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
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
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
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 effe...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.展开更多
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 lea...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.展开更多
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...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.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
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 pept...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.展开更多
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 bene...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.展开更多
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.Meth...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
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 deca...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.展开更多
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 represent...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.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.
文摘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.
文摘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.
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.
基金The authors work on incretin peptides has been supp- orted over many years by Diabetes United Kingdom, European Foundation for the Study of Diabetes, Invest Northern Ireland, Irish Endocrine Society, SAAD Trading and Contracting Company, Department of Education and Learning Northern Ireland, Diabetes Research Wellness Foundation and University of Ulster strategic research funding
文摘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.
文摘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.
文摘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
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.
文摘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.
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.