Glucagon-like peptide-2 analogues for Crohn’s disease patients with short bowel syndrome and intestinal failure

Short bowel syndrome(SBS)with intestinal failure(IF)is a rare but severe complication of Crohn’s disease(CD),which is the most frequent benign condition that leads to SBS after repeated surgical resections,even in the era of biologics and small molecules.Glucagon-like peptide-2 analogues have been deeply studied recently for the treatment of SBS-IF.These drugs have a significant intestinotrophic effect and the potential to reduce the chronic dependence of SBSIF patients on parenteral support or nutrition.Teduglutide has been approved for the treatment of SBS-IF,and apraglutide is currently in clinical development.The use of these drugs was examined with a focus on their use in CD patients.

Glucagon-like peptide-2 modulates the nitrergic neurotransmission in strips from the mouse gastric fundus

AIM To investigate whether glucagon-like peptide-2(GLP-2) influences the neurally-induced responses in gastric strips from mice, since no data are available. METHODS For functional experiments, gastric fundal strips were mounted in organ baths containing Krebs-Henseleit solution. Mechanical responses were recorded via forcedisplacement transducers, which were coupled to a polygraph for continuous recording of isometric tension. Electrical field stimulation(EFS) was applied via two platinum wire rings through which the preparationwas threaded. The effects of GLP-2(2 and 20 nmol/L) were evaluated on the neurally-induced contractile and relaxant responses elicited by EFS. Neuronal nitric oxide synthase(n NOS) enzyme was evaluated by immunohistochemistry.RESULTS In the functional experiments, electrical field stimulation(EFS, 4-16 Hz) induced tetrodotoxin(TTX)-sensitive contractile responses, which were reduced in amplitude by GLP-2(P < 0.05). In the presence of the nitric oxide(NO) synthesis inhibitor L-NNA, GLP-2 no longer influenced the neurally-evoked contractile responses(P > 0.05). The direct smooth muscle response to methacholine was not influenced by GLP-2(P > 0.05). In the presence of guanethidine and carbachol, the addition of GLP-2 to the bath medium evoked TTX-sensitive relaxant responses that were unaffected by L-NNA(P > 0.05). EFS induced a fast NO-mediated relaxation, whose amplitude was enhanced in the presence of the hormone(P < 0.05). Immunohistochemical experiments showed a significant increase(P < 0.05) in n NOS immunoreactivity in the nerve structures after GLP-2 exposure. CONCLUSION The results demonstrate that in gastric fundal strips, GLP-2 influences the amplitude of neurally-induced responses through the modulation of the nitrergic neurotransmission and increases n NOS expression.

Role of gut-liver axis and glucagon-like peptide-1 receptor agonists in the treatment of metabolic dysfunction-associated fatty liver disease

Metabolic dysfunction-associated fatty liver disease(MAFLD)is a hepatic manifestation of the metabolic syndrome.It is one of the most common liver diseases worldwide and shows increasing prevalence rates in most countries.MAFLD is a progressive disease with the most severe cases presenting as advanced fibrosis or cirrhosis with an increased risk of hepatocellular carcinoma.Gut microbiota play a significant role in the pathogenesis and progression of MAFLD by disrupting the gut-liver axis.The mechanisms involved in maintaining gut-liver axis homeostasis are complex.One critical aspect involves preserving an appropriate intestinal barrier permeability and levels of intestinal lumen metabolites to ensure gutliver axis functionality.An increase in intestinal barrier permeability induces metabolic endotoxemia that leads to steatohepatitis.Moreover,alterations in the absorption of various metabolites can affect liver metabolism and induce liver steatosis and fibrosis.Glucagon-like peptide-1 receptor agonists(GLP-1 RAs)are a class of drugs developed for the treatment of type 2 diabetes mellitus.They are also commonly used to combat obesity and have been proven to be effective in reversing hepatic steatosis.The mechanisms reported to be involved in this effect include an improved regulation of glycemia,reduced lipid synthesis,β-oxidation of free fatty acids,and induction of autophagy in hepatic cells.Recently,multiple peptide receptor agonists have been introduced and are expected to increase the effectiveness of the treatment.A modulation of gut microbiota has also been observed with the use of these drugs that may contribute to the amelioration of MAFLD.This review presents the current understanding of the role of the gutliver axis in the development of MAFLD and use of members of the GLP-1 RA family as pleiotropic agents in the treatment of MAFLD.

Is it necessary to stop glucagon-like peptide-1 receptor agonists prior to endoscopic procedure? A retrospective study

BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1 RA)are effective in diabetes and obesity,reducing hyperglycemia by increasing insulin release and delaying gastric emptying.However,they can cause gastroparesis,raising concerns about aspiration during procedures.Recent guidelines advise discontinuing GLP-1 RA before surgery to reduce the risk of pulmonary aspiration.AIM To evaluate the effect of GLP-1 RAs on gastric residual contents during endosco-pic procedures.METHODS A retrospective chart review at BronxCare Health System,New York,from January 2019 to October 2023,assessed gastric residue and aspiration in GLP-1 RA patients undergoing endoscopic procedures.Two groups were compared based on dietary status before the procedure.Data included demographics,symptoms of gastroparesis,opiate use,hemoglobin A1c,GLP-1 agonist indication,endo-scopic details,and aspiration occurrence.IBM SPSS was used for analysis,cal-culating means,standard deviations,and applying Pearson’s chi-square and t-tests for associations,with P<0.05 as being significant.RESULTS During the study,306 patients were included,with 41.2%on a clear liquid/low residue diet and 58.8%on a regular diet before endoscopy.Most patients(63.1%)were male,with a mean age of 60±12 years.The majority(85.6%)were on GLP-1 RAs for diabetes,and 10.1%reported digestive symptoms before endoscopy.Among those on a clear liquid diet,1.5%had residual food at endoscopy compared to 10%on a regular diet,which was statistically significant(P=0.03).Out of 31 patients with digestive symptoms,13%had residual food,all from the regular diet group(P=0.130).No complications were reported during or after the procedures.CONCLUSION The study reflects a significant rise in GLP-1 RA use for diabetes and obesity.A 24-hour liquid diet seems safe for endoscopic procedures without aspiration.Patients with upper gastrointestinal symptoms might have a higher residual food risk,though not statistically significant.Further research is needed to assess risks based on diabetes duration,gastroparesis,and GLP-1 RA dosing,aiming to minimize interruptions in therapy during procedures.

Practical guide:Glucagon-like peptide-1 and dual glucosedependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonists in diabetes mellitus

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.

Glucagon-like peptide-1 receptor agonists as a possible intervention to delay the onset of type 1 diabetes:A new horizon

Type 1 diabetes(T1D)is a chronic autoimmune condition that destroys insulinproducing beta cells in the pancreas,leading to insulin deficiency and hyperglycemia.The management of T1D primarily focuses on exogenous insulin replacement to control blood glucose levels.However,this approach does not address the underlying autoimmune process or prevent the progressive loss of beta cells.Recent research has explored the potential of glucagon-like peptide-1 receptor agonists(GLP-1RAs)as a novel intervention to modify the disease course and delay the onset of T1D.GLP-1RAs are medications initially developed for treating type 2 diabetes.They exert their effects by enhancing glucose-dependent insulin secretion,suppressing glucagon secretion,and slowing gastric emptying.Emerging evidence suggests that GLP-1RAs may also benefit the treatment of newly diagnosed patients with T1D.This article aims to highlight the potential of GLP-1RAs as an intervention to delay the onset of T1D,possibly through their potential immunomodulatory and anti-inflammatory effects and preservation of beta-cells.This article aims to explore the potential of shifting the paradigm of T1D management from reactive insulin replacement to proactive disease modification,which should open new avenues for preventing and treating T1D,improving the quality of life and long-term outcomes for individuals at risk of T1D.

A Retrospective Analysis of Glucagon-Like Peptide 1 Receptor Agonists in Treating Type 2 Diabetes Mellitus Complicated by Nonalcoholic Fatty Liver Disease

Background: The objective of this study was to compare and analyze the variations in clinical indices before and after treatment of type 2 mellitus (T2DM) combined with nonalcoholic fatty liver disease (NAFLD) that were treated with glucagon-like peptide 1 receptor agonists (GLP-1RAs). Methods: The electronic medical record system was utilized to search for a total of 16 patients with type 2 diabetes complicated by NAFLD who were hospitalized at the First Affiliated Hospital of Yangtze University from October 2022 to April 2023 and treated with GLP-1RA for the first time. The clinical indices were compared before and after 12 weeks of treatment with GLP-1RA. Results: The liver-spleen CT ratio (L/S), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) in all patients treated with GLP-1RA after 12 weeks were significantly different (P 0.05). The patients were categorized into two groups based on the types of GLP-1RAs. The changes in L/S, TC, TG, and LDL-C in the long-acting group after treatment were statistically significant (P Conclusions: GLP-1RAs can improve liver function, regulate lipid metabolism, and reduce the severity of fatty liver in patients with T2DM complicated by NAFLD, which demonstrates the importance of clinical applications.

Effects of glucagon-like peptide-1 receptor agonists on glucose excursion and inflammation in overweight or obese type 2 diabetic patients

BACKGROUND Currently,the lack of comparative studies between weekly and daily formulations of glucagon-like peptide-1 receptor agonists(GLP-1RAs)for glucose excursion is worth investigation.AIM To investigate the effects of weekly and daily formulations of GLP-1RA on glucose excursion and inflammation in overweight and obese patients with type 2 diabetes.METHODS Seventy patients with type 2 diabetes mellitus who were treated at our hospital between January 2019 and January 2022 were enrolled in this retrospective analysis.All patients were treated with metformin.We evaluated changes in blood glucose levels and a series of important indicators in patients before and after treatment with either a weekly or daily preparation of GLP-1RA(group A;n=33 and group B;n=37).RESULTS The degree of decrease in the levels of fasting blood glucose,mean blood glucose,mean amplitude of glycemic excursions,total cholesterol,triglycerides,tumor necrosis factor-α,interleukin-6,and high-sensitivity C-reactive protein after treatment in group A was higher than that in group B(P<0.05),whereas the 2-h postprandial blood glucose levels decreased more so in group B than in group A(P<0.001).However,there were no statistically significant differences in the levels of glycated hemoglobin,standard deviation of blood glucose,coefficient of variation,absolute mean of daily differences,percentage of time with 3.9 mmol/L<glucose<10 mmol/L,and high-and low-density lipoproteins between the two groups(P>0.05).The incidence of adverse reactions was significantly lower in group A than in group B(P<0.05).CONCLUSION The effect of the weekly preparation of GLP-1RA in controlling blood glucose levels in the patients,suppressing inflammation,and reducing adverse reactions was significantly higher than that of the daily preparations,which is worthy of clinical promotion.

Type-2 Diabetes Mellitus and Glucagon-Like Peptide-1 Receptor toward Predicting Possible Association

Aim: This study aimed to investigate the effect of non-synonymous SNPs (nsSNPs) of the Glucagon-like peptide-1 Receptor (GLP-1R) gene in protein function and structure using different computational software. Introduction: The GLP1R gene provides the necessary instruction for the synthesis of the insulin hormones which is needed for glucose catabolism. Polymorphisms in this gene are associated with diabetes. The protein is an important drug target for the treatment of type-2 diabetes and stroke. Material and Methods: Different nsSNPs and protein-related sequences were obtained from NCBI and ExPASY database. Gene associations and interactions were predicted using GeneMANIA software. Deleterious and damaging effects of nsSNPs were analyzed using SIFT, Provean, and Polyphen-2. The association of the nsSNPs with the disease was predicted using SNPs & GO software. Protein stability was investigated using I-Mutant and MUpro software. The structural and functional impact of point mutations was predicted using Project Hope software. Project Hope analyzes the mutations according to their size, charge, hydrophobicity, and conservancy. Results: The GLP1R gene was found to have an association with 20 other different genes. Among the most important ones is the GCG (glucagon) gene which is also a trans membrane protein. Overall 7229 variants were seen, and the missense variants or nsSNPs (146) were selected for further analysis. The total number of nsSNPs obtained in this study was 146. After being subjected to SIFT software (27 Deleterious and 119 Tolerated) were predicted. Analysis with Provean showed that (20 deleterious and 7 neutral). Analysis using Polyphen-2 revealed 17 probably damaging, 2 possibly damaging and 1 benign nsSNPs. Using two additional software SNPs & GO and PHD-SNPs showed that 14 and 17 nsSNPs had a disease effect, respectively. Project Hope software predicts the effect of the 14 nsSNPs on the protein function due to differences in charge, size, hydrophobicity, and conservancy between the wild and mutant types. Conclusion: In this study, the 14 nsSNPs which were highly affected the protein function. This protein is providing the necessary instruction for the synthesis of the insulin hormones which is needed for glucose catabolism. Polymorphisms in this gene are associated with diabetes and also affect the treatment of diabetic patients due to the fact that the protein acts as an important drug target.

Glucagon-like peptide-2 exhibits protective effect on hepatic ischemia-reperfusion injury in rats

Glucagon-like peptide-2 （GLP-2） has potent anti-inflammatory effects and protects against experimental ischemia/reperfusion （I/R） injury in pulmonary, intestinal, and myocardial tissue. However, its protective abilities against I/R injury in the liver are unknown. We investigated the potential role of GLP-2 pretreatment on hepatic I/R injury in rats. A total of 24 rats were randomly divided into three groups （n = 8）. The first group was the control group; the second group was the vehicle-treated hepatic ischemia/reperfusion （HIR, vehicle saline-treated） group; and the third group was the GLP-2 pretreated I/R （GLP2-IR） group. Each rat in the third group was intraperitoneally administered 5 ~tg GLP-2 for 5 d before the procedure. A portal triad was created to induce ischemia with a vascular atraumatic clamp. After 40 min, the clamp was released to initiate hepatic reperfusion for 6 h. Blood samples and tissue specimens from the fiver were obtained. Alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels significantly increased in the saline- treated HIR group （P 〈 0.001）, whereas GLP-2 pretreatment significantly decreased their levels （P 〈 0.01）. Our data suggested that GLP-2 pretreatment may have a protective effect on liver I/R injury. However, dose-response studies are necessary to determine the most effective dose.

Cardioprotective effects of glucagon-like peptide 1 receptor agonists in heart failure: Myth or truth?

Therapy with glucagon-like peptide 1(GLP1)receptor agonists has raised great interest for its beneficial cardiovascular effects in preventing atherosclerosis and heart failure-related outcomes.However,while evidence about atherosclerosis consistently suggests a cardioprotective potential with class effect,controversies remain on its impact on heart failure.GLP1 receptor agonists appear to prevent hospitalization for new-onset heart failure and reduce symptoms in heart failure with preserved ejection fraction(as demonstrated by the recent STEP-HFpEF Trial).Still,GLP1 agonism has resulted in neutral or even harmful effects in patients with established heart failure with reduced ejection fraction(the LIVE trial).GLP1 receptor agonists benefit the cardiovascular system indirectly through their marked metabolic effects(improved weight management,glycemic control,blood pressure,systemic and tissue inflammation),while direct effects on the heart have been questioned.Nonetheless,weight loss alone achieved through GLP1 receptor agonists has failed in improving left ventricular functions.Tirzepatide is a dual agonist of GLP1 and glucose-dependent insulinotropic polypeptide,representing an innovative treatment option in diabetes with a major impact on weight loss and promising cardiovascular benefits.Whether this class of therapies is going to change the history of heart failure is an ongoing debate.

Fixed-ratio combinations of basal insulin and glucagon-like peptide-1 receptor agonists as a promising strategy for treating diabetes

The maintenance of appropriate glycemic control is important for the prevention of diabetic complications in people with type 2 diabetes(T2D). Numerous oral antidiabetic drugs are now clinically available, but in particular, the introduction of injection regimens using insulin and/or glucagon-like peptide-1 receptor agonist(GLP-1RA)s represents promising step-up options for oral antidiabetic drug treatment. The recently licensed fixed-ratio combination(FRC) products,which comprise basal insulin and a GLP-1RA, have potent anti-hyperglycemic effects and reduce the undesirable side-effects of each component, such as body weight gain, hypoglycemia, and gastrointestinal symptoms. Two FRCs-insulin degludec/Liraglutide and insulin glargine/Lixisenatide-are now clinically available and, to date, several phase Ⅱ/Ⅲ trials have been conducted in particular groups of subjects with T2D. However, their utility in real-world clinical settings is of interest for most clinicians. Recently reported real-world clinical trials of these two FRCs in various situations have demonstrated their efficacy regarding glycemic control and the quality of life of people with T2D. Their long-term safety and efficacy require confirmation, but a treatment strategy that includes an FRC may be compatible with the concept of “well-balanced” therapy in certain groups of patients with T2D who have inadequate glycemic control.

Postprandial glucagon-like peptide 1 secretion is associated with urinary albumin excretion in newly diagnosed type 2 diabetes patients

BACKGROUND Microalbuminuria is an early and informative marker of diabetic nephropathy.Our study found that microalbuminuria developed in patients with newly diagnosed type 2 diabetes mellitus(T2DM).AIM To investigate the association between glucagon-like peptide 1(GLP-1)and microalbuminuria in newly diagnosed T2DM patients.METHODS In total,760 patients were recruited for this cross-sectional study.The GLP-1 levels during a standard meal test and urinary albumin-creatinine ratio(UACR)were determined.RESULTS Patients with microalbuminuria exhibited lower GLP-1 levels at 30 min and 120 min during a standard meal test than patients with normal albuminuria(30 min GLP-1,16.7±13.3 pmol vs 19.9±15.6 pmol,P=0.007;120 min GLP-1,16.0±14.1 pmol vs 18.4±13.8 pmol,P=0.037).The corresponding area under the curve for active GLP-1(AUCGLP-1)was also lower in microalbuminuria patients(2257,1585 to 3506 vs 2896,1763 to 4726,pmol×min,P=0.003).Postprandial GLP-1 levels at 30 min and 120 min and AUCGLP-1 were negatively correlated with the UACR(r=0.159,r=0.132,r=0.206,respectively,P<0.001).The prevalence of microalbuminuria in patients with newly diagnosed T2DM was 21.7%,which decreased with increasing quartiles of AUCGLP-1 levels(27.4%,25.3%,18.9%and 15.8%).After logistic regression analysis adjusted for sex,age,hemoglobin A1c,body mass index,systolic blood pressure,estimated glomerular filtration rate,homeostasis model assessment of insulin resistance,AUC_(glucose)and AUC_(glucagon)patients in quartile 4 of the AUCGLP-1 presented a lower risk of microalbuminuria compared with the patients in quartile 1(odds ratio=0.547,95%confidence interval:0.325-0.920,P=0.01).A consistent association was also found between 30 min GLP-1 or 120 min GLP-1 and microalbuminuria.CONCLUSION Postprandial GLP-1 levels were independently associated with microalbuminuria in newly diagnosed Chinese T2DM patients.

Mutated recombinant human glucagon-like peptide-1 induces differentiation of PC12 cells

Glucagon-like peptide-1 （GLP-1） and its long-acting analogues have neuroprotective and neurotrophic properties and are emerging as potential treatments for neurodegenerative diseases. Its short half-life has limited the application of GLP-1 in the clinic. We generated a mutated form of human GLP-1 （mGLP-1） using site-directed mutagenesis and gene recombination techniques, and found that these modifications significantly prolonged the biological half-life of GLP-1 compared with native GLP-1 （nGLP-1）. This study investigated the role of mGLP-1 on inducing PC12 cell differentiation, mGLP-1 induced PC12 cell differentiation with neurite outgrowth and increased the expression of growth-associated protein-43 and neuronal class III I^-tubulin, and significantly increased cyclic adenosine monophosphate level. No significant difference was found between mGLP-1 and nGLP-I. The results indicate that mGLP-1 activates the GLP-1 receptor, induces PC12 cell differentiation, and has neurotrophic effects.

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.

Adropin and glucagon-like peptide-2 are associated with glucose metabolism in obese children

Background The interaction of adropin,glucagon-like peptide-2(GLP2),angiopoietin-like protein 4(ANGPTL4),and with childhood obesity and glucose metabolism is inconsistent.This study is to evaluate the association of the three cytokines and glucose homeostasis.Methods This was a cross-sectional study of children with obesity ranging from 5 to 14 years compared to age-and sex-matched children of normal weight.Fasting plasma glucose(FPG),oral glucose tolerance test 2-hour plasma glucose(OGT-T2hPG),and insulin(INS)were measured,and serum adropin,GLP2,and ANGPTL41evels were measured by enzyme-linked immunosorbent assay.The body mass index(BMI),BMI-Z scores,waist-to-hip ratio(WHR),and homeostasis model assessment of insulin resistance(HOMA-IR)were calculated.Results Thirty-nine children(9.70±1.71 years,18 females)with obesity and 29 normal weight children(8.98±1.98 years,16 females)were assessed.The levels of INS,HOMA-IR and GLP2 of the obesity group were significantly higher than the controls(P<0.05).Pearson correlation analysis showed that serum GLP2 was positively associated with WHR,FPG,and OGTT2hPG,and adropin was negatively associated with BMI,BMI-Z,WHR,INS,and HOMA-IR(all P<0.05).Further-more,GLP2 were negatively associated with adropin and ANGPTL4(both P<0.05).By binary logistic regression,adropin and GLP2 were found to be independent markers of obesity.Multiple linear regression showed that GLP2 was associated with OGTT2hPG,and adropin was associated with INS and HOMA-IR(all P<0.05).Conclusions Obese children had elevated GLP2 concentrations,and adropin and GLP2 associated with both childhood obesity and glucose homeostasis.Furthermore,there may be a physiologic interplay between adropin and GLP2 in obese children.

The prolonged effect of glucagon-like peptide 2 pretreatment on growth performance and intestinal development of weaned piglets

Background： Glucagon-like peptide 2 （GLP-2） is a potent epithelium-specific intestinal growth factor. The aim of this study was to demonstrate the prolonged effect of GLP-2 on the growth performance of weaned piglets. Forty piglets weaned at the age of 28 d with an average BW of 6.8 ＋ 0.4 kg were assigned to four treatments： （i） non- challenged control; （ii） LPS-challenged control; （iii） LPS ＋ low GLP-2; and （iv） LPS ＋ high GLP-2. Piglets in groups （i）, （ii）, and （iv） were s.c. injected with PBS supplemented with human [Gly2]GLP-21-34 at doses of 0, 2 and 10 nmol/kg BW per day for seven consecutive days. BW, gain：feed ratio （G：F）, and plasma GLP-2 levels were determined on d 0 7, and 14 after weaning. Piglets were challenged with i.p. administration of Escherichia coil lipopolysaccharide （LPS） at a dose of 100 pg/kg on d 14 to induce intestinal damage. Twenty-four hours later, intestinal tract samples were collected to assess intestinal morphology and quantify enzyme activity. Results： Plasma GLP-2 levels decreased after weaning, but in the high GLP-2 group, plasma GLP-2 was maintained on d 7 and even increased to a level higher than the preweaning level on d ]4 （P 〈 0.05）. High GLP-2 treatment significantly increased the duodenal, jejunal and ileal weight, as well as the gross weight of the small intestine （SI）, and the SI weight index （P 〈 0.05）. LPS caused villous atrophy and disrupted intestinal morphology in the duodenum, jejunum and ileum. GLP-2 also significantly increased the villus height and the villus height/crypt depth ratio （VCR） of the duodenum, jejunum, and ileum （P 〈 0.05）. Histological examination revealed that in GLP-2-treated groups, the integrity of the villus was maintained, and the villus was protected against LPS-induced damage. GLP-2 significantly increased the activity of alkaline phosphatase （AKP）, y-glutamyltranspeptidase （y-G-i-）, and pancreatic lipase in the duodenum and jejunum （P 〈 0.05）. GLP-2 treatment also significantly increased the average daily gain （ADG） and G：F of piglets at 0 to 7, 7 to 14, as well as 0 to14 d （P 〈 0.05）, resulting in a significant increase of final 8W in high GLP-2 pigs （P = 0.016）. Conclusions： Exogenous GLP-2 improved the growth of weaned piglets and protected them against LPS-induced intestinal damage. These effects may be due to the ability of GLP-2 to promote the secretion of endogenous GLP-2 to stimulate the small intestinal development.

Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation

Glucagon-like peptide1(GLP-1)is secreted from Langerhans cells in response to oral nutrient intake.Glucagon-like peptide-1 receptor agonists(GLP-1RAs)are a new class of incretin-based anti-diabetic drugs.They function to stimulate insulin secretion while suppressing glucagon secretion.GLP-1-based therapies are now well established in the management of type 2 diabetes mellitus(T2DM),and recent literature has suggested potential applications of these drugs in the treatment of obesity and for protection against cardiovascular and neurological diseases.As we know,along with change in lifestyles,the prevalence of non-alcoholic fatty liver disease(NAFLD)in China is rising more than that of viral hepatitis and alcoholic fatty liver disease,and NAFLD has become the most common chronic liver disease in recent years.Recent studies further suggest that GLP-1RAs can reduce transaminase levels to improve NAFLD by improving blood lipid levels,cutting down the fatcontent to promote fat redistribution,directly decreasing fatty degeneration of the liver,reducing the degree of liver fibrosis and improving inflammation.This review shows the NAFLD-associated effects of GLP-1RAs in animal models and in patients with T2DM or obesity who are participants in clinical trials.

Coagonist of glucagon-like peptide-1 and glucagon receptors ameliorates kidney injury in murine models of obesity and diabetes mellitus

AIM To investigate the role of glucagon-like peptide-1(GLP-1)/glucagon receptors coagonist on renal dysfunction associated with diabetes and obesity. METHODS Chronic high-fat diet fed C57 BL/6 J mice, streptozotocintreated high-fat diet fed C57 BL/6 J mice and diabeticC57 BLKS/J db/db mice were used as models of diabetes-induced renal dysfunction. The streptozotocintreated high-fat diet fed mice and db/db mice were treated with the GLP-1 and glucagon receptors coagonist(Aib2 C24 Chimera2, 150 μg/kg, sc) for twelve weeks, while in chronic high-fat diet fed mice, coagonist(Aib2 C24 Chimera2, 150 μg/kg, sc) treatment was continued for forty weeks. Kidney function, histology, fibrosis, inflammation, and plasma biochemistry were assessed at the end of the treatment. RESULTS Coagonist treatment decreased body weight, plasma lipids, insulin resistance, creatinine, blood urea nitrogen, urinary albumin excretion rate and renal lipids. In kidney, expression of lipogenic genes(SREBP-1 C, FAS, and SCD-1) was decreased, and expression of genes involved in β-oxidation(CPT-1 and PPAR-α) was increased due to coagonist treatment. In plasma, coagonist treatment increased adiponectin and FGF21 and decreased IL-6 and TNF-?. Coagonist treatment reduced expression of inflammatory(TNF-α, MCP-1, and MMP-9) and pro-fibrotic(TGF-β, COL1 A1, and α-SMA) genes and also improved histological derangement in renal tissue.CONCLUSION Coagonist of GLP-1 and glucagon receptors alleviated diabetes and obesity-induced renal dysfunction by reducing glucose intolerance, obesity, and hyperlipidemia.

Glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease: An update

Non-alcoholic fatty liver disease(NAFLD)is the predominant cause of chronic liver disease worldwide.NAFLD progresses in some cases to non-alcoholic steatohepatitis(NASH),which is characterized,in addition to liver fat deposition,by hepatocyte ballooning,inflammation and liver fibrosis,and in some cases may lead to hepatocellular carcinoma.NAFLD prevalence increases along with the rising incidence of type 2 diabetes mellitus(T2DM).Currently,lifestyle interventions and weight loss are used as the major therapeutic strategy in the vast majority of patients with NAFLD.Glucagon-like peptide-1 receptor agonists(GLP-1RAs)are used in the management of T2DM and do not have major side effects like hypoglycemia.In patients with NAFLD,the GLP-1 receptor production is down-regulated.Recently,several animal and human studies have emphasized the role of GLP-1RAs in ameliorating liver fat accumulation,alleviating the inflammatory environment and preventing NAFLD progression to NASH.In this review,we summarize the updated literature data on the beneficial effects of GLP-1RAs in NAFLD/NASH.Finally,as GLP-1RAs seem to be an attractive therapeutic option for T2DM patients with concomitant NAFLD,we discuss whether GLP-1RAs should represent the first line pharmacotherapy for these patients.