classes of antidiabetic drugs. Moreover, recent studies have shown improved therapeutic effects following simultaneous modulation of multiple receptor signalling pathways by combination therapy or use of dual/triple agonist peptides. However, timing and composition of injections may be important to permit interludes of beta-cell rest. The review also addresses the possible perils of incretin based drugs for treatment of prediabetes. Finally, the unanticipated utility of stable gut peptides as effective treatments for complications of diabetes, bone disorders, cognitive impairment and cardiovascular dysfunction is considered.

Incretin based therapy and pancreatic cancer:Realising the reality

Incretin-based therapies like glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors help maintain the glycaemic control in patients with type 2 diabetes mellitus with additional systemic benefits and little risk of hypoglycaemia.These medications are associated with low-grade chronic pancreatitis in animal models inconsistently.The incidence of acute pancreatitis was also reported in some human studies.This inflammation provides fertile ground for developing pancreatic carcinoma(PC).Although the data from clinical trials and population-based studies have established safety regarding PC,the pathophysiological possibility that low-grade chronic pancreatitis leads to PC remains.We review the existing literature and describe the relationship between incretin-based therapies and PC.

Effects of Acarbose on incretins in newly diagnosed type 2 diabetic patients in different carbohydrate tolerance test

Objective To evaluate the effects of Acarbose on incretin level(glucagon-like peptide 1(GLP-1)and gastric inhibitory polypeptide(GIP)of type 2 diabetes mellitus(T2DM)patients after different kinds of glucose load.Methods A total of 32 newly diagnosed T2DM patients were enrolled in this study and randomly divided into

Hypothesis that alpha-amylase evokes regulatory mechanisms originating in the pancreas,gut and circulation,which govern glucose/insulin homeostasis

The anti-incretin theory involving the abolishment of diabetes type(DT)II by some of methods used in bariatric surgery,first appeared during the early years of the XXI century and considers the existence of anti-incretin substances.However,to date no exogenous or endogenous anti-incretins have been found.Our concept of the acini-islet-acinar axis assumes that insulin intra-pancreatically stimulates alpha-amylase synthesis(“halo phenomenon”)and in turn,alphaamylase reciprocally inhibits insulin production,thus making alpha-amylase a candidate for being an anti-incretin.Additionally,gut as well as plasma alphaamylase,of pancreatic and other origins,inhibits the appearance of dietary glucose in the blood,lowering the glucose peak after iv or oral glucose loading.This effect of alpha-amylase can be interpreted as an insulin down regulatory mechanism,possibly limiting the depletion of pancreatic beta cells and preventing their failure.Clinical observations agree with the above statements,where patients with high blood alpha-amylase concentrations are seldom obese and seldom develop DT2.Obese-DT2,as well as DT1 patients,usually develop exocrine pancreatic insufficiency(EPI)and vice versa.Ultimately,DT2 patients develop DT1,when the pancreatic beta cells are exhausted and insulin production ceases.Studies on biliopancreatic diversion(BPD)and on BPD with duodenal switch,a type of bariatric surgery,as well as studies on EPI pigs,allow us to observe and investigate the above-mentioned phenomena of intra-pancreatic interactions.

口服新型降糖多肽ODA的设计及其口服降糖活性

肠促胰岛素分泌肽胰高血糖素样肽-1(GLP-1)和葡萄糖依赖性促胰岛素释放多肽(GIP)能通过血糖依赖机制促进胰岛素分泌,其特异性结合受体GLP-1R和GIPR是治疗2型糖尿病的良好靶点。以本实验室前期设计的口服降糖多肽OHP2为基础,设计了可口服的新型降糖多肽——ODA。ODA较OHP2的亲脂性提高,在Caco-2细胞中的胞吞能力及跨细胞转运能力更强。ODA保留了OHP2对GLP-1R的激活能力,增强了与GIPR的结合能力。口服低剂量ODA(0.53 mg/kg)即可达到与口服OHP2(1.06 mg/kg)相当的降糖水平。研究结果显示,ODA是治疗2型糖尿病极具潜力的口服药物。

肠促胰岛素治疗不同体质指数2型糖尿病合并非酒精性脂肪性肝病患者差异性分析

目的探索肠促胰岛素对于不同体质指数(BMI)的2型糖尿病患者合并非酒精性脂肪性肝病(NAFLD)的临床效果,分析2型糖尿病合并非酒精性脂肪性肝病患者NAFLD改善情况与BMI的相关性。方法从2020年6月至2021年6月纳入北大医疗淄博医院内分泌科收治的2型糖尿病合并NAFLD病患者120例,并根据不同BMI值分为3组。3组患者在维持原来的用药基础和饮食习惯上,每组均给予肠促胰素皮下注射,连续治疗24周后,观察并比较3组患者BMI、丙氨酸转氨酶(ALT)、甘油三酯(TG)、糖化血红蛋白(HbA_(1)c)、空腹血糖(FBG)、空腹胰岛素(FINS)、肝脏超声积分、胰岛素抵抗指数(HOMA-IR)变化情况。结果3组患者通过24周的肠促胰岛素治疗,各组BMI、ALT、TG、HbA_(1)c、FBG、肝脏超声积分评分均较治疗前明显下降,差异有统计学意义(P<0.05)。3组HOMA-IR较治疗前下降,差异有统计学意义;NAFLD改善情况与治疗前BMI呈正相关(r=0.37,P<0.05)。结论肠促胰岛素可以明显降低患者BMI,改善患者非酒精性脂肪性肝病状况,NAFLD改善情况与治疗前BMI呈正相关,对于2型糖尿病合并NAFLD病患者应用肠促胰岛素能够改善糖脂代谢,减轻胰岛素抵抗,逆转NAFLD及其不良结局。

Development of therapeutic options on type 2 diabetes in years:Glucagon-like peptide-1 receptor agonist’s role intreatment; from the past to future

Diabetes mellitus (DM) is a chronic metabolic disease characterized by hyperglycemia.Type 2 diabetes (T2DM) accounting for 90% of cases globally.The worldwide prevalence of DM is rising dramatically over the last decades,from 30 million cases in 1985 to 382 million cases in 2013.It’s estimated that 451 million people had diabetes in 2017.As the pathophysiology was understood over the years,treatment options for diabetes increased.Incretin-based therapy is one of them.Glucagon-like peptide-1 receptor agonist (GLP-1 RA) not only significantly lower glucose level with minimal risk of hypoglycemia but also,they have an important advantage in themanagement of cardiovascular risk and obesity.Thus,we will review here GLP-1 RAsrole in the treatment of diabetes.

基于胰高血糖素类肽-1受体的2型糖尿病治疗药物研究进展

胰高血糖素类肽-1(GLP-1)和葡萄糖依赖性促胰岛素多肽(GIP)为肠内分泌细胞在机体摄入营养时分泌的激素,因其能促进胰岛素的分泌和维持血糖的动态平衡,又被称为肠促胰素。而机体内广泛存在的二肽基肽酶-4(DPP-4)可快速灭活GLP-1和GIP,因此抑制DPP-4的活性可增强GLP-1和GIP激素的活性水平,从而改善2型糖尿病(T2DM)患者的胰岛功能和血糖控制,越来越多基于该靶点的药物被开发出来用于治疗2型糖尿病。本文综述了近年来国内外相关文献,阐述了肠促胰岛素与T2DM之间的关系,并介绍GLP-1发挥效应的机制,以及GLP类降糖药物、DPP-4抑制剂的开发设计原理。

初诊2型糖尿病患者肠促胰岛素和胰高血糖素水平的变化

目的探讨初诊2型糖尿病(T2DM)患者血清肠促胰岛素和胰高血糖素水平的变化。方法选取21例初诊T2DM患者(T2DM组)和17例血糖正常的健康体检者(对照组)。两组均行口服葡萄糖耐量试验(OGTT),测定0、30、120min时静脉血中胰高血糖素样肽1(GLP-1)、葡萄糖依赖性促胰岛素分泌多肽(GIP)和胰高血糖素水平。结果 T2DM组患者OGTT中各时点的GLP-1水平[分别为(11.6±4.4)、(14.2±5.4)、(15.1±7.3)pmol/L]较对照组[分别为(18.8±3.1)、(21.8±4.2)、(23.7±4.8)pmol/L]显著降低,差异有统计学意义(P<0.05);而两组患者各时点GIP水平无显著变化;但T2DM组患者各时点胰高血糖素水平[(16.1±4.3)、(25.1±5.4)、(25.2±5.6)pg/ml]显著高于对照组[(14.8±5.9)、(18.7±4.7)、(15.7±5.2)pg/ml],差异有统计学意义(P<0.05)。结论对于初诊的T2DM患者,空腹及糖负荷后30、120min时GLP-1水平显著下降,GIP水平无变化,胰高血糖素水平显著升高。

Dipeptidyl peptidase-4: A key player in chronic liver disease

Dipeptidyl peptidase-4 (DPP-4) is a membrane-associated peptidase, also known as CD26. DPP-4 has widespread organ distribution throughout the body and exerts pleiotropic effects via its peptidase activity. A representative target peptide is glucagon-like peptide-1, and inactivation of glucagon-like peptide-1 results in the development of glucose intolerance/diabetes mellitus and hepatic steatosis. In addition to its peptidase activity, DPP-4 is known to be associated with immune stimulation, binding to and degradation of extracellular matrix, resistance to anti-cancer agents, and lipid accumulation. The liver expresses DPP-4 to a high degree, and recent accumulating data suggest that DPP-4 is involved in the development of various chronic liver diseases such as hepatitis C virus infection, non-alcoholic fatty liver disease, and hepatocellular carcinoma. Furthermore, DPP-4 occurs in hepatic stem cells and plays a crucial role in hepatic regeneration. In this review, we described the tissue distribution and various biological effects of DPP-4. Then, we discussed the impact of DPP-4 in chronic liver disease and the possible therapeutic effects of a DPP-4 inhibitor.

肠促胰素研究的新视野

肠促胰素是肠道细胞受食物刺激分泌并释放入血,包括胰高糖素样多肽1(glucagon like peptide-1,GLP-1)、葡萄糖依赖性促胰岛素多肽(glucose-dependent insulintropic polypeptide)等,能促进胰岛素分泌并调节血糖.GLP-1为小肠L细胞分泌,并通过特异性的GLP-1受体(glucagon like peptide-1receptor,GLP-1R)介导发挥生物学作用.而GLP-1R广泛分布于胰腺及胰腺外组织中包括中枢神经系统、胃肠道系统、心血管系统、肺、肾等组织器官.近年来,GLP-1类药物除了用于糖尿病患者的降糖治疗,因其在保护b细胞,降低体质量,改善内皮细胞功能,预防老年性痴呆均有一定的作用,而备受关注.本文将从GLP-1的合成分泌、对味觉、阿茨海默病的影响、与其他胃肠道激素关系对其进行阐述,为GLP-1更广泛的用于临床和未来的研发提供参考.

不同饮食负荷对葡萄糖依赖性促胰岛素分泌多肽的影响

目的探讨不同饮食负荷对正常糖耐量人群的葡萄糖依赖性促胰岛素分泌多肽(glucose-dependent insulinotropicploypeptide,GIP)分泌模式的影响,及其与胰岛素分泌、血浆葡萄糖水平的关系。方法 14例正常糖耐量受试者先后接受75 g葡萄糖耐量及混合餐耐量试验,检测空腹及葡萄糖或混合餐后15,30,60,90和120 min的血糖、胰岛素及GIP。结果(1)葡萄糖负荷后GIP的第一个峰值在糖负荷后15 min(45.09±4.67)pmol/L,短暂下降之后持续上升至120 min(59.66±11.73)pmol/L;(2)混合餐负荷后GIP分泌呈双时相曲线,第一峰值在15 min(71.69±14.19)pmol/L,显著高于同时点的葡萄糖负荷(P<0.05);第二个峰在90 min(55.35±13.19)pmol/L。两种饮食负荷后GIP曲线下面积无统计学差异(P>0.05);(3)随着混合餐负荷时GIP早期分泌(15 min)第一峰值升高幅度较葡萄糖负荷大,胰岛素达峰时间提前(30 min vs 60min),同时混合餐负荷后15 min血糖升高幅度明显低于葡萄糖负荷(P<0.05)。结论正常糖耐量人群两种饮食负荷后GIP分泌曲线明显不同,混合餐后GIP分泌呈典型的双相分泌,其第一峰值显著高于葡萄糖负荷,提示混合餐(含脂肪)刺激GIP释放较强,使胰岛素达峰时间提前,可能是混合餐血糖峰值较低的重要原因之一。