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.

The Association between GLP-1 Receptor-Based Agonists and the Incidence of Asthma in Patients with Type 2 Diabetes and/or Obesity:A Meta-Analysis

Objective Recent studies have indicated potential anti-inflammatory effects of glucagon-like peptide-1 receptor agonists(GLP-1RAs)on asthma,which is often comorbid with type 2 diabetes mellitus(T2DM)and obesity.Therefore,we conducted a meta-analysis to assess the association between the administration of glucagon-like peptide-1(GLP-1)receptor-based agonists and the incidence of asthma in patients with T2DM and/or obesity.Methods PubMed,Web of Science,Embase,the Cochrane Central Register of Controlled Trials,and Clinicaltrial.gov were systematically searched from inception to July 2023.Randomized controlled trials(RCTs)of GLP-1 receptor-based agonists(GLP-1RA,GLP-1 based dual and triple receptor agonist)with reports of asthma events were included.Outcomes were computed as risk ratios(RR)using a fixedeffects model.Results Overall,39 RCTs with a total of 85,755 participants were included.Compared to non-GLP-1 receptor-based agonist users,a trend of reduced risk of asthma was observed in patients with T2DM or obesity using GLP-1 receptor-based agonist treatments,although the difference was not statistically significant[RR=0.91,95%confidence interval(CI):0.68 to 1.24].Further Subgroup analyses indicated that the use of light-molecular-weight GLP-1RAs might be associated with a reduced the risk of asthma when compared with non-users(RR=0.65,95%CI:0.43 to 0.99,P=0.043).We also performed sensitivity analyses for participant characteristics,study design,drug structure,duration of action,and drug subtypes.However,no significant associations were observed.Conclusion Compared with non-users,a modest reduction in the incidence of asthma was observed in patients with T2DM or obesity using GLP-1 receptor-based agonist treatments.Further investigations are warranted to assess the association between GLP-1 receptor-based agonists and the risk of asthma.

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.

Uncoupling protein 2 regulates glucagon-like peptide-1 secretion in L-cells

AIM:To investigate whether uncoupling protein 2(UCP2) affects oleic acid-induced secretion of glucagonlike peptide-1(GLP-1) in L-cells.METHODS:mRNA and protein expression of UCP2 were analyzed in human NCI-H716 cells,which serve as a model for enteroendocrine L-cells,by quantitative reverse transcription-polymerase chain reaction and Western blotting before and after treatment with oleic acid.Localization of UCP2 and GLP-1 in NCI-H716 cells was assessed by immunofluorescence labeling.NCI-H716 cells were transiently transfected with a small interfering RNA(siRNA) that targets UCP2(siUCP2) or with a nonspecific siRNA using Lipofectamine 2000.The concentrations of bioactive GLP-1 in the medium were measured by enzyme linked immunosorbent assay.RESULTS:Both GLP-1 and UCP2 granules were expressed mainly in the cytoplasm of NCI-H716 cells.NCI-H716 cells that secreted GLP-1 also expressed UCP2.Time-course experiments revealed that release of GLP-1 from NCI-H716 cells into the medium reached a maximum at 120 min and remained stable until at least 180 min after treatment with oleic acid(the level of GLP-1 increased about 2.3-fold as compared with the level of GLP-1 in the control cells,P < 0.05).In an experiment to determine dose dependence,stimulation of NCI-H716 cells with ≤ 8 mmol oleic acid led to a concentration-dependent release of GLP-1 into the medium;10 mmol oleic acid diminished the release of GLP-1.Furthermore,GLP-1 secretion induced by oleic acid from NCI-H716 cells that were transfected with siUCP2 decreased to 41.8%,as compared with NCI-H716 cells that were transfected with a non-specific siRNA(P < 0.01).CONCLUSION:UCP2 affected GLP-1 secretion induced by oleic acid.UCP2 plays an important role in L-cell secretion that is induced by free fatty acids.

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.

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.

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.

Reconsidering the role of depression and common psychiatric disorders as partners in the type 2 diabetes epidemic

Common psychiatric disorders(CPDs)and depression contribute significantly to the global epidemic of type 2 diabetes(T2D).We postulated a possible pathophysiological mechanism that through Bridge-Symptoms present in depression and CPDs,promotes the establishment of emotional eating,activation of the reward system,onset of overweight and obesity and,ultimately the increased risk of developing T2D.The plausibility of the proposed pathophysiological mechanism is supported by the mechanism of action of drugs such as naltrexonebupropion currently approved for the treatment of both obesity/overweight with T2D and as separate active pharmaceutical ingredients in drug addiction,but also from initial evidence that is emerging regarding glucagon-like peptide 1 receptor agonists that appear to be effective in the treatment of drug addiction.We hope that our hypothesis may be useful in interpreting the higher prevalence of CPDs and depression in patients with T2D compared with the general population and may help refine the integrated psychiatric-diabetic therapy approach to improve the treatment and or remission of T2D.

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.

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 analogs in combination with insulin on myocardial infarct size in rats with type 2 diabetes mellitus

AIM To evaluate the effects of glucagon-like peptide-1 analogs(GLP-1 a) combined with insulin on myocardial ischemiareperfusion injury in diabetic rats.METHODS Type 2 diabetes mellitus(T2 DM) was induced in maleWistar rats with streptozotocin(65 mg/kg) and verified using an oral glucose tolerance test. After anesthesia, the left coronary artery was occluded for 40 min followed by 80 min reperfusion. Blood glucose level was measured during surgery. Rats were randomized into six groups as follows:(1) control rats;(2) insulin(0.1 U/kg) treated rats prior to ischemia;(3) insulin(0.1 U/kg) treated rats at reperfusion;(4) GLP-1 a(140 mg/kg) treated rats prior to ischemia;(5) GLP-1 a(140 mg/kg) treated rats at reperfusion; and(6) rats treated with GLP-1 a(140 mg/kg) prior to ischemia plus insulin(0.1 U/kg) at reperfusion. Myocardial area at risk and infarct size was measured planimetrically using Evans blue and triphenyltetrazolium chloride staining, respectively.RESULTS There was no significant difference in the myocardial area at risk among groups. Insulin treatment before ischemia resulted in a significant increase in infarct size(34.7% ± 3.4% vs 18.6% ± 3.1% in the control rats, P < 0.05). Post-ischemic administration of insulin or GLP-1 a had no effect on infarct size. However, pre-ischemic administration of GLP-1 a reduced infarct size to 12% ± 2.2%(P < 0.05). The maximal infarct size reduction was observed in the group treated with GLP-1 a prior to ischemia and insulin at reperfusion(8% ± 1.6%, P < 0.05 vs the control and GLP-1 a alone treated groups).CONCLUSION GLP-1 a pre-administration results in myocardial infarct size reduction in rats with T2 DM. These effects are maximal in rats treated with GLP-1 a pre-ischemia plus insulin at reperfusion.

Is there a role for glucagon-like peptide-1 receptor agonists in the management of diabetic nephropathy?

Chronic kidney disease constitutes a major microvascular complication of diabetes mellitus.Accumulating data suggest that glucagon-like peptide-1 receptor agonists(GLP-1 RAs)might have a role in the management of diabetic kidney disease(DKD).GLP-1 RAs appear to reduce the incidence of persistent macro-albuminuria in patients with type 2 diabetes mellitus.This beneficial effect appears to be mediated not only by the glucose-lowering action of these agents but also on their blood pressure lowering,anti-inflammatory and antioxidant effects.On the other hand,GLP-1 RAs do not appear to affect the rate of decline of glomerular filtration rate.However,this might be due to the relatively short duration of the trials that evaluated their effects on DKD.Moreover,these trials were not designed nor powered to assess renal outcomes.Given than macrolbuminuria is a strong risk factor for the progression of DKD,it might be expected that GLP-1 RAs will prevent the deterioration in renal function in the long term.Nevertheless,this remains to be shown in appropriately designed randomized controlled trials in patients with DKD.

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.

Review on the Effect of Glucagon-Like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors for the Treatment of Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease（NAFLD） is a common liver disease and it represents the hepatic manifestation of metabolic syndrome, which includes type 2 diabetes mellitus（T2DM）, dyslipidemia, central obesity and hypertension. Glucagon-like peptide-1（GLP-1） analogues and dipeptidyl peptidase-4（DPP-4） inhibitors were widely used to treat T2 DM. These agents improve glycemic control, promote weight loss and improve lipid metabolism. Recent studies have demonstrated that the GLP-1 receptor（GLP-1R） is present and functional in human and rat hepatocytes. In this review, we present data from animal researches and human clinical studies that showed GLP-1 analogues and DPP-4 inhibitors can decrease hepatic triglyceride（TG） content and improve hepatic steatosis, although some effects could be a result of improvements in metabolic parameters. Multiple hepatocyte signal transduction pathways and m RNA from key enzymes in fatty acid metabolism appear to be activated by GLP-1 and its analogues. Thus, the data support the need for more rigorous prospective clinical trials to further investigate the potential of incretin therapies to treat patients with NAFLD.

Exercise and glucagon-like peptide-1: Does exercise potentiate the effect of treatment?

Recently, glucagon-like peptide-1(GLP-1) receptor agonists have become a cornerstone for the treatment of obese patients with type 2 diabetes(T2D), exhibiting favorable effects on the cardiovascular outcome. In T2D, impaired GLP-1 secretion/function is observed, and gut microbiota dysbiosis is related to the GLP-1 resistance. Prior research has revealed that exercise increases GLP-1 levels in healthy and obese individuals; however, the efficacy of exercise on GLP-1 levels in patients with T2D remains unclear. Exercise may improve GLP-1 resistance rather than GLP-1 secretion in patients with T2D. Exercise increases the gut microbiota diversity, which could contribute to improving the GLP-1 resistance of T2D. Furthermore, the gut microbiota may play a role in the correlation between exercise and GLP-1. The combination of exercise and GLP-1-based therapy may have a synergistic effect on the treatment of T2D. Although the underlying mechanism remains unknown, exercise potentiates the efficacy of GLP-1 receptor agonist treatment in patients with T2D.

Cytoprotection and Cytothetic Effects of GLP-2 on Enterocytes from a Weaned Piglet Injured by β-conglycinin in Vitro

The experiment was conducted to study the effects and possible mechanism of GLP-2 on proliferation,metabolism and apoptosis of cultured enterocytes from a 28-d weaned piglet injured by exposure to β-conglycinin.A cell damage model was established to investigate cell proliferation, metabolism and apoptosis by exposing primary cell cultures of intestinal epithelial cells(IEC) to 1.2 and 2.4 mg/mL β-conglycinin.A 2×3 factorial experiment was then used to study the effect of different GLP-2 concentrations of(1×10-9,1×10-8 and 1×10-7mol/L),in combination with the two concentrations ofβ-conglycinin.Cells exposed to the allergenβ-conglycinin had decreased(P【0.05) MTT OD;decreased (P【0.01) protein retention and total protein content of cells;increased(P【0.01) LDH and caspase-3 activities and decreased(P【0.05) Na+,K+-ATPase activity.When GLP-2 was used in combination withβ-conglycinin,MTT OD,protein retention,total protein content and Na+,K+-ATPase activity significantly increased(P【0.05);LDH activity gradually decreased(P【0.05 or P【0.01) and Caspase-3 activity significantly decreased(P【0.01) with increasing concentrations of GLP-2.The results indicated thatβ-conglycinin had adverse effects on proliferation and integrity of IEC in vitro.GLP-2 relieved or prevented the adverse effects ofβ-conglycinin on proliferation and integrity of IEC by regulating Na+,K+- ATPase and Caspase-3 activities,and consequently affecting cell metabolism.

Analysis of long noncoding RNA-associated competing endogenous RNA network in glucagon-like peptide-1 receptor agonist-mediated protection inβcells

BACKGROUND Long noncoding RNAs(lncRNAs)and mRNAs are widely involved in various physiological and pathological processes.The use of glucagon-like peptide-1 receptor agonists(GLP-1RAs)is a novel therapeutic strategy that could promote insulin secretion and decrease the rate ofβ-cell apoptosis in type 2 diabetes mellitus(T2DM)patients.However,the specific lncRNAs and mRNAs and their functions in these processes have not been fully identified and elucidated.AIM To identify the lncRNAs and mRNAs that are involved in the protective effect of GLP-1RA inβcells,and their roles.METHODS Rat gene microarray was used to screen differentially expressed(DE)lncRNAs and mRNAs inβcells treated with geniposide,a GLP-1RA.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were performed to assess the underlying functions of DE mRNAs.Hub mRNAs were filtered using the STRING database and the Cytoscape plugin,CytoHubba.In order to reveal the regulatory relationship between lncRNAs and hub mRNAs,their co-expression network was constructed based on the Pearson coefficient of DE lncRNAs and mRNAs,and competing endogenous RNA(ceRNA)mechanism was explored through miRanda and TargetScan databases.RESULTS We identified 308 DE lncRNAs and 128 DE mRNAs with a fold change filter of≥1.5 and P value<0.05.GO and KEGG pathway enrichment analyses indicated that the most enriched terms were G-protein coupled receptor signaling pathway,inflammatory response,calcium signaling pathway,positive regulation of cell proliferation,and ERK1 and ERK2 cascade.Pomc,Htr2a,and Agtr1a were screened as hub mRNAs using the STRING database and the Cytoscape plugin,CytoHubba.This result was further verified using SwissTargetPrediction tool.Through the co-expression network and competing endogenous(ceRNA)mechanism,we identified seven lncRNAs(NONRATT027738,NONRATT027888,NONRATT030038,etc.)co-expressed with the three hub mRNAs(Pomc,Htr2a,and Agtr1a)based on the Pearson coefficient of the expression levels.These lncRNAs regulated hub mRNA functions by competing with six miRNAs(rno-miR-5132-3p,rno-miR-344g,rno-miR-3075,etc.)via the ceRNA mechanism.Further analysis indicated that lncRNA NONRATT027738 interacts with all the three hub mRNAs,suggesting that it is at a core position within the ceRNA network.CONCLUSION We have identified key lncRNAs and mRNAs,and highlighted here how they interact through the ceRNA mechanism to mediate the protective effect of GLP-1RA inβcells.

胰高血糖素样肽-2在仔猪中的应用及其长效化研究进展

断奶应激引起的肠道形态及结构的破坏,导致仔猪出现腹泻、生长停滞等现象,严重危害着仔猪健康。胰高血糖素样肽-2(GLP-2)是一种多肽类胃肠激素,在促进肠道生长及损伤修复中起重要作用。文章分别综述了胰高血糖素样肽-2的合成代谢、对仔猪肠道的保护作用及长效化应用,并对其在断奶仔猪上的应用作了展望。

利拉鲁肽治疗2型糖尿病的临床疗效观察

目的:观察利拉鲁肽对2型糖尿病患者的疗效和安全性。方法:选取笔者所在医院收治的150例2型糖尿病患者,按照随机原则分为五组干预治疗组,各30例,分别给予二甲双胍、格列齐特、那格列奈、甘精胰岛素、利拉鲁肽治疗。另选取30例健康体检者为正常对照组,观察治疗前和治疗后1年六组的体重指数(BMI)、收缩压(SBP)、舒张压(DBP)、空腹血糖(FBG)、餐后2 h血糖(2 h PBG)、糖化血红蛋白(HbA1c)、甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白(LDL-C)、高密度脂蛋白(HDL-C)等指标。结果:利拉鲁肽组治疗后BMI、FBG下降,与治疗前比较,差异有统计学意义(P<0.05),2 h PBG及HbA1c明显下降,与治疗前比较,差异有统计学意义(P<0.01),TG、TC及LDL-C有所下降,但与治疗前比较差异无统计学差异(P>0.05)。利拉鲁肽组未出现严重低血糖反应。结论:利拉鲁肽在2型糖尿病患者中有较好的疗效和安全性。