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.

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.

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.

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.

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.

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.

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.

司美格鲁肽与2型糖尿病患者恶性肿瘤风险相关性的Meta分析

目的系统评价2型糖尿病(T2DM)患者使用胰高血糖素样肽1受体激动剂司美格鲁肽治疗与恶性肿瘤风险的相关性。方法检索the Cochrane Library、PubMed、Embase、ClinicalTrials.gov、中国知网、万方、中国生物医学文献数据库,纳入结局指标中包含恶性肿瘤事件的司美格鲁肽治疗T2DM患者的随机对照试验(RCT),检索时间为建库起至2024年6月。采用RevMan 5.3软件对纳入人群恶性肿瘤风险进行Meta分析。结果最终纳入24项RCT(26个试验),共24145例患者。Meta分析结果显示,与安慰剂对照相比,接受司美格鲁肽治疗在胰腺癌[RR=0.39,95%CI(0.10,1.50),P=0.17]、甲状腺癌[RR=1.29,95%CI(0.38,4.36),P=0.68]、前列腺癌[RR=1.05,95%CI(0.36,3.12),P=0.92]、皮肤癌[RR=1.27,95%CI(0.80,2.02),P=0.31]、胃癌[RR=1.00,95%CI(0.47,2.14),P=1.00]、结直肠癌[RR=0.96,95%CI(0.40,2.26),P=0.92]、肺癌[RR=1.62,95%CI(0.74,3.55),P=0.23]、乳腺癌[RR=1.25,95%CI(0.45,3.51),P=0.67]以及总体恶性肿瘤[RR=0.96,95%CI(0.76,1.21),P=0.73]发生风险方面的差异均无统计学意义;与其他降糖药物对照相比,接受司美格鲁肽治疗在胰腺癌[RR=0.62,95%CI(0.18,2.09),P=0.44]、甲状腺癌[RR=1.09,95%CI(0.25,4.78),P=0.90]、前列腺癌[RR=2.09,95%CI(0.46,9.47),P=0.34]、皮肤癌[RR=1.76,95%CI(0.65,4.72),P=0.26]、胃癌[RR=0.68,95%CI(0.19,2.35),P=0.54]、结直肠癌[RR=0.60,95%CI(0.20,1.78),P=0.36]、肺癌[RR=1.00,95%CI(0.24,4.11),P=1.00]、乳腺癌[RR=0.82,95%CI(0.25,2.66),P=0.74]以及总体恶性肿瘤[RR=1.36,95%CI(0.96,1.94),P=0.09]发生风险方面的差异亦无统计学意义。结论司美格鲁肽不增加T2DM患者任何类型恶性肿瘤的发生风险。

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.

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.

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.

Efficacy of sodium-glucose cotransporter-2 inhibitors and glucagonlike peptide-1 receptor agonists on proteinuria and weight in a diabetes cohort

BACKGROUND With accumulating evidence showing a benefit in the renal and cardiovascular systems,diabetes guidelines recommend that patients with diabetes and chronic kidney disease(CKD)be treated with sodium-glucose cotransporter-2 inhibitor(SGLT2i)and/or glucagon like peptide-1 receptor agonists(GLP-1RAs)for renal protection.The real-world efficacy of the two medications on the urinary albumin-creatinine ratio(UACR)and estimated glomerular filtration rate(eGFR)remains to be explored.AIM To evaluate the SGLT2i and GLP-1RA application rates and UACR alterations after intervention in a real-world cohort of patients with diabetes.METHODS A cohort of 5482 patients with type 2 diabetes were enrolled and followed up at the Integrated Care Clinic for Diabetes of Peking University First Hospital for at least 6 months.Propensity score matching was performed,and patients who were not recommended for GLP-1RA or SGLT2i with comparable sex categories and ages were assigned to the control group at a 1:2 ratio.Blood glucose,body weight,UACR and eGFR were evaluated after 6 months of treatment in real-world clinical practice.RESULTS A total of 139(2.54%)patients started GLP-1RA,and 387(7.06%)received SGLT2i.After 6 months,the variations in fasting blood glucose,prandial blood glucose,and glycosylated hemoglobin between the GLP-1RA group and the SGLT2i and control groups were not significantly different.UACR showed a tendency toward a greater reduction compared with the control group,although this difference was not statistically significant(GLP-1RA vs control,-2.20 vs 30.16 mg/g,P=0.812;SGLT2i vs control,-20.61 vs 12.01 mg/g,P=0.327);eGFR alteration also showed no significant differences.Significant weight loss was observed in the GLP-1RA group compared with the control group(GLP-1RA vs control,-0.90 vs 0.27 kg,P<0.001),as well as in the SGLT2i group(SGLT2i vs control,-0.59 vs-0.03 kg,P=0.010).CONCLUSION Compared with patients who received other glucose-lowering drugs,patients receiving SGLT2i or GLP-1RAs presented significant weight loss,a decreasing trend in UACR and comparable glucose-lowering effects in realworld settings.

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.

益气通络方对2型糖尿病患者疗效的影响

目的观察益气通络方对2型糖尿病(type 2 diabetes mellitus,T2DM)患者血清载脂蛋白B(apolipoprotein B,ApoB)、载脂蛋白A-Ⅰ(apolipoprotein A-Ⅰ,ApoA-Ⅰ)、胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)水平及糖代谢的影响。方法选取商洛市中心医院2020年8月至2023年8月收治的98例T2DM患者进行随机对照试验。采用随机数字表法将其分为对照组和观察组,每组49例。对照组男24例,女25例,年龄(47.85±6.14)岁,病程(8.34±2.48)年。观察组男22例,女27例,年龄(46.59±6.03)岁,病程(8.56±2.25)年。对照组在常规治疗的基础上加用甲钴胺片,观察组在对照组基础上加用益气通络方;两组均治疗2个月。比较两组临床疗效,中医证候积分,血清ApoB、ApoA-Ⅰ、GLP-1水平,糖代谢,下肢神经传导速度,不良反应。采用χ^(2)检验和t检验进行统计分析。结果观察组总有效率高于对照组[95.92%(47/49)比79.59%(39/49);χ^(2)=6.078,P<0.05]。观察组中医证候积分总分低于对照组[(3.89±1.03)分比(4.94±1.21)分],差异有统计学意义(t=4.625,P<0.05)。观察组ApoB水平低于对照组[(0.94±0.17)g/L比(1.05±0.25)g/L],ApoA-Ⅰ、口服葡萄糖耐量试验(oral glucose tolerance test,OGTT)0 min GLP-1、OGTT 2 h GLP-1水平均高于对照组[(1.18±0.21)g/L比(1.06±0.15)g/L、(132.47±15.21)g/L比(118.37±16.45)g/L、(154.23±21.43)mol/L比(125.91±23.59)mol/L],差异均有统计学意义(t=2.547、3.255、5.030、8.636,均P<0.05)。观察组空腹血糖(fasting blood glucose,FBG)、餐后1 h血糖(postprandial 1 h blood glucose,1hPBG)、餐后2 h血糖(postprandial 2 h blood glucose,2hPBG)、糖化血红蛋白(hemoglobin A1c,HbA1c)水平均低于对照组[(6.51±0.82)mmol/L比(7.49±1.18)mmol/L、(8.53±1.19)mmol/L比(9.04±1.05)mmol/L、(10.57±1.38)mmol/L比(11.26±1.43)mmol/L、(6.17±0.52)%比(6.96±0.68)%],差异均有统计学意义(t=4.774、2.250、2.430、6.460,均P<0.05)。观察组正中神经运动神经传导速度(motor nerve conduction velocity,MNCV)、感觉神经传导速度(sensory nerve conduction velocity,SNCV)和腓总神经MNCV、SNCV均高于对照组[(47.24±2.58)m/s比(44.32±3.14)m/s、(47.25±3.73)m/s比(45.09±3.26)m/s、(43.58±4.33)m/s比(41.04±4.51)m/s、(42.10±3.45)m/s比(39.61±3.27)m/s],差异均有统计学意义(t=5.030、3.052、2.844、3.667,均P<0.05)。结论益气通络方联合甲钴胺片能提高T2DM患者临床疗效,改善患者血清因子水平及糖代谢,加快患者下肢神经传导速度。

司美格鲁肽对2型糖尿病合并超重及肥胖患者的胰腺和肝脏脂肪含量以及胰岛β细胞功能的影响

目的探讨司美格鲁肽对2型糖尿病(T2DM)合并超重及肥胖患者的血糖控制、胰腺和肝脏脂肪含量以及胰岛β细胞功能的影响。方法采用单中心、前瞻性、临床病例对照试验的方法,选取2021年10月至2022年10月在金华市中心医院诊断为T2DM合并超重(BMI 25~<28 kg/m^(2))及肥胖(BMI≥28 kg/m^(2))的86例患者为研究对象,均接受稳定剂量的二甲双胍单药或联合口服用药至少3个月,糖化血红蛋白(HbA1C)为6.5%~8.0%。采用随机数字表法将患者分为对照组和观察组,各43例。对照组继续原方案口服降糖,观察组在原方案的基础上联合司美格鲁肽(起始剂量0.25 mg,4周后增加至0.5 mg并稳定,1次/周,皮下注射)。两组均干预24周。比较两组患者血糖(FPG、餐后2 h血糖和HbA1C)、血脂(TC、TG、LDL-C、HDL-C)、BMI、腰围、胰岛细胞功能[空腹胰岛素(FINS)、胰岛β细胞功能指数(HOMA-β)和胰岛素抵抗指数(HOMA-IR)]。通过非对称回波的最小二乘估算法迭代水脂分离序列测量胰头、胰体和胰尾的胰腺脂肪分数(PFF),计算平均PFF并进行组间比较;测量肝脏右上、右下和左叶的肝脏脂肪分数(HFF),计算平均HFF并进行组间比较。结果对照组39例和观察组40例随访至研究结束。治疗后观察组患者FPG、餐后2 h血糖、HbA1C、BMI、FINS、HOMA-IR、平均PFF和平均HFF均低于对照组,而HOMA-β高于对照组,差异均有统计学意义(均P<0.01)。结论司美格鲁肽应用方便,对T2DM合并超重及肥胖患者能够在常规降糖药的基础上进一步改善胰岛素和胰岛β细胞功能,降低血糖水平、胰腺和肝脏脂肪含量,同时可产生额外的减重获益。

达格列净联合胰高血糖素样肽-1受体激动剂对2型糖尿病的疗效研究

目的探讨达格列净联合胰高血糖素样肽-1受体激动剂(GLP-1 RAs)对2型糖尿病患者血液流变学及胰岛素抵抗的影响。方法将2020年11月—2022年10月泉州市中医院收治的102例2型糖尿病患者随机分为2组,每组51例。对照组给予达格列净治疗,研究组采用达格列净联合GLP-1 RAs(利拉鲁肽)的治疗方案。比较2组临床疗效、血糖指标[空腹血糖(FBG)、餐后2 h血糖(2 hPG)、糖化血红蛋白(HbA1c)]、空腹胰岛素(FINS)及胰岛素抵抗[胰岛素抵抗指数(HOMA-IR)、胰岛素分泌指数(HOMA-β)]、血脂指标[总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)]、血液流变学指标[红细胞聚集指数(EAI)、红细胞压积(HCT)、红细胞变形指数(EDI)、血浆黏度(PV)]和不良反应。结果研究组总有效率为94.12%,高于对照组的80.39%,差异有统计学意义(P<0.05)。研究组和对照组治疗后FBG、2 hPG、HbAlc、BMI均低于治疗前,且研究组治疗后FBG、2 hPG、HbAlc水平低于对照组,差异有统计学意义(P<0.05)。治疗后,研究组FINS、HOMA-β水平高于对照组,HOMA-IR水平低于对照组,差异有统计学意义(P<0.05)。研究组和对照组治疗后HDL-C均高于治疗前,TC、TG、LDL-C水平均低于治疗前;研究组治疗后HDL-C水平高于对照组,TC、TG、LDL-C水平低于对照组,差异均有统计学意义(P<0.05)。治疗后,研究组和对照组EAI、HCT、EDI、PV水平均低于治疗前,且研究组EAI、HCT、EDI、PV水平低于对照组,差异均有统计学意义(P<0.05)。研究组不良反应总发生率为11.76%,与对照组的9.80%比较,差异无统计学意义(P>0.05)。结论达格列净联合GLP-1 RAs(利拉鲁肽)治疗2型糖尿病的疗效确切,可有效调节患者血糖及血脂水平,缓解胰岛素抵抗,改善血液流变学指标。

Is Glucagon-like peptide-1, an agent treating diabetes, a new hope for Alzheimer's disease?

Glucagon-like peptide- 1 （GLP- 1） has been endorsed as a promising and attractive agent in the treatment of type 2 diabetes mellitus （T2DM）. Both Alzheimer＇s disease （AD） and T2DM share some common pathophysiologic hallmarks, such as amyloid β （Aβ）, phosphoralation of tau protein, and glycogen synthase kinase-3. GLP-1 possesses neurotropic properties and can reduce amyloid protein levels in the brain. Based on extensive studies during the past decades, the understanding on AD leads us to believe that the primary targets in AD are the Aβ and tau protein. Combine these findings, GLP- 1 is probably a promising agent in the therapy of AD. This review was focused on the biochemistry and physiology of GLP- 1, communities between T2DM and AD, new progresses of GLP - 1 in treating T2MD and improving some pathologic hanmarks of AD.

GLP-1RA与DPP-4i治疗2型糖尿病的疗效及对患者并发症的影响

目的探讨胰高糖素样肽1受体激动剂(GLP-1RA)与二肽基肽酶4抑制剂(DPP-4i)治疗2型糖尿病(T2MD)的疗效及对患者并发症的影响。方法选取2020年6月至2022年6月邯郸市第一医院收治的110例T2MD随机分为GLP-1RA组和DPP-4i组,每组55例,GLP-1RA组采用利拉鲁肽或艾塞那肽治疗,DPP-4i组采用西格列汀或利格列汀治疗。对比2组临床疗效,治疗前后糖脂代谢指标[空腹血糖(FPG)、糖化血红蛋白(HbA1c)、总胆固醇、三酰甘油]、炎症指标[白介素-6(IL-6)、C反应蛋白(CRP)、中性粒细胞/淋巴细胞(NLR)]、肾功能[尿素氮、肌酐、胱抑素C];观察并统计2组并发症及不良反应。结果2组总有效率、并发症总发生率比较差异均无统计学意义(P>0.05)。治疗18周后,2组FPG、HbA1c、三酰甘油、总胆固醇水平低于治疗前,且GLP-1RA组低于DPP-4i组(P<0.05)。治疗18周后,2组IL-6、CRP、NLR水平低于治疗前(P<0.05),但2组间差异无统计学意义(P>0.05)。2组治疗前和治疗18周后尿素氮、肌酐、胱抑素C水平比较差异均无统计学意义(P>0.05)。GLP-1RA组不良反应总发生率高于DPP-4i组(P<0.05)。结论GLP-1RA与DPP-4i均能改善T2MD患者糖脂水平,减轻炎性反应,保护肾功能,预防并发症发生,但GLP-1RA在控制血糖、调脂方面优于DPP-4i,而DPP-4i耐受性更好。

Glucagon-like peptide-1 protects against cardiac microvascular endothelial cells injured by high glucose

Objective:To investigate the protective effect of glucagon-like peptid-1(GLP-l) against cardiac microvascular endothelial cell(GTFCs) injured by high glucose.Methods:CMECs were isolated and cultured.Superoxide assay kit and dihydroethidine(DHE) staining were used to assess oxidative stress.TENEL staining and caspase 3 expression were used to assess the apoptosis of CMECs.H89 was used to inhibit eAMP/PKA pathway:fasudil was used to inhibit Rho/ROCK pathway.The protein expressions of Rho.ROCK uere examined by Western blol analysis.lesults:High glucose increased the production of ROS.the activity of NADPH.the apoptosis rate and the expression level of Rho/ROCK in CMECs.while GLP- 1 decreased high glucose-induced ROS production.the NADPH activity and the apoptosis rate and the expression level of Rho/ROCK in CMECs,the difference were statistically significant(P<0.05).Conclusions:GLP-1 could protect the cardiac microvessels against oxidative stress and apoptosis.The protective effects of GLP-1 are dependent on downstream inhibition of Rho through a cAMP/PKA-dependent manner,resulting in a subsequent decrease in the expression of NADPH oxidase.

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.