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...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.展开更多
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 i...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.展开更多
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 ...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.展开更多
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 patien...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.展开更多
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-incre...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.展开更多
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 pat...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.展开更多
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,...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.展开更多
文摘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.
文摘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.
文摘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.
文摘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.
文摘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.
文摘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.
文摘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.
