Effects Of Glucagon-like Peptide-1 Research Articles

Role of glucagon-like peptide 1 (GLP-1) and its association with inflammatory markers in the pathogenesis of type 2 diabetes mellitus

Background: Diabetes mellitus is a multifactorial disease associated with hyperglycemia and increased risk of progression of vascular complications. Stimulation of insulin secretion by the incretin hormone glucagon-like peptide 1 (GLP-1) has been found to be diminished in hyperglycemia. We hypothesized that this impairment is due to defect at the receptor level induced by the diabetic state. Inflammatory markers like TNF-α and IL-6 plays a potential role in the pathogenesis of T2DM. Therefore, the present study aims to evaluate whether GLP-1 plays a role in the development of T2DM by modulating the balance between pro and anti-inflammatory markers. Material and methods: A total of 60 subjects were recruited in this study among them 30 were T2DM cases and 30 were healthy controls. m-RNA expression and protein level of GLP-1 receptor, TNF-α and IL-6 in peripheral blood lymphocytes were determined by real time PCR and ELISA respectively. Results: We observed plasma level of GLP-1 was significantly lower in diabetic subjects while serum level of IL-6 and TNF-α were significantly higher level in diabetic subjects (p < 0.05). We found significant down regulation of GLP-1 receptor m-RNA expression in diabetic subjects while expression level of IL-6 and TNF-α were 5.8 and 4 folds respectively higher in diabetic subjects. We found significant negative correlation of m-RNA expression of GLP-1 with protein level while IL-6 and TNF-α showed significant positive correlation. Conclusion: Inflammation plays an important role in the pathogenesis of diabetes mellitus and low GLP-1 levels may promote expression of inflammatory markers due to lack of anti-inflammatory effects of GLP-1

Imaging the effects of GLP-1 on the developing pancreas

GLP-1 (Glucagon-like peptide 1) is an incretin (a metabolic hormone modulating glucose metabolism) known to lower blood glucose by stimulating insulin release and inhibiting glucagon release. The effects of GLP-1 are well documented in adults, but little is known about the role of GLP-1 during development. The hypothesis of this project is that GLP-1 assists the pancreas in development, differentiation, and proliferation. To test this hypothesis, Glucagon-like peptide 1 receptor knockout mice (GLP-1R KO) were compared to control mice to block the mechanism of GLP-1. Sections of the pancreas were taken from both GLP-1R KO and control mice and were stained for insulin, glucagon, and proliferation. The data from the experiment suggests that GLP-1R KO mice have less islet cell mass (both α and β) and proliferation compared to controls. Further studies could investigate the role of GLP-1 during pancreatic organogenesis.

Current and emerging medications for the management of obesity in adults.

Current and emerging medications for the management of obesity in adults.

Efficacy and Safety of Tirzepatide in Type 2 Diabetes and Obesity Management.

The combination of glucagon-like peptide-1 (GLP-1) with other gut hormones including the glucose-dependent insulinotropic polypeptide (GIP) has been explored to complement and enhance further the GLP-1 effects on glycemia and weight loss. Tirzepatide is the first dual GLP-1/GIP receptor co-agonist which has been approved for treatment of type 2 diabetes mellitus (T2DM) based on the findings from the SURPASS program. The SURPASS trials assessed the safety and efficacy of tirzepatide in people with T2DM, from monotherapy through to insulin add-on in global populations, with another two trials dedicated to Japanese population. Over periods of treatment up to 104 weeks, once weekly tirzepatide 5 to 15 mg reduced glycosylated hemoglobin (1.87% to 3.02%), body weight (5.4 to 12.9 kg) and improved multiple cardiometabolic risk factors (including reduction in liver fat, new-onset macroalbuminuria, blood pressure, and lipids) across the T2DM spectrum. Tirzepatide provided better efficacy than placebo and other commonly used glucose-lowering medications such as semaglutide 1 mg, dulaglutide, insulin degludec, and glargine. All tirzepatide doses were well tolerated with similar side-effect profile to the GLP-1 receptor analogues. In people without diabetes, tirzepatide 5 to 15 mg once weekly for the treatment for obesity (SURMOUNT-1) resulted in substantial reductions in body weight (16.5% to 22.4%) over 72 weeks. Overall, the SURPASS program and SURMOUNT-1 study suggest that tirzepatide is marking a new era in T2DM and/or obesity management through dual agonism of gut hormones.

The role of glucagon-like peptide-1 (GLP-1) in fluid and food intakes in vasopressin-deficient Brattleboro rats

Eating and drinking co-occur and many of the same mechanisms that control one are involved in the control of the other, making it difficult to isolate specific mechanisms for the control of fluid intake. Glucagon-like peptide-1 (GLP-1) is a peptide that seems to be involved in the endogenous control of both ingestive behaviors, but we lack a thorough understanding of how and where GLP-1 is acting to control fluid intake. Vasopressin-deficient Brattleboro rats are a model of hereditary hypothalamic diabetes insipidus that have been used extensively for the study of vasopressin actions in behavior and physiology. Here, we propose that these rats, that eat normally but drink excessively, provide a useful model to dissociate central controls of food and fluid intakes. As an initial step toward establishing this model for these purposes, we focused on GLP-1. Similar to the effect observed after treatment with a GLP-1 receptor (GLP-1R) agonist, the intake difference between wildtype and Brattleboro rats was largely a function in the number of licking bursts, indicating differences in post-ingestive feedback (e.g., satiation). When given central injections of a GLP-1R agonist, the effect on feeding was comparable between wildtype and Brattleboro rats, but the effect of drug on fluid intake was markedly exaggerated in Brattleboro rats. Additionally, Brattleboro rats did not respond to GLP-1R antagonism, whereas wildtype rats did. Taken together, these results suggest that Brattleboro rats exhibit a selective disruption to GLP-1′s control of water intake. Overall, these experiments provide foundational studies of the ingestive behavior of Brattleboro rats and demonstrate the potential to use these rats to disentangle the effects of GLP-1 on food and fluid intakes.

Semaglutide inhibits ischemia/reperfusion-induced cardiomyocyte apoptosis through activating PKG/PKCε/ERK1/2 pathway

Apoptosis is a major pathophysiological change following myocardial ischemia/reperfusion (I/R) injury. Glucagon-like peptide 1 (GLP-1) and its receptor GLP-1R are widely expressed in the cardiovascular system and GLP-1/GLP-1R activates the protein kinase G (PKG)-related signaling pathway. Therefore, this study tested whether semaglutide, a new GLP-1 analog, inhibits I/R injury-induced cardiomyocyte apoptosis by activating the PKG/PKCε/ERK1/2 pathway. We induced myocardial I/R injury in rats and hypoxia/reoxygenation (H/R) injury in H9C2 cells and detected the effects of semaglutide, a PKG analog (8-Br-cGMP), and a PKG inhibitor (KT-5823) on the PKG/PKCε/ERK1/2 pathway and cardiomyocyte apoptosis. We found that semaglutide upregulated GLP-1R levels, and both semaglutide and 8-Br-cGMP activated the PKG/PKCε/ERK1/2 pathway, inhibited myocardial infarction (MI), decreased hs-cTNT levels, increased NT-proBNP levels, and suppressed cardiomyocyte apoptosis in I/R rats and H/R H9C2 cells. However, KT-5823 exerted contrasting effects with semaglutide and 8-Br-cGMP, and KT-5823 weakened the cardioprotective effects of semaglutide. In conclusion, semaglutide inhibits I/R injury-induced cardiomyocyte apoptosis by activating the PKG/PKCε/ERK1/2 pathway. The beneficial effect of GLP-1/GLP-1R, involved in the activation of the PKG/PKCε/ERK1/2 pathway, may provide a novel treatment method for myocardial I/R injury.

Glucagon-like peptide-1 promotes Leydig cell regeneration from stem cells in rats.

Glucagon-like peptide-1 stimulates stem Leydig cell development. Glucagon-like peptide-1 stimulates stem Leydig cell differentiation without affecting its proliferation. The regulators of stem Leydig cell (SLC) development remain largely unknown. The effect of glucagon-like peptide-1 (GLP-1) on rat SLC proliferation and differentiation was investigated using a 3D tissue culture system and an ethane dimethane sulfonate (EDS)-treated in vivo LC regeneration model. RNA-seq analysis was performed to analyze pathways in which GLP-1 may be involved. GLP-1 (3 and 30 nmol/L) significantly increased medium testosterone abundances and upregulated the expression of Scarb1, Cyp11a1, and Hsd11b1. GLP-1 in vitro did not affect SLC proliferation by 5-Ethynyl-2'- deoxyuridine (EdU) incorporation assay. Intratesticular injection of GLP-1 (10 and 100 ng/testis) into the LC-depleted testis from day 14 to day 28 post-EDS significantly increased serum testosterone abundances and upregulated the expression of Cyp11a1, Hsd3b1, and Hsd11b1. It did not affect the number of HSD11B1+ and CYP11A1+ LCs. RNA-seq analysis revealed that GLP-1 upregulated several pathways, including cAMP-PKA-EPAC1 and MEK/ERK1/2. GLP-1 stimulates SLC differentiation without affecting its proliferation, showing its novel action and mechanism on rat SLC development.

Advances in GLP-1 receptor agonists for the treatment of type 2 diabetes

Glucagon-like peptide-1 (GLP-1), an incretin secreted by intestinal L cells, has become a critical target for the treatment of type 2 diabetes because of its physiological effects of augmenting insulin secretion, suppressing glucagon secretion, and decelerating gastric emptying. Human endogenous GLP-1 is found to be proteolytically degraded and inactivated by DPP-4, which considerably limits the therapeutic effects of GLP-1. In contrast, GLP-1RAs undergo significant improvement in drug stability. In this context, several successful strategies for the development of GLP-1RAs and the corresponding problems are fully elaborated. The assay gives a brief overview of the pharmacological effects, advantages and common adverse effects of GLP-1RAs, shedding light on the latest research progress of GLP-1RAs, including new dosage forms, new drug targets and new clinical applications.

The Effect of Glucagon-Like Peptide 1 Receptor Blockade on Glucagon-Induced Stimulation of Insulin Secretion.

Data from transgenic rodent models suggest that glucagon acts as an insulin secretagogue by signaling through the glucagon-like peptide 1 receptor (GLP-1R) present on β-cells. However, its net contribution to physiologic insulin secretion in humans is unknown. To address this question, we studied individuals without diabetes in two separate experiments. Each subject was studied on two occasions in random order. In the first experiment, during a hyperglycemic clamp, glucagon was infused at 0.4 ng/kg/min, increasing by 0.2 ng/kg/min every hour for 5 h. On one day, exendin-9,39 (300 pmol/kg/min) was infused to block GLP-1R, while on the other, saline was infused. The insulin secretion rate (ISR) was calculated by nonparametric deconvolution from plasma concentrations of C-peptide. Endogenous glucose production and glucose disappearance were measured using the tracer-dilution technique. Glucagon concentrations, by design, did not differ between study days. Integrated ISR was lower during exendin-9,39 infusion (213 ± 26 vs. 191 ± 22 nmol/5 h, saline vs. exendin-9,39, respectively; P = 0.02). In the separate experiment, exendin-9,39 infusion, compared with saline infusion, also decreased the β-cell secretory response to a 1-mg glucagon bolus. These data show that, in humans without diabetes, glucagon partially stimulates the β-cell through GLP-1R.

GLP-1 receptor agonist as a modulator of innate immunity.

Glucagon-like peptide-1 (GLP-1) is a 30-amino acid hormone secreted by L cells in the distal ileum, colon, and pancreatic α cells, which participates in blood sugar regulation by promoting insulin release, reducing glucagon levels, delaying gastric emptying, increasing satiety, and reducing appetite. GLP-1 specifically binds to the glucagon-like peptide-1 receptor (GLP-1R) in the body, directly stimulating the secretion of insulin by pancreatic β-cells, promoting proliferation and differentiation, and inhibiting cell apoptosis, thereby exerting a glycemic lowering effect. The glycemic regulating effect of GLP-1 and its analogues has been well studied in human and murine models in the circumstance of many diseases. Recent studies found that GLP-1 is able to modulate innate immune response in a number of inflammatory diseases. In the present review, we summarize the research progression of GLP-1 and its analogues in immunomodulation and related signal pathways.

Glucagon-Like Peptide-1 (GLP-1) Rescue Diabetic Cardiac Dysfuntions in Human iPSC-Derived Cardiomyocytes.

Glucagon-like peptide-1 (GLP-1) can improve cardiac function and cardiovascular outcomes in diabetic cardiomyopathy; however, the beneficial effect of GLP-1 on human diabetic cardiomyocytes (DCMs) and its mechanism have not been fully elucidated. Here, the DCMs model by human-induced pluripotent stem cells-derived cardiomyocytes is developed. Two subtypes of GLP-1, GLP-17-36 and GLP-19-36 , are evaluated for their efficacy on the DCMs model. Diabetogenic condition is sufficient to induce most characteristics of diabetic cardiomyopathy in vitro, such as cardiac hypertrophy, lipid accumulation, impaired calcium transients, and abnormal electrophysiological properties. GLP-17-36 and GLP-19-36 can restore cardiomyocyte hypertrophic phenotype, impaired calcium transient frequency, abnormal action potential amplitude, depolarization, and repolarization velocity. Interestingly, RNA-seq reveals different pathways altered by GLP-17-36 and GLP-19-36 , respectively. Differentially expressed gene analysis reveals that possible targets of GLP-17-36 involve the regulation of mitotic nuclear division and extracellular matrix-receptor interaction, while possible targets of GLP-19-36 involve kinetochore assembly, and the complement and coagulation cascades. This study demonstrates the therapeutic effects of GLP-1 on human DCMs and provides a novel platform to unveil the cellular mechanisms of diabetic cardiomyopathy, shedding light on discovering better targets for novel therapeutic interventions.

PSUN326 An Interim Analysis of Healthcare Professionals’ Gaps in Incretin Knowledge Before and After Education

Abstract Background Patients with type 2 diabetes (T2D) who have poor glycemic control are at increased risk for macrovascular and microvascular disease. The growing body of cardiovascular (CV) and renal outcomes data for newer agents such as glucagon-like peptide 1 (GLP-1) receptor agonists has shifted management approaches toward therapies that provide extra glycemic benefits in addition to glucose-lowering ability. The rapidly evolving role of these new agents and new data on the potential role of a glucose-dependent insulinotropic polypeptide (GIP) agonist/GLP-1 agonist combination agent may create confusion among healthcare professionals (HCPs) treating patients with T2D. Greater competence is needed on the actions and clinical applications of current and emerging incretin-based therapies. Therefore, Clinical Care Options (CCO) created a series of online-based microlearning modules on the topic of incretin therapy in patients with T2D and cardiometabolic comorbidities for HCPs. This ongoing program, which was supported by an unrestricted medical education grant, is providing us with rich outcomes data that characterizes HCPs’ learning and current knowledge gaps regarding the use of incretins in patients with T2D. Aim The goal of this analysis was to determine the interim educational impact as well as remaining knowledge gaps among HCPs following education on incretin therapies. This information could inform future medical education that closes knowledge gaps and arms HCPs with the tools to effectively manage patients with T2D. Methods CCO produced an online educational program on incretin therapies, released in August 2021. We used pre/post questions to mine data on HCPs’ gaps. Questions measuring HCPs’ knowledge and competence were asked at baseline ("pre") and then repeated after the education was delivered ("post"). To uncover key educational gaps, we identified questions with the lowest correct responses at baseline as well as persistence of incorrect responses post education. Interim Results HCP Demographics N = 9837; MD: 61%; RPh: 10%; NP/PA: 12%; RN: 5%; other HCP: 5%, non-HCP: 8% Baseline and Remaining Gaps Incretin-based questions with topics including GLP-1 effects on glucose homeostasis, metabolic effects of GIP/GLP-1 coagonists, and the A1C-lowering ability of tirzepatide all scored <50% at baseline. Following education, the GLP-1 effect on glucose homeostasis increased only slightly from 36% to 40%, and the metabolic effects of GIP/GLP-1 coagonists increased from 19% to 54%, indicating that HCPs still struggle with understanding the effects of these agents. Conclusions This analysis demonstrates that HCPs who care for patients with T2D have significant knowledge gaps in the effects of newer incretin agents. As guidelines are placing more emphasis on the use of newer incretin agents as first-line therapy, HCPs must have the knowledge and competence of their actions to initiate incretin therapy in the primary care setting. Comparison to a similar program with an alternative format may provide further insight. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

PSUN299 GLP-1 Contribution to Insulin Secretory Response to Protein Ingestion and Insulin Kinetics Following Gastric Bypass and Sleeve Gastrectomy

Abstract Rapid passage of ingested nutrients to the gut after Roux-en-Y gastric bypass (GB) and sleeve gastrectomy (SG) results in hyperinsulinemia after glucose ingestion, in part due to an enhanced glucagon-like peptide-1 (GLP-1)-induced insulin secretory response (ISR) and reduced metabolic clearance rate of insulin (MCRI). The effect of endogenous GLP-1 on insulin kinetics is unknown, and so is GLP-1 contribution to insulin secretory response to non-glucose nutrient ingestion. In non-surgical subjects, protein ingestion enhances insulin secretion and reduces MCRI. We hypothesized that protein ingestion enhances GLP-1-induced ISR and alters MCRI in proportion to changes in nutrient influx after GB and SG. To test this hypothesis ISR, β-cell sensitivity to glucose (BGS), MCRI, and oral glucose insulin sensitivity (OGIS) were measured on 3 days during 50 g glucose ingestion as well as 50 g protein ingestion with and without GLP-1R antagonist, exendin (9-39) [Ex-9] infusion. Ten GB-treated subjects, 9 SG-treated, and 7 non-operated controls (CN) were enrolled. The 3 non-diabetic groups were matched for age, BMI, fat-free mass, HbA1c; surgical groups were matched for weight loss and time post-surgery. Fasting glucose, insulin, and ISR were similar among the 3 groups and among the 3 studies but fasting MCRI was greater in surgical groups than CN (p<0.05). Compared to glucose, protein ingestion led to larger BGS in 3 groups despite smaller overall ISR response (AUCISR3h) (p<0.05). Blocking GLP-1R during protein ingestion decreased AUCISR3h only in surgical subjects (p<0.05 for interaction), whereas BGS was reduced similarly in 3 groups during Ex-9 infusion (p<0.05). OGIS was smaller during protein than glucose ingestion in 3 groups (p<0.05). GLP-1R blockade did not affect insulin sensitivity. Following nutrient ingestion in parallel with increase in insulin secretion MCRI was reduced to nadir values at 40 minutes, but then gradually increased approaching premeal values at different pace among surgical and non-surgical subjects (p<0.05). The slope of MCRI: Insulin (0-40 min) was smaller after protein ingestion than glucose, and after protein with Ex-9 infusion than without in 3 groups (p<0.05). Blocking GLP-1R had no effect on MCRI values in the latter phase of protein ingestion when insulin secretion reduced approaching premeal values. There was no association between parameters of insulin sensitivity and insulin clearance during glucose or protein ingestion. Our findings indicate that the regulation of insulin secretion and clearance during protein ingestion is altered after GB and SG. Further, endogenous GLP-1 contribution to insulin secretory response to protein ingestion after GB and SG is enhanced, but GLP-1 effect on insulin kinetics is trivial. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Effects of GLP-1 Infusion Upon Whole-body Glucose Uptake and Skeletal Muscle Perfusion During Fed-state in Older Men.

Ageing skeletal muscles become both insulin resistant and atrophic. The hormone glucagon-like peptide 1 (GLP-1) facilitates postprandial glucose uptake as well as augmenting muscle perfusion, independent of insulin action. We thus hypothesized exogenous GLP-1 infusions would enhance muscle perfusion and positively affect glucose metabolism during fed-state clamps in older people. Eight men (71 ± 1 years) were studied in a randomized crossover trial. Basal blood samples were taken before postprandial (fed-state) insulin and glucose clamps, accompanied by amino acid infusions, for 3 hours. Reflecting this, following insertions of peripheral and femoral vessels cannulae and baseline measurements, peripheral IV infusions of octreotide, insulin (Actrapid), 20% glucose, and mixed amino acids; Vamin 14-EF with or without a femoral arterial GLP-1 infusion were started. GLP-1, insulin, and C-peptide were measured by ELISA. Muscle microvascular blood flow was assessed via contrast enhanced ultrasound. Whole-body glucose handling was assayed by assessing glucose infusion rate parameters. Skeletal muscle microvascular blood flow significantly increased in response to GLP-1 vs feeding alone (5.0 ± 2.1 vs 1.9 ± 0.7 fold-change from basal, respectively; P = 0.008), while also increasing whole-body glucose uptake (area under the curve 16.9 ± 1.7 vs 11.4 ± 1.8 mg/kg-1/180 minutes-1, P = 0.02 ± GLP, respectively). The beneficial effects of GLP-1 on whole-body glycemic control are evident with insulin clamped at fed-state levels. GLP-1 further enhances the effects of insulin on whole-body glucose uptake in older men, underlining its role as a therapeutic target. The effects of GLP-1 in enhancing microvascular flow likely also affects other glucose-regulatory organs, reflected by greater whole-body glucose uptake.

Effect of glucagon-like peptide-1 (GLP-1) agonists on the example of semaglutide on the cardiovascular system and their role in the treatment of obesity.

Obesity nowadays affects an increasing number of people. We can talk about it when the patient's BMI is ≥ 30.0 kg/m² (BMI 25.0-29.9 kg/m² - overweight). While obesity in itself may not be a problem for people suffering from it, its complications can be global and sometimes pose a serious threat to health or even life. Its main complications in the cardiovascular system include: hypercholesterolaemia, arterial hypertension, left ventricular hypertrophy, early atherosclerotic changes, heart and cerebral infarction. Treatment of obesity is based mainly on changing the patient's lifestyle - diet and physical activity, which can sometimes be problematic and difficult to apply.
 However, there is a new group of hypoglycaemic drugs - glucagon-like peptide-1 (GLP-1) agonists, which can make obesity treatment easier. These drugs use the incretin effect in the body to increase insulin secretion in response to a meal containing carbohydrates and prevent postprandial hyperglycemia. In this article, we will analyze the latest studies on the effects of GLP-1 receptor agonists, using semaglutide as an example, on the cardiovascular system and on weight loss in patients.

Effects of GLP-1 and GIP on Islet Function in Glucose-Intolerant, Pancreatic-Insufficient Cystic Fibrosis.

Impaired insulin and incretin secretion underlie abnormal glucose tolerance (AGT) in pancreatic insufficient cystic fibrosis (PI-CF). Whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can enhance pancreatic islet function in cystic fibrosis (CF) is not known. We studied 32 adults with PI-CF and AGT randomized to receive either GLP-1 (n = 16) or GIP (n = 16) during glucose-potentiated arginine (GPA) testing of islet function on two occasions, with either incretin or placebo infused, in a randomized, double-blind, cross-over fashion. Another four adults with PI-CF and normal glucose tolerance (NGT) and four matched control participants without CF underwent similar assessment with GIP. In PI-CF with AGT, GLP-1 substantially augmented second-phase insulin secretion but without effect on the acute insulin response to GPA or the proinsulin secretory ratio (PISR), while GIP infusion did not enhance second-phase or GPA-induced insulin secretion but increased the PISR. GIP also did not enhance second-phase insulin in PI-CF with NGT but did so markedly in control participants without CF controls. These data indicate that GLP-1, but not GIP, augments glucose-dependent insulin secretion in PI-CF, supporting the likelihood that GLP-1 agonists could have therapeutic benefit in this population. Understanding loss of GIP's insulinotropic action in PI-CF may lead to novel insights into diabetes pathogenesis.

Effect of glucagon-like peptide-1 (GLP-1) analogues on epicardial adipose tissue: A meta-analysis

Background and aimsGlucagon-like peptide-1 (GLP-1) analogues reduce body fat and cardiovascular events in patients with type 2 diabetes. Accumulation of epicardial adipose tissue (EAT) is associated with increased cardio-metabolic risks and coronary events in type 2 diabetes. MethodsA systematic review and meta-analysis were performed from Glucagon-like peptide-1 analogues therapy on type 2 diabetes patients, reporting data from changes in EAT, after searching the PubMed/MEDLINE, Embase, Science Direct, Scopus, Google Scholar, and Cochrane databases. ResultsIt has been found a limited number of studies, a total of 4 studies (n = 160 patients with GLP-1 analogues therapy) were included in the final analysis. Pooled analysis revealed that GLP-1 analogues reduce EAT (MD: 1.83 mm [-2.50; −1.10]; P < 0.01). Compared with the patients before the treatment, the patients after the treatment had a smaller HbA1c (MD -1.10%[-1.80; −0.30]; p = 0.0143) and body mass index was reduced (MD -2.20 kg/m2[-3.70; −0.60]; p = 0.0058), GLP-1 therapy reduced low-density lipoprotein levels (MD-13.53 mg/dL [-21.74; −5.31]; p = 0.001) and reduced triglycerides levels significantly (MD -18.32 -28.20 mg/dL; −8.50); p = 0.0003). ConclusionsThis meta-analysis suggests that the amount of EAT is significantly reduced in T2D patients with Glucagon-like peptide-1 analogues.

An inter-organ neural circuit for appetite suppression

Glucagon-like peptide-1 (GLP-1) is a signal peptide released from enteroendocrine cells of the lower intestine. GLP-1 exerts anorectic and antimotility actions that protect the body against nutrient malabsorption. However, little is known about how intestinal GLP-1 affects distant organs despite rapid enzymatic inactivation. We show that intestinal GLP-1 inhibits gastric emptying and eating via intestinofugal neurons, a subclass of myenteric neurons that project to abdominal sympathetic ganglia. Remarkably, cell-specific ablation of intestinofugal neurons eliminated intestinal GLP-1 effects, and their chemical activation functioned as a GLP-1 mimetic. GLP-1 sensing by intestinofugal neurons then engaged a sympatho-gastro-spinal-reticular-hypothalamic pathway that links abnormal stomach distension to craniofacial programs for food rejection. Within this pathway, cell-specific activation of discrete neuronal populations caused systemic GLP-1-like effects. These molecularly identified, delimited enteric circuits may be targeted to ameliorate the abdominal bloating and loss of appetite typical of gastric motility disorders.

A GLP-1/glucagon (GCG)/CCK2 receptors tri-agonist provides new therapy for obesity and diabetes.

Glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptor dual agonist have promising therapeutic effects in the treatment of obesity and diabetes. Moreover, GLP-1 and cholecystokinin 2 (CCK2 ) dual agonists have been shown to restore pancreas function and improve glycaemic control in preclinical studies. We describe, for the first time, the beneficial effects of GLP-1/glucagon receptor and GLP-1/CCK2 dual agonists, which can be integrated into one peptide, resulting in significant anti-diabetes and anti-obesity effectiveness. The in vitro potency of this novel peptide Xenopus (x) GLP-1/GCG/CCK2 tri-agonist (xGLP/GCG/gastrin) against GLP-1, GCG, CCK1 and CCK2 receptors was determined on cells expressing the corresponding receptors by cAMP accumulation or ERK1/2 phosphorylation assays. The in vivo anti-diabetes and anti-obesity effects of this tri-agonist xGLP/GCG/gastrin were studied in both db/db and diet induced obesity (DIO) mice. xGLP/GCG/gastrin was a potent and selective GLP-1, GCG and CCK2 tri-agonist. In DIO mice, the metabolic benefits of xGLP-1/GCG/gastrin, such as reduction of body weight and hepatic lipid contents were significantly better than those of the peptide ZP3022 (GLP-1/CCK-2 dual agonist) and liraglutide. In a short-term study in db/db mice, xGLP/GCG/gastrin treatment had considerable effects, increasing islet numbers, islet areas and insulin content. In a long-term treatment study using db/db mice, xGLP-1/GCG/gastrin showed a significantly and sustained improvement in glucose tolerance and glucose control compared with that of liraglutide, ZP3022, cotadutide (GLP-1/GCG dual agonist) and xGLP/GCG-15. These results demonstrate the therapeutic potential of xGLP-1/GCG/gastrin for the treatment of obesity and diabetes.

Wei-Tong-Xin ameliorates functional dyspepsia via inactivating TLR4/MyD88 by regulating gut microbial structure and metabolites

BackgroundWei-Tong-Xin (WTX) is a traditional Chinese medicine (TCM) that has been screened and improved in accordance with the famous ancient Chinese formula "Wan Ying Yuan". It has been shown to be clinically effective in treating gastric dysmotility, but its underlying molecular mechanism remains unclear. PurposeThis study primarily dealt with the effects and mechanisms of WTX on functional dyspepsia (FD) induced by chemotherapeutic drug cisplatin (CIS). MethodsFirstly, the UPLC fingerprint and multi-component determination of WTX were established. In vivo, gastrointestinal motility of mice was detected by charcoal propulsion test. Besides, H&E, western blot and qRT-PCR were performed to evaluate the occurrence of gastric antral inflammation. ROS-DHE staining was used to detect ROS levels. Further, the gut microbiota were subjected to sequencing by 16S rRNA, and the levels of bacterial metabolites short-chain fatty acids (SCFAs) and lipopolysaccharide (LPS) were detected by GC-MS and Limulus kits, respectively. The levels of GLP-1 in gastric antrum were assessed by ELISA kits. Finally, siRNA-FFAR2 experiment was performed in Raw 264.7 cells. Results23 common peaks were obtained from the UPLC fingerprint, and the content of 10 target components was determined. WTX increased the relative abundance of Firmicutes and decreased the number of Verrucomicrobia, accompanied by changes in the levels of SCFAs and LPS. By mediating the expression changes of free fatty acid receptor 2 (FFAR2) and toll-like receptor 4 (TLR4), WTX inhibited the phosphorylation of nuclear factor-κB (NF-κB), JNK and P38, decreased the levels of IL-1β, inducible nitric oxide synthase (iNOS) and ROS, increased the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), IL-4 and arginase-1 (Arg-1). Decreased expressions of glucagon-like peptide 1 (GLP-1) induced by WTX promoted gastric motility in FD mice. In vitro, siRNA-FFAR2 of Raw 264.7 cells eliminated the effects of WTX on TLR4 signaling pathway. ConclusionsIn this study, the chemical profile of WTX was first reported. Based on remodeling the gut microbiota structure and adjusting the levels of metabolites (SCFAs and LPS), WTX inactivated the TLR4/MyD88 signaling pathway to inhibit the occurrence of gastric antral inflammation, which reversed the inhibitory effect of GLP-1 on gastric motility, and improved CIS-induced FD symptoms.