Practical guide:Glucagon-like peptide-1 and dual glucosedependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonists in diabetes mellitus common second-line choice after metformin for treating T2...Practical guide:Glucagon-like peptide-1 and dual glucosedependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonists in diabetes mellitus common second-line choice after metformin for treating T2DM.Various considerations can make selecting and switching between different GLP-1 RAs challenging.Our study aims to provide a comprehensive guide for the usage of GLP-1 RAs and dual GIP and GLP-1 RAs for the management of T2DM.展开更多
Various kinds of biologically active peptides have previously been isolated from the skin secretions of Amolops loloensis frog,such as antimicrobial peptides,bradykinin-like peptides and algesic peptides.A novel insul...Various kinds of biologically active peptides have previously been isolated from the skin secretions of Amolops loloensis frog,such as antimicrobial peptides,bradykinin-like peptides and algesic peptides.A novel insulinotropic peptide named amolopin was identified in A.loloensis frog’s skin secretion.Its primary structure sequence was determined by Edman degradation as:FLPIVGKSLSGLSGKL-NH2.BLAST search indicates that the amino acid sequence of amolopin is quite different from other known insulin secretagogues,including mastoparan,exendins and a-latrotoxin,nor does it like incretins(e.g.glucagons like peptide-1 and glucose-dependent insulinotropic ploypeptide)either.However,amolopin shows certain structural similarity with amphibian antimicrobial temporins and vespid chemotactic peptides isolated from Vespa magnifica.Amolopin can stimulate insulin release in INS-1 cells in a dose-dependent manner.Primary investigation on its action mechanisms reveals that amolopin does not increase the influx of Ca2?.In conclusion,a novel 16-amino acid peptide with insulin-releasing activity is initially discovered from the skin secretion of A.loloensis frog.Further work is necessary to evaluate its potential as novel anti-diabetic candidate.展开更多
Dear Editor： Glucose-dependent insulinotropic polypeptide （GIP） and proglucagon product glucagon-like peptide-1 （GLP- 1） and their corresponding receptors promote secretion of glucose-dependent insulin and may b...Dear Editor： Glucose-dependent insulinotropic polypeptide （GIP） and proglucagon product glucagon-like peptide-1 （GLP- 1） and their corresponding receptors promote secretion of glucose-dependent insulin and may be responsible for up to 70% of postprandial insulin secretions.展开更多
A recent article highlighted the hepatic benefits of intermittent fasting,particularly during Ramadan.However,the rising use of glucagon-like peptide-1(GLP-1)/glucose-dependent insulinotropic polypeptide(GIP)receptor ...A recent article highlighted the hepatic benefits of intermittent fasting,particularly during Ramadan.However,the rising use of glucagon-like peptide-1(GLP-1)/glucose-dependent insulinotropic polypeptide(GIP)receptor agonists(RAs)is altering public behavior,leading to decreased interest in diet and exercise.With a focus on hepatic health,we analyzed global search trends using Google Trends™data from January 1,2022 to December 31,2024,focusing on the keywords"fasting","intermittent fasting","diet","nutrition","liver",Semaglutide("Ozempic"™,the most widely known GLP-1 RA)and Tirzepatide("Mounjaro"™,a newer dual GLP-1 and GIP RA).Search interest for"intermittent fasting"and"diet"showed a significant decline over time(Spearman's rho:-0.582 and-0.605,respectively,both P<0.001),while interest in"fasting"and"nutrition"remained stable.Search interest for Semaglutide,Tirzepatide,"fasting and liver","diet and liver"and Semaglutide and"liver"increased(Spearman's rho:+0.914,+0.936,+0.369,+0.297 and+0.808,respectively,all P<0.001).These findings suggest a trend of shifting away from traditional dieting toward broader health concerns,likely influenced by the increasing use of GLP-1/GIP RAs.展开更多
This editorial is stimulated by the article by Alqifari et al published in the World Journal of Diabetes(2024).Alqifari et al focus on practical advice for the clinical use of glucagon-like-peptide-1(GLP-1)receptor ag...This editorial is stimulated by the article by Alqifari et al published in the World Journal of Diabetes(2024).Alqifari et al focus on practical advice for the clinical use of glucagon-like-peptide-1(GLP-1)receptor agonists(GLP-1RAs)in the management of type 2 diabetes and this editorial provides complementary information.We initially give a brief historical perspective of the development of GLP-1RAs stimulated by recognition of the‘incretin effect’,the substantially greater insulin increase to enteral when compared to euglycaemic intravenous glucose,and the identification of the incretin hormones,GIP and GLP-1.In addition to stimulating insulin,GLP-1 reduces postprandial glucose levels by slowing gastric emptying.GLP-1RAs were developed because native GLP-1 has a very short plasma half-life.The majority of current GLP-1RAs are administered by subcutaneous injection once a week.They are potent in glucose lowering without leading to hypoglycaemia,stimulate weight loss in obese individuals and lead to cardiovascular and renal protection.The landscape in relation to GLP-1RAs is broadening rapidly,with different formulations and their combination with other peptides to facilitate both glucose lowering and weight loss.There is a need for more information relating to the effects of GLP-1RAs to induce gastrointestinal symptoms and slow gastric emptying which is likely to allow their use to become more effective and personalised.展开更多
AIM: To investigated changes in intestinal Akkermansia muciniphila(A. muciniphila) and explored the mechanism underlying the therapeutic effects of Roux-en-Y gastric bypass(RYGB) surgery on type 2 diabetes in diabetic...AIM: To investigated changes in intestinal Akkermansia muciniphila(A. muciniphila) and explored the mechanism underlying the therapeutic effects of Roux-en-Y gastric bypass(RYGB) surgery on type 2 diabetes in diabetic Goto-Kakizaki(GK) rats. METHODS: Male diabetic GK rats(n = 12) aged 8 wk were randomly assigned to the surgery group(GK-RYGB) or sham surgery group(GK-Sham)(n = 6 per group), and another 6 male Wistar rats aged 8 wk served as controls(WS-Sham). In the surgery group, RYGB surgery was conducted, and a sham operation was performed in both sham groups. Fasting blood glucose(FBG) levels before and after surgery, fasting levels of serum insulin and serum glucagon-like peptide-1(GLP-1) and levels 30 min after intragastric injection of glucose, and the amount of A. muciniphila in the stool were determined. Insulin and GLP-1 were measured by enzyme-linked immunosorbent assay, and A. muciniphila were detected by fluorescence-based quantitative polymerase chain reaction. RESULTS: The FBG was improved, and serum GLP-1 and insulin increased significantly(P < 0.05) in the GKRYGB group after surgery compared to levels before surgery and to levels in the GK-Sham group. Before surgery, the amounts of A. muciniphila in the GK-RYGB and GK-Sham groups were significantly lower than in the WS-Sham group(P < 0.05). After surgery, the amount of A. muciniphila in the GK-RYGB group increased markedly compared to that before surgery and to that in the GKSham and WS-Sham groups(P < 0.05). In addition, the A.muciniphila amount was positively related to GLP-1(r = 0.86, P < 0.05). CONCLUSION: Our results demonstrated RYGB surgery may increase GLP-1 secretion, elevate serum insulin after intragastric injection of glucose, and improve insulin resistance in diabetic GK rats, thereby contributing to a significant reduction in blood glucose. The increased amount of A. muciniphila after RYGB surgery may be related to elevated GLP-1 secretion.展开更多
AIM To examine the role that enzyme Acyl-CoA:diacylglycerol acyltransferase-1(DGAT1) plays in postprandial gut peptide secretion and signaling.METHODS The standard experimental paradigm utilized to evaluate the incret...AIM To examine the role that enzyme Acyl-CoA:diacylglycerol acyltransferase-1(DGAT1) plays in postprandial gut peptide secretion and signaling.METHODS The standard experimental paradigm utilized to evaluate the incretin response was a lipid challenge.Following a lipid challenge,plasma was collected via cardiac puncture at each time point from a cohort of 5-8 mice per group from baseline at time zero to 10 h.Incretin hormones [glucagon like peptide-1(GLP-1),peptide tyrosine-tyrosine(PYY) and glucose dependent insulinotropic polypeptide(GIP)] were then quantitated.The impact of pharmacological inhibition of DGAT1 on the incretin effect was evaluated in WT mice.Additionally,a comparison of loss of DGAT1 function either by genetic ablation or pharmacological inhibition.To further elucidate the pathways and mechanisms involved in the incretin response to DGAT1 inhibition,other interventions [inhibitors of dipeptidyl peptidase-IV(sitagliptin),pancreatic lipase(Orlistat),GPR119 knockout mice] were evaluated.RESULTS DGAT1 deficient mice and wildtype C57/BL6J mice werelipid challenged and levels of both active and total GLP-1 in the plasma were increased.This response was further augmented with DGAT1 inhibitor PF-04620110 treated wildtype mice.Furthermore,PF-04620110 was able to dose responsively increase GLP-1 and PYY,but blunt GIP at all doses of PF-04620110 during lipid challenge.Combination treatment of PF-04620110 and Sitagliptin in wildtype mice during a lipid challenge synergistically enhanced postprandial levels of active GLP-1.In contrast,in a combination study with Orlistat,the ability of PF-04620110 to elicit an enhanced incretin response was abrogated.To further explore this observation,GPR119 knockout mice were evaluated.In response to a lipid challenge,GPR119 knockout mice exhibited no increase in active or total GLP-1 and PYY.However,PF-04620110 was able to increase total GLP-1 and PYY in GPR119 knockout mice as compared to vehicle treated wildtype mice.CONCLUSION Collectively,these data provide some insight into the mechanism by which inhibition of DGAT1 enhances intestinal hormone release.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
Obesity affects over 1 billion people worldwide and is linked to more than 230 health complications,with cardiovascular disease being a leading cause of mortality.Losing 5%-10%of body weight is considered clinically s...Obesity affects over 1 billion people worldwide and is linked to more than 230 health complications,with cardiovascular disease being a leading cause of mortality.Losing 5%-10%of body weight is considered clinically significant for improving health.This weight loss can be achieved through pharmacotherapy,including glucagon-like peptide 1(GLP-1)receptor agonists,GLP-1/glucosedependent insulinotropic peptide dual receptor agonists,and GLP-1/glucosedependent insulinotropic peptide/glucagon triple receptor agonists(such as semaglutide,tirzepatide,and retatrutide,respectively).While much of the weight loss comes from fat mass,these treatments also result in the loss of lean mass,including muscle.This loss of muscle may contribute to difficulties in maintaining weight over the long term and can lead to sarcopenia.Therefore,the focus of new anti-obesity treatments should be primarily on reducing fat mass while minimizing the loss of muscle mass,ideally promoting muscle gain.Research focusing on human myocytes has identified more than 600 myokines associated with muscle contraction,which may play a crucial role in preserving both muscle mass and function.We explored the potential of new anti-obesity agents and their combinations with incretin-based therapies to achieve these outcomes.Further studies are needed to better understand the functional implications of lean mass expansion during weight loss and weight maintenance programs.展开更多
文摘Practical guide:Glucagon-like peptide-1 and dual glucosedependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonists in diabetes mellitus common second-line choice after metformin for treating T2DM.Various considerations can make selecting and switching between different GLP-1 RAs challenging.Our study aims to provide a comprehensive guide for the usage of GLP-1 RAs and dual GIP and GLP-1 RAs for the management of T2DM.
文摘Various kinds of biologically active peptides have previously been isolated from the skin secretions of Amolops loloensis frog,such as antimicrobial peptides,bradykinin-like peptides and algesic peptides.A novel insulinotropic peptide named amolopin was identified in A.loloensis frog’s skin secretion.Its primary structure sequence was determined by Edman degradation as:FLPIVGKSLSGLSGKL-NH2.BLAST search indicates that the amino acid sequence of amolopin is quite different from other known insulin secretagogues,including mastoparan,exendins and a-latrotoxin,nor does it like incretins(e.g.glucagons like peptide-1 and glucose-dependent insulinotropic ploypeptide)either.However,amolopin shows certain structural similarity with amphibian antimicrobial temporins and vespid chemotactic peptides isolated from Vespa magnifica.Amolopin can stimulate insulin release in INS-1 cells in a dose-dependent manner.Primary investigation on its action mechanisms reveals that amolopin does not increase the influx of Ca2?.In conclusion,a novel 16-amino acid peptide with insulin-releasing activity is initially discovered from the skin secretion of A.loloensis frog.Further work is necessary to evaluate its potential as novel anti-diabetic candidate.
文摘Dear Editor： Glucose-dependent insulinotropic polypeptide （GIP） and proglucagon product glucagon-like peptide-1 （GLP- 1） and their corresponding receptors promote secretion of glucose-dependent insulin and may be responsible for up to 70% of postprandial insulin secretions.
文摘A recent article highlighted the hepatic benefits of intermittent fasting,particularly during Ramadan.However,the rising use of glucagon-like peptide-1(GLP-1)/glucose-dependent insulinotropic polypeptide(GIP)receptor agonists(RAs)is altering public behavior,leading to decreased interest in diet and exercise.With a focus on hepatic health,we analyzed global search trends using Google Trends™data from January 1,2022 to December 31,2024,focusing on the keywords"fasting","intermittent fasting","diet","nutrition","liver",Semaglutide("Ozempic"™,the most widely known GLP-1 RA)and Tirzepatide("Mounjaro"™,a newer dual GLP-1 and GIP RA).Search interest for"intermittent fasting"and"diet"showed a significant decline over time(Spearman's rho:-0.582 and-0.605,respectively,both P<0.001),while interest in"fasting"and"nutrition"remained stable.Search interest for Semaglutide,Tirzepatide,"fasting and liver","diet and liver"and Semaglutide and"liver"increased(Spearman's rho:+0.914,+0.936,+0.369,+0.297 and+0.808,respectively,all P<0.001).These findings suggest a trend of shifting away from traditional dieting toward broader health concerns,likely influenced by the increasing use of GLP-1/GIP RAs.
文摘This editorial is stimulated by the article by Alqifari et al published in the World Journal of Diabetes(2024).Alqifari et al focus on practical advice for the clinical use of glucagon-like-peptide-1(GLP-1)receptor agonists(GLP-1RAs)in the management of type 2 diabetes and this editorial provides complementary information.We initially give a brief historical perspective of the development of GLP-1RAs stimulated by recognition of the‘incretin effect’,the substantially greater insulin increase to enteral when compared to euglycaemic intravenous glucose,and the identification of the incretin hormones,GIP and GLP-1.In addition to stimulating insulin,GLP-1 reduces postprandial glucose levels by slowing gastric emptying.GLP-1RAs were developed because native GLP-1 has a very short plasma half-life.The majority of current GLP-1RAs are administered by subcutaneous injection once a week.They are potent in glucose lowering without leading to hypoglycaemia,stimulate weight loss in obese individuals and lead to cardiovascular and renal protection.The landscape in relation to GLP-1RAs is broadening rapidly,with different formulations and their combination with other peptides to facilitate both glucose lowering and weight loss.There is a need for more information relating to the effects of GLP-1RAs to induce gastrointestinal symptoms and slow gastric emptying which is likely to allow their use to become more effective and personalised.
文摘AIM: To investigated changes in intestinal Akkermansia muciniphila(A. muciniphila) and explored the mechanism underlying the therapeutic effects of Roux-en-Y gastric bypass(RYGB) surgery on type 2 diabetes in diabetic Goto-Kakizaki(GK) rats. METHODS: Male diabetic GK rats(n = 12) aged 8 wk were randomly assigned to the surgery group(GK-RYGB) or sham surgery group(GK-Sham)(n = 6 per group), and another 6 male Wistar rats aged 8 wk served as controls(WS-Sham). In the surgery group, RYGB surgery was conducted, and a sham operation was performed in both sham groups. Fasting blood glucose(FBG) levels before and after surgery, fasting levels of serum insulin and serum glucagon-like peptide-1(GLP-1) and levels 30 min after intragastric injection of glucose, and the amount of A. muciniphila in the stool were determined. Insulin and GLP-1 were measured by enzyme-linked immunosorbent assay, and A. muciniphila were detected by fluorescence-based quantitative polymerase chain reaction. RESULTS: The FBG was improved, and serum GLP-1 and insulin increased significantly(P < 0.05) in the GKRYGB group after surgery compared to levels before surgery and to levels in the GK-Sham group. Before surgery, the amounts of A. muciniphila in the GK-RYGB and GK-Sham groups were significantly lower than in the WS-Sham group(P < 0.05). After surgery, the amount of A. muciniphila in the GK-RYGB group increased markedly compared to that before surgery and to that in the GKSham and WS-Sham groups(P < 0.05). In addition, the A.muciniphila amount was positively related to GLP-1(r = 0.86, P < 0.05). CONCLUSION: Our results demonstrated RYGB surgery may increase GLP-1 secretion, elevate serum insulin after intragastric injection of glucose, and improve insulin resistance in diabetic GK rats, thereby contributing to a significant reduction in blood glucose. The increased amount of A. muciniphila after RYGB surgery may be related to elevated GLP-1 secretion.
文摘AIM To examine the role that enzyme Acyl-CoA:diacylglycerol acyltransferase-1(DGAT1) plays in postprandial gut peptide secretion and signaling.METHODS The standard experimental paradigm utilized to evaluate the incretin response was a lipid challenge.Following a lipid challenge,plasma was collected via cardiac puncture at each time point from a cohort of 5-8 mice per group from baseline at time zero to 10 h.Incretin hormones [glucagon like peptide-1(GLP-1),peptide tyrosine-tyrosine(PYY) and glucose dependent insulinotropic polypeptide(GIP)] were then quantitated.The impact of pharmacological inhibition of DGAT1 on the incretin effect was evaluated in WT mice.Additionally,a comparison of loss of DGAT1 function either by genetic ablation or pharmacological inhibition.To further elucidate the pathways and mechanisms involved in the incretin response to DGAT1 inhibition,other interventions [inhibitors of dipeptidyl peptidase-IV(sitagliptin),pancreatic lipase(Orlistat),GPR119 knockout mice] were evaluated.RESULTS DGAT1 deficient mice and wildtype C57/BL6J mice werelipid challenged and levels of both active and total GLP-1 in the plasma were increased.This response was further augmented with DGAT1 inhibitor PF-04620110 treated wildtype mice.Furthermore,PF-04620110 was able to dose responsively increase GLP-1 and PYY,but blunt GIP at all doses of PF-04620110 during lipid challenge.Combination treatment of PF-04620110 and Sitagliptin in wildtype mice during a lipid challenge synergistically enhanced postprandial levels of active GLP-1.In contrast,in a combination study with Orlistat,the ability of PF-04620110 to elicit an enhanced incretin response was abrogated.To further explore this observation,GPR119 knockout mice were evaluated.In response to a lipid challenge,GPR119 knockout mice exhibited no increase in active or total GLP-1 and PYY.However,PF-04620110 was able to increase total GLP-1 and PYY in GPR119 knockout mice as compared to vehicle treated wildtype mice.CONCLUSION Collectively,these data provide some insight into the mechanism by which inhibition of DGAT1 enhances intestinal hormone release.
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Obesity affects over 1 billion people worldwide and is linked to more than 230 health complications,with cardiovascular disease being a leading cause of mortality.Losing 5%-10%of body weight is considered clinically significant for improving health.This weight loss can be achieved through pharmacotherapy,including glucagon-like peptide 1(GLP-1)receptor agonists,GLP-1/glucosedependent insulinotropic peptide dual receptor agonists,and GLP-1/glucosedependent insulinotropic peptide/glucagon triple receptor agonists(such as semaglutide,tirzepatide,and retatrutide,respectively).While much of the weight loss comes from fat mass,these treatments also result in the loss of lean mass,including muscle.This loss of muscle may contribute to difficulties in maintaining weight over the long term and can lead to sarcopenia.Therefore,the focus of new anti-obesity treatments should be primarily on reducing fat mass while minimizing the loss of muscle mass,ideally promoting muscle gain.Research focusing on human myocytes has identified more than 600 myokines associated with muscle contraction,which may play a crucial role in preserving both muscle mass and function.We explored the potential of new anti-obesity agents and their combinations with incretin-based therapies to achieve these outcomes.Further studies are needed to better understand the functional implications of lean mass expansion during weight loss and weight maintenance programs.
