Glucagon-like Peptide-1 Levels Research Articles

Hypoglycemic Effect of Ginsenoside Compound K Mediated by N-Acetylserotonin Derived From Gut Microbiota.

Ginsenoside compound K (GCK) has been proved to have great hypoglycemic effect pertinent to gut microbiota. However, the improvement of high-fat-diet (HFD)-induced type 2 diabetes (T2D) as well as the mechanism of GCK mediated by gut microbiota is not well-known. This study aimed to investigate the hypoglycemic effects and mechanism of GCK on a HFD-induced diabetic mouse model. HFD-induced pseudo-germ free (GF) T2D mice model and fecal microbiota transplantation (FMT) experiments were performed to clarify the role of gut microbiota in the hypoglycemic effect of GCK. Differential metabolites were screened by untargeted metabolomics analysis and their functions were verified by suppling to T2D mice. The level of glucagon-like peptide-1 (GLP-1) in plasma was detected by ELISA analysis to explore the potential hypoglycemic mechanism of GCK. The results showed GCK alleviated metabolic disorders and altered gut microbiota in HFD-induced diabetic mice, which was transmitted to pseudo-GF diabetic mice via FMT experiment to reproduce the hypoglycemic effect. Non-targeted metabolites analysis on cecal content samples indicated that N-acetylserotonin (NAS) was markedly increased after GCK treatment. Moreover, gavage with NAS improved insulin sensitivity and increased the secretion of GLP-1 in HFD mice. Our study showed that GCK had hypoglycemic effect through modifying gut microbiota profiling.

P-Coumaric Acid alleviates non-alcoholic fatty liver disease by promoting GLP-1 secretion via the GRP78-Ca2+ signaling axis

In individuals with obesity-related non-alcoholic fatty liver disease (NAFLD), endogenous Glucagon-like peptide-1 (GLP-1) secretion is compromised, and supplementation with GLP-1 receptor agonists has shown efficacy in ameliorating NAFLD. However, there is currently a scarcity of research focused on the direct promotion of endogenous GLP-1 secretion from L-cells by plant-derived phenolic acids. Hence, this study reveals that p-Coumaric Acid (p-CA), a widely occurring phenolic acid in the plant, holds potential as a therapeutic approach by stimulating the secretion of GLP-1 to improve glucose-lipid metabolism alterations and alleviate NAFLD symptoms. In diet-induced obese (DIO) mouse models, administration of high doses of p-CA led to a significant elevation in serum GLP-1 levels, as well as improvements in body weight gain, glucose level, insufficient insulin secretion, and biochemical abnormalities associated with NAFLD in mice fed with a high-fat diet. Moreover, the number of lipid droplets in the liver tissue of p-CA-treated mice was notably reduced, suggesting its effectiveness in mitigating liver fat accumulation and ameliorating NAFLD severity. Experimental evidence suggests that p-CA exerts its effects by influencing the transcriptional regulation of Glucose-regulated protein 78 kDa (GRP78) through interaction with Nucleophosmin 1 (NPM1), thereby downregulating GRP78 expression. This decrease in GRP78 expression subsequently leads to an increase in intracellular Calcium ions (Ca2+) concentration, which promotes the production and exocytosis of GLP-1-containing vesicles in L cells, consequently enhancing GLP-1 secretion. This research demonstrates the mechanistic role and therapeutic effects of p-CA in regulating GLP-1 secretion and its implications for improving NAFLD, underscoring the pharmacological significance of this natural compound as a dietary supplement.

Effects of Fructus Aurantii Extract on Growth Performance, Nutrient Apparent Digestibility, Serum Parameters, and Fecal Microbiota in Finishing Pigs.

This study investigated the effects of Fructus Aurantii extract (FAE) on growth performance, nutrient apparent digestibility, serum parameters, fecal microbial composition, and short-chain fatty acids (SCFAs) in finishing pigs. In total, 75 Duroc × Landrace × Yorkshire pigs (equally divided by sex), with an initial body weight of 79.49 ± 4.27 kg, were randomly assigned to three treatment groups. The pigs were fed either a basic diet (CON) or a basal diet supplemented with 500 mg/kg of FAE (FAE500) and 1000 mg/kg of FAE (FAE1000). The FAE1000 group exhibited a significantly higher final body weight (FBW) (p < 0.05), and the average daily feed intake (ADFI) showed an increasing tendency in the FAE500 and FAE1000 groups (p = 0.056) compared to the CON group. Additionally, the inclusion of FAE resulted in the significantly higher apparent digestibility of crude ash (Ash), gross energy (GE), and crude protein (CP) (p < 0.05), with a tendency to the increased digestibility of dry matter (DM) (p = 0.053). Dietary FAE supplementation led to elevated serum levels of reduced glutathione (GSH) and decreased levels of serum L-lactic dehydrogenase (LDH), along with a tendency to increase serum glucose (GLU) levels (p = 0.084). The FAE500 group demonstrated higher serum concentrations of motilin (MTL) and gastrin (GAS) (p < 0.05), and a tendency for reduced serum glucagon-like peptide-1 (GLP-1) level (p = 0.055) compared to the CON group. Furthermore, alpha diversity analysis revealed that the FAE500 group significantly increased the Chao 1 and Observed_species indexes (p < 0.05). Similarly, beta diversity analysis indicated that FAE feeding altered the fecal microbial structure (p = 0.083). Notably, compared with the control group, CF231, Pediococcus, and Mogibacterium displayed higher relative abundance in the feces of the FAE500 group, whereas Tenericutes showed a reduction in relative abundance (p < 0.05). Additionally, the relative abundance of Tenericute was negatively correlated with the digestibility of DM, GE, Ash, and CP (p < 0.05). Serum MTL and GAS levels correlated positively with the Coprococcus, Dorea, Pediococcus, and Mogibacterium relative abundances (p < 0.05). Collectively, dietary FAE supplementation could enhance growth performance by boosting beneficial bacteria in feces, stimulating gastrointestinal hormone secretion, and improving nutrient digestibility.

Intestinal glucagon-like peptide-1 in hypoglycemic counterregulation for type 1 diabetes management.

Type 1 diabetes (T1D) is characterized by the autoimmune destruction of pancreatic beta cells, leading to absolute insulin deficiency and the need for exogenous insulin. A significant concern in T1D management is hypoglycemia, which is worsened by impaired counterregulatory mechanisms. Effective counterregulation involves hormones such as glucagon and adrenaline, which work to restore normal blood glucose levels. However, in T1D, these mechanisms often fail, particularly after recurrent hypoglycemia, resulting in hypoglycemia-associated autonomic failure. Recent research indicates that elevated levels of intestinal glucagon-like peptide-1 (GLP-1) impair counterregulatory responses by reducing the secretion of glucagon and adrenaline. This editorial underscores GLP-1's role beyond its incretin effects, contributing to impaired hypoglycemic counterregulation. This understanding necessitates a nuanced approach to GLP-1-based therapies in T1D, balancing the benefits of glycemic control with potential risks. Future research should delve into the mechanisms behind GLP-1's effects and explore potential interventions to improve hypoglycemic counterregulation. The goal is to enhance the safety and quality of life for T1D patients.

Comprehensive Assessment of Cannabidiol and HU308 in Acute and Chronic Colitis Models: Efficacy, Safety, and Mechanistic Innovations.

Cannabinoids are emerging as promising treatments for inflammatory diseases such as ulcerative colitis. Specifically, cannabinoid 2 (CB2) receptors, which are upregulated during inflammation, have been distinctively linked to anti-inflammatory and analgesic effects. HU308, a synthetic cannabinoid developed to activate CB2 receptors selectively, aims to minimize unwanted off-target side effects. This study evaluated the effectiveness of both cannabidiol (CBD) and HU308 in mouse models of dextran sodium sulphate (DSS)-induced colitis, which mimic the acute and chronic phases of ulcerative colitis. Mice were treated with DSS in drinking water (four percent for the acute model and one to two percent for the chronic model) to induce colitis, as indicated by increased disease activity index (DAI) scores and inflammatory markers. Treatment with 60 mg/kg of CBD, but not lower doses, significantly reduced colitis symptoms, such as inflammation, cytokine levels, and MPO activity, while also normalizing glucagon-like peptide-1 (GLP-1) levels. HU308 showed comparable efficacy to high-dose CBD (60 mg/kg) but at a much lower dose (2.5 mg/kg), without observable toxicity. HU308 effectively normalized DAI scores, colon inflammation, ammonia levels, and GLP-1 expression in both colitis models. These results suggest that both CBD and HU308 are promising treatments for ulcerative colitis. However, HU308 demonstrates enhanced therapeutic potential by achieving similar outcomes at a fraction of the dose required for CBD, reducing the risk of off-target side effects. The ability of HU308 to modulate GLP-1, a biomarker of gut endocrine function, further underscores its promise as a novel treatment option.

Protective effect of Dulaglutide, a GLP1 agonist, on acetic acid-induced ulcerative colitis in rats: involvement of GLP-1, TFF-3, and TGF-β/PI3K/NF-κB signaling pathway.

A chronic inflammatory condition of the colon called ulcerative colitis (UC) is characterized by mucosal surface irritation that extends from the rectum to the near proximal colon portions. The rationale of this work was to conclude if dulaglutide (Dula) could protect rats from developing colitis caused by exposure to acetic acid (AA). Rats were randomly divided into seven groups (each with eight rats): Normal control, Dula control, AA (received 2 milliliters of 3% v/v AA through the rectum), Sulfasalazine (SLZ); given SLZ (100 mg/kg) orally from day 11 to day 21 then AA intrarectally on day 22 and Dula groups ( pretreated with 50, 100 or 150 μg/kg subcutaneous injection of Dula - once weekly for three weeks and AA on day 22 to induce ulcerative colitis, colon tissues and blood samples were taken on day 23. By generating colonic histological deviations such as inflammatory processes, goblet cell death, glandular hyperplasia, and mucosa ulcers, Dula dropped AA-induced colitis. Additionally, these modifications diminished blood lactate dehydrogenase (LDH), C-reactive protein (CRP), colon weight, and the weight/length ratio of the colon. In addition, Dula decreased the oxidative stress biomarker malondialdehyde (MDA) and increased the antioxidant enzymes (total antioxidant capacity (TAC), reduced glutathione (GSH), and superoxide dismutase (SOD) concentrations). Dula also significantly reduced the expression of transforming growth factor-1 (TGF-β1), phosphatidylinositol-3-kinase (PI3K), protein kinase B (AKT) signaling pathway, and the inflammatory cytokines: nuclear factor kappa B (NF-κB), interleukin-6 (IL-6), and interferon-γ (IFN-γ) in colonic cellular structures. In addition, Dula enforced the levels of glucagon-like peptide-1 (GLP-1) and trefoil factor-3 (TFF-3) that were crucial to intestinal mucosa regeneration and healing of wounds. By modulating TGF-β1 in conjunction with other inflammatory pathways like PI3K/AKT and NF-κB, regulating the oxidant/antioxidant balance, and improving the integrity of the intestinal barrier, Dula prevented AA-induced colitis in rats.

Weizmannia coagulans BC99 Improves Strength Performance by Enhancing Protein Digestion and Regulating Skeletal Muscle Quality in College Students of Physical Education Major.

Background: The dietary proteins are one of the most important factors determining health conditions in humans. The sufficient digestion and absorption of dietary proteins in the digestive tract has positive effects on performance and recovery in sportspeople and athletes. Improving protein digestibility is a strategy for maintaining health status and optimal performance in sport and exercise activities. Objectives: The aim of the present study is to verify whether Weizmannia coagulans BC 99 (BC99) can increase muscle mass and strength. Methods: This randomized double-blind, controlled trial assigned 72 male college students to receive probiotics (n = 36, 20.25 ± 1.03 years; 179.00 ± 5.94 cm; 73.55 ± 8.73 kg, protein powder with BC99) or the placebo (n = 36, 20.19 ± 0.79 years; 179.25 ± 5.16 cm; 73.61 ± 8.24 kg, protein powder) for 12 weeks. At the baseline and final stages of the study, strength tests and body composition assessment were performed. Blood and stool samples were taken at the end of the 12-week intervention, and digestive enzymatic activity of stool samples, biochemical parameters, amino acids and hormone level of plasma were analyzed. Results: BC99 administration significantly improved strength performance, skeletal muscle mass, activity of pepsin and trypsin, the concentrations of branched chain amino acids and essential amino acids, reduced activities of creatine kinase and lactic dehydrogenase and urea nitrogen (BUN) level and increased testosterone and glucagon-like peptide-1 level in male college students. Conclusions: Therefore, BC99 supplementation can be an important nutritional strategy to improve strength performance, body composition, protein digestion and body metabolism in healthy young males.

Huanglian-Renshen-Decoction Maintains Islet β-Cell Identity in T2DM Mice through Regulating GLP-1 and GLP-1R in Both Islet and Intestine.

To elucidate the effect of Huanglian-Renshen-Decoction (HRD) on ameliorating type 2 diabetes mellitus by maintaining islet β -cell identity through regulating paracrine and endocrine glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) in both islet and intestine. The db/db mice were divided into the model (distilled water), low-dose HRD (LHRD, 3 g/kg), high-dose HRD (HHRD, 6 g/kg), and liraglutide (400 µ g/kg) groups using a random number table, 8 mice in each group. The db/m mice were used as the control group (n=8, distilled water). The entire treatment of mice lasted for 6 weeks. Blood insulin, glucose, and GLP-1 levels were quantified using enzyme-linked immunosorbent assay kits. The proliferation and apoptosis factors of islet cells were determined by immunohistochemistry (IHC) and immunofluorescence (IF) staining. Then, GLP-1, GLP-1R, prohormone convertase 1/3 (PC1/3), PC2, v-maf musculoaponeurotic fibrosarcoma oncogene homologue A (MafA), and pancreatic and duodenal homeobox 1 (PDX1) were detected by Western blot, IHC, IF, and real-time quantitative polymerase chain reaction, respectively. HRD reduced the weight and blood glucose of the db/db mice, and improved insulin sensitivity at the same time (P<0.05 or P<0.01). HRD also promoted mice to secrete more insulin and less glucagon (P<0.05 or P<0.01). Moreover, it also increased the number of islet β cell and decreased islet α cell mass (P<0.01). After HRD treatment, the levels of GLP-1, GLP-1R, PC1/3, PC2, MafA, and PDX1 in the pancreas and intestine significantly increased (P<0.05 or P<0.01). HRD can maintain the normal function and identity of islet β cell, and the underlying mechanism is related to promoting the paracrine and endocrine activation of GLP-1 in pancreas and intestine.

Mechano-regulation of GLP-1 production by Piezo1 in intestinal L cells.

Glucagon-like peptide 1 (GLP-1) is a gut-derived hormone secreted by intestinal L cells and vital for postprandial glycemic control. As open-type enteroendocrine cells, whether L cells can sense mechanical stimuli caused by chyme and thus regulate GLP-1 synthesis and secretion is unexplored. Molecular biology techniques revealed the expression of Piezo1 in intestinal L cells. Its level varied in different energy status and correlates with blood glucose and GLP-1 levels. Mice with L cell-specific loss of Piezo1 (Piezo1 IntL-CKO) exhibited impaired glucose tolerance, increased body weight, reduced GLP-1 production and decreased CaMKKβ/CaMKIV-mTORC1 signaling pathway under normal chow diet or high-fat diet. Activation of the intestinal Piezo1 by its agonist Yoda1 or intestinal bead implantation increased the synthesis and secretion of GLP-1, thus alleviated glucose intolerance in diet-induced-diabetic mice. Overexpression of Piezo1, Yoda1 treatment or stretching stimulated GLP-1 production and CaMKKβ/CaMKIV-mTORC1 signaling pathway, which could be abolished by knockdown or blockage of Piezo1 in primary cultured mouse L cells and STC-1 cells. These experimental results suggest a previously unknown regulatory mechanism for GLP-1 production in L cells, which could offer new insights into diabetes treatments.

Mechano-regulation of GLP-1 production by Piezo1 in intestinal L cells

Glucagon-like peptide 1 (GLP-1) is a gut-derived hormone secreted by intestinal L cells and vital for postprandial glycemic control. As open-type enteroendocrine cells, whether L cells can sense mechanical stimuli caused by chyme and thus regulate GLP-1 synthesis and secretion is unexplored. Molecular biology techniques revealed the expression of Piezo1 in intestinal L cells. Its level varied in different energy status and correlates with blood glucose and GLP-1 levels. Mice with L cell-specific loss of Piezo1 (Piezo1 IntL-CKO) exhibited impaired glucose tolerance, increased body weight, reduced GLP-1 production and decreased CaMKKβ/CaMKIV-mTORC1 signaling pathway under normal chow diet or high-fat diet. Activation of the intestinal Piezo1 by its agonist Yoda1 or intestinal bead implantation increased the synthesis and secretion of GLP-1, thus alleviated glucose intolerance in diet-induced-diabetic mice. Overexpression of Piezo1, Yoda1 treatment or stretching stimulated GLP-1 production and CaMKKβ/CaMKIV-mTORC1 signaling pathway, which could be abolished by knockdown or blockage of Piezo1 in primary cultured mouse L cells and STC-1 cells. These experimental results suggest a previously unknown regulatory mechanism for GLP-1 production in L cells, which could offer new insights into diabetes treatments.

Postprandial Effects of Four Test Meals Containing Wholegrain Rye or Refined Wheat Foods on Circulating Incretins, Ghrelin, Glucose, and Inflammatory Markers

BackgroundHigh intake of whole grains has consistently been associated with reduced risk of obesity, coronary artery disease, and type 2 diabetes. Dietary interventions have shown beneficial metabolic effects of whole grains, but the metabolic response varies with different types of cereals. ObjectivesWe evaluate the metabolic effects of substituting refined wheat with wholegrain rye foods within a complex diet, examining the day-long postprandial response of glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1), ghrelin, glucose, and inflammatory biomarkers in individuals with overweight and obesity. MethodsTwenty-nine healthy adults with body mass index of 32 ± 9 kg/m2 were randomly assigned to 3 intervention days, separated by 1-wk washout. Participants adhered to a hypocaloric diet rich in wholegrain rye for 1 intervention and refined wheat for the second intervention and were randomly assigned to either diet for the third intervention with continuous blood sampling. ResultsNo differences in GIP, GLP-1, or ghrelin levels were found between the diets when measured throughout the whole intervention day. GIP total area under the curve after the rye-based lunch was 31% (P < 0.05) lower compared with the wheat-based lunch, and ghrelin concentrations were 29% (P < 0.05) lower after the rye-based dinner. Baseline Homeostatic Model Assessment for Insulin Resistance-adjusted model showed 61% (P = 0.015) lower whole-day GLP-1 and 40% (P = 0.03) lower GIP after the rye-based diet. Day-long glucose incremental area under the curve was 30% (P < 0.001) lower after the rye-based diet, and glycemic variability was measured as SD reduced (−0.13 mmol/L, P = 0.04). The rye-based diet compared with refined wheat induced higher glycoprotein N-acetylation A, as measured by z-scores (0.36, P = 0.014). ConclusionsOverall, no day-long differences in gut hormone levels were observed, but the wholegrain rye-based compared with refined wheat-based dinner showed lower postprandial ghrelin concentrations. The rye-based diet improved day-long glycemic control in individuals with overweight and obesity. Observations of diet-induced inflammation after whole-grain rye intake warrant further investigation. Trial registration numberThis study was registered at Clinical Trials Registry of clinicaltrials.gov (NCT05004584): https://clinicaltrials.gov/study/NCT05004584?locStr=Gothenburg,%20Sweden&country=Sweden&state=V%C3%A4stra%20G%C3%B6taland%20County&city=Gothenburg&distance=50&term=appetite&aggFilters=status:com&rank=1.

A Specific Collagen Hydrolysate Improves Postprandial Glucose Tolerance in Normoglycemic and Prediabetic Mice and in a First Proof of Concept Study in Healthy, Normoglycemic and Prediabetic Humans.

In response to nutrients, intestinal L- and K-cells naturally secrete glucagon-like peptide 1 (GLP-1). GLP-1 regulates postprandial blood glucose by increasing insulin secretion, slowing down gastric emptying and inducing satiety. A selection of specifically developed collagen hydrolysates was screened for their ability to enhance natural GLP-1 production invitro. The best performing hydrolysate, H80 (Nextida GC), was orally administered at different doses to lean, normoglycemic mice and overweight, prediabetic mice. Lean mice were acutely challenged 45 min before an oral glucose load. While daily supplemented for 6 weeks, prediabetic mice were acutely challenged at day 21 and 34. Oral glucose tolerance, plasma insulin and GLP-1 levels were assessed, and a gastric emptying assay performed in prediabetic mice. H80 significantly lowered the blood glucose response in lean and prediabetic mice, at a 4 g/kg dose (-25% and -36%, respectively), compared to vehicle. In chronically supplemented, prediabetic mice, acute H80 administration slowed down gastric emptying (-60%) after 21 days and increased plasma insulin (+166%) after 35 days of supplementation. H80 increased plasma active GLP-1 in lean (+217%) and prediabetic (+860%) mice. Overall, the data indicate that the specific collagen hydrolysate, H80, has significant GLP-1-mediated effects on oral glucose tolerance in lean and prediabetic mice. Furthermore, effects on postprandial glucose tolerance were evaluated in a small, human, proof of concept study. H80 reduced the postprandial glucose response at a 5 g dose in healthy, normoglycemic and prediabetic participants. Oral supplementation with H80 might thus be a promising strategy to maintain normal glucose tolerance.

The role of incretins in gestational diabetes: a case-control study on the impact of obesity

BackgroundThis study aimed to evaluate the role of serum Glucagon-Like Peptide-1 (GLP-1), Glucagon-Like Peptide-2 (GLP-2), and Glucose-Dependent Insulinotropic Polypeptide (GIP) levels in relation to obesity and gestational diabetes mellitus (GDM) in pregnancy.MethodsA case-control study was conducted, including 96 pregnant women with singleton pregnancies who underwent the Oral Glucose Tolerance Test (OGTT) for GDM diagnosis during the 24th–28th weeks of gestation. Blood samples were collected for measuring GLP-1, GLP-2, GIP, and fasting glucose. Statistical analyses included receiver operating characteristic (ROC) curves and correlation analysis.ResultsAmong the 96 women, no significant difference in age was observed between the groups, but Body Mass Index (BMI) was significantly higher in GDM-O (Gestational Diabetes Mellitus-Obese) and non-GDM-O groups (p < 0.001). GLP-1 had an area under the curve (AUC) of 0.666 (95% CI: 0.553–0.778, p = 0.005) for diagnosing GDM. The optimal GLP-1 cutoff was 815.86 ng/mL, with 65% sensitivity and 77% specificity. A significant correlation was found between GLP-2 and GIP (r = 0.289, p = 0.004), but no significant correlations were observed between GLP-1 and other peptides or gestational age (p > 0.05).ConclusionsImpaired secretion of GLP-1, GLP-2, and GIP likely contributes to the pathogenesis of GDM. GLP-1 may serve as a potential biomarker for diagnosing GDM.

Medium-chain fatty acid receptor GPR84 deficiency leads to metabolic homeostasis dysfunction in mice fed high-fat diet.

Overconsumption of food, especially dietary fat, leads to metabolic disorders such as obesity and type 2 diabetes. Long-chain fatty acids, such as palmitoleate are recognized as the risk factors for these disorders owing to their high-energy content and lipotoxicity. In contrast, medium-chain fatty acids (MCFAs) metabolic benefits; however, their underlying molecular mechanisms remain unclear. GPR84 is an MCFA receptor, particularly for C10:0. Although evidence from invitro experiments and oral administration of C10:0 in mice suggests that GPR84 is related to the metabolic benefits of MCFAs via glucose metabolism, its precise roles invivo remain unclear. Therefore, the present study investigated whether GPR84 affects glucose metabolism and metabolic function using Gpr84-deficient mice. Although Gpr84-deficient mice were lean and had increased endogenous MCFAs under high-fat diet feeding conditions, they exhibited hyperglycemia and hyperlipidemia along with lower plasma insulin and glucagon-like peptide-1 (GLP-1) levels compared with wild-type mice. Medium-chain triglyceride (C10:0) intake suppressed obesity, and improved plasma glucose and lipid levels, and increased plasma GLP-1 levels in wild-type mice; however, these effects were partially attenuated in Gpr84-deficient mice. Our results indicate that long-term MCFA-mediated GPR84 activation improves the dysfunction of glucose and lipid homeostasis. Our findings may be instrumental for future studies on drug development with GPR84 as a potential target, thereby offering new avenues for the treatment of metabolic disorders like obesity and type 2 diabetes.

Enteropancreatic hormone changes in caloric-restricted diet interventions associate with post-intervention weight maintenance

Background & AimsTo explore enteropancreatic hormone changes during isocaloric-restricted dietary interventions and their impact on post-intervention weight maintenance. Methods253 individuals with overweight / obesity and prediabetes were randomly assigned to 25% isocaloric-restricted diets: Control diet, Traditional Jiangnan diet or Mediterranean diet. Serum hormones and clinical indices were evaluated at 0, 3 and 6 months. Body weight values were collected again 6 months after completing interventions. ResultsWe observed decreased fasting and post-glucose load levels of glucagon, amylin, peptide YY, and glucagon-like peptide-1 (GLP-1) while increased ghrelin at three months after 25% caloric restriction (CR) of three dietary interventions, and most of these changes sustained to six month-treatment. Interestingly, changes in appetite-inhibitory hormones glucagon, amylin and GLP-1 showed positive associations with body weight change while appetite-promoting hormone ghrelin showed inverse association during intervention. Furthermore, subjects with more reduction in amylin and GLP-1, or more increase in ghrelin during intervention showed greater increase in body weight after completing intervention. ConclusionsCR intervention results in consistent hormone signatures regardless of dietary patterns. More changes in amylin, GLP-1 or ghrelin levels during CR is associated with poor weight maintenance after intervention, supporting that CR-induced hormone changes as biomarkers for predicting weight maintenance after intervention. Trial registrationClinicaltrials.gov NCT03856762

Fam3a-mediated prohormone convertase switch in α-cells regulates pancreatic GLP-1 production in an Nr4a2-Foxa2-dependent manner

BackgroundFam3a has been demonstrated to regulate pancreatic β-cell function and glucose homeostasis. However, the role and mechanism of Fam3a in regulating α-cell function remain unexplored. MethodsGlucagon and glucagon-like peptide-1 (GLP-1) levels in pancreas and plasma were measured in global Fam3a knockout (Fam3a−/−) mice. Human islet single-cell RNA sequencing (scRNA-seq) datasets were utilized to analyze gene expression correlations between FAM3A and PCSK1 (encoding PC1/3, which processes proglucagon into GLP-1). Mouse pancreatic α-cell line αTC1.9 cells were transfected with Fam3a siRNA or plasmid for Fam3a knockdown or overexpression to explore the effects of Fam3a on PC1/3 expression and GLP-1 production. The downstream mediator (including Nr4a2) was identified by transcriptomic analysis, and its role was confirmed by Fam3a knockdown or overexpression in αTC1.9 cells. Based on the interacted protein of Nr4a2 and the direct binding to Pcsk1 promoter, the transcription factor Foxa2 was selected for further verification. Nuclear translocation assay and dual-luciferase reporter assay were used to clarify the involvement of Fam3a-Nr4a2-Foxa2 pathway in PC1/3 expression and GLP-1 production. Moreover, α-cell-specific Fam3a knockout (Fam3aα−/−) mice were constructed to evaluate the metabolic variables and hormone levels under normoglycemic, high-fat diet (HFD)-fed and streptozotocin (STZ)-induced diabetic conditions. Exendin 9–39 (Ex9), a GLP-1 receptor antagonist, was used to investigate GLP-1 paracrine effects in Fam3aα−/− mice and in their primary islets. ResultsCompared with wild-type mice, pancreatic and plasma active GLP-1 levels were increased in Fam3a−/− mice. Analysis of human islet scRNA-seq datasets showed a significant negative correction between FAM3A and PCSK1 in α-cells. Fam3a knockdown upregulated PC1/3 expression and GLP-1 production in αTC1.9 cells, while Fam3a overexpression displayed inverse effects. Transcriptomic analysis identified Nr4a2 as a key downstream mediator of Fam3a, and Nr4a2 expression in αTC1.9 cells was downregulated and upregulated by Fam3a knockdown and overexpression, respectively. Nr4a2 silencing increased PC1/3 expression, albeit Nr4a2 did not directly bind to Pcsk1 promoter. Instead, Nr4a2 formed a complex with Foxa2 to facilitate Fam3a-mediated Foxa2 nuclear translocation. Foxa2 negatively regulated PC1/3 expression and GLP-1 production. Besides, Foxa2 inhibited the transcriptional activity of Pcsk1 promoter at specific binding sites 10 and 6, and this inhibition was intensified by Nr4a2 in αTC1.9 cells. Compared with Flox/cre littermates, improved glucose tolerance, increased active GLP-1 level in pancreas and plasma, upregulated plasma insulin level in response to glucose, and decreased plasma glucagon level were observed in Fam3aα−/− mice. Primary islets isolated from Fam3aα−/− mice also showed an increase in active GLP-1 and insulin release. In addition, the insulinotropic effect of intra-islet GLP-1 was blocked by Ex9 in Fam3aα−/− mice and in their primary islets. Similarly, HFD-fed Fam3aα−/− mice also exhibited an improved glucose tolerance. Both HFD-fed and STZ-induced diabetic Fam3aα−/− mice showed an increased pancreatic active GLP-1 level, an elevated plasma insulin level and a reduced plasma glucagon level. ConclusionsFam3a deficiency in α-cells enhances pancreatic GLP-1 production to improve β-cell function via paracrine signaling in an Nr4a2-Foxa2-PC1/3-dependent manner. Our study unveils a novel strategy for reprogramming α-cell proglucagon processing output from glucagon to GLP-1 and deepen the understanding of crosstalk between α-cells and β-cells.

Semaglutide treatment for PRevention Of Toxicity in high-dosE Chemotherapy with autologous haematopoietic stem-cell Transplantation (PROTECT): study protocol for a randomised, double-blind, placebo-controlled, investigator-initiated study

IntroductionCancer treatment with high-dose chemotherapy damages the mucosal barrier of the gastrointestinal (GI) tract and is associated with severe toxicity involving mucositis, severe inflammation and organ dysfunction. Currently, there is...

Expression of Glucagon-Like Peptide-1 Receptors in the Submandibular Gland of Mice and Its Implications in Type 2 Diabetes.

Introduction Type 2 diabetes mellitus (T2DM) not only affects the pancreas directly involved in glucose metabolism but also impairs salivary gland function. Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone that lowers postprandial blood glucose levels by stimulating insulin secretion from the pancreas. Previous studies have revealed the presence of GLP-1 receptors (GLP-1R) in salivary glands. However, the effect of diabetes on salivary gland GLP-1R remains unclear. This study aimed to observe the impact of T2DM on GLP-1R in the submandibular gland (SMG). Materials and methods Twenty-five-week-old mice were randomly divided into four groups (n=5 each): 11w and 13w control groups (CON), and 11w and 13wdiabetes mellitusgroups (DM). After a five-day adaptation period, the DM group mice were subjected to a high-fat diet, while the CON group received a standard diet. The DM group mice were then induced into a state of T2DM by a single low-dose streptozotocin injection at nine weeks of age. Oral glucose tolerance tests (OGTT) were conducted to evaluate mouse glucose tolerance. At 11 and 13 weeks of age, SMG was excised under general anesthesia, and the morphology of SMG was evaluated by hematoxylin-eosin staining, while the distribution and expression of GLP-1R were assessed by immunohistochemical staining. The data obtained were subjected to the Shapiro-Wilk test to confirm normal distribution, the t-test for the OGTTresults, and statistical analysis for other results by one-way analysis of variance. Results Consistent with previous reports, the mice in the DM group showed higher body weight and lower glucose tolerance.Histological analysis revealed an increase in the acinar area and a decrease in the ductal area of the SMG in the DM group. Although there was no significant decrease in the cell count regarding the ductal area, a tendency towardluminal dilation was observed. Interestingly, the expression pattern of GLP-1R was limited to the ductal portion of the SMG, with a decrease in anti-GLP-1R-positive areas observed in the DM group compared to the CON group.While there was no significant difference in anti-GLP-1R-positive areas between the CON11w and CON13w groups, the DM13w group exhibited a significant decrease compared to the DM11w group. These data suggest that diabetes induces both structural changes in the SMG and a reduction in GLP-1R expression, particularly in the ductal regions. Conclusions We found that the expression level of GLP-1R in SMG was decreased in the DM group mice. This data demonstrates the potential relationship between T2DM and GLP-1R expression. Moreover, there was an indication of a temporal decrease in anti-GLP-1R positive areas over time.Thisresult may suggest the involvement of salivary gland GLP-1R in the mechanism of impaired SMG function caused by T2DM, potentially mediated through the decrease in blood GLP-1 levels.

Fibroblast growth factor 21 improves insulin sensitivity by modulating the bile acid-gut microbiota axis in type Ⅱ diabetic mice

BackgroundFibroblast growth factor 21 (FGF21) is an important regulator of glycolipid metabolism. However, whether the gut microbiota is related to the anti-diabetic and obesity effects of FGF21 remains unclear. MethodsOur research used KO/KO db/db male mice and streptozotocin (STZ)-induced to simulate the construction of two type II diabetic mellitus (T2DM) models, and detected impaired glucose tolerance in the model by using the ipGTT and ITT assays, and collected feces from the model mice for sequencing of the intestinal flora and the content of short-chain fatty acids. H＆E staining was used to detect changes in intestinal tissue, the serum levels of LPS and GLP-1 were detected by ELISA. ResultsIn this study, we found that FGF21 significantly improved insulin sensitivity, attenuated intestinal lesions, and decreased serum lipopolysaccharide (LPS) concentrations in T2DM mice. Moreover, FGF21 reshaped the gut microbiota and altered their metabolic pathways in T2DM mice, promoting the production of short-chain fatty acids (SCFAs) and the secretion of glucagon-like peptide 1 (GLP-1). Fecal transplantation experiments further confirmed that feces from FGF21-treated diabetic mice demonstrated similar effects as FGF21 in terms of anti-diabetic activity and regulation of gut microbiota dysbiosis. Additionally, the antibiotic depletion of gut microbiota abolished the beneficial effects of FGF21, including increased GLP-1 secretion and fecal SCFA concentration. Additionally, the FGF21 effects of ameliorating intestinal damage and suppressing plasma LPS secretion were suppressed. All these findings suggest that FGF21 prevents intestinal lesions by modifying the gut microbiota composition. Furthermore, FGF21 affected bile acid synthesis by inhibiting CYP7A1, the key enzyme of bile acid synthesis. ConclussionTherefore, FGF21 enriched beneficial bacteria by preventing bile acid synthesis and stimulating the secretion of the intestinal hormone GLP-1 via the increased production of gut microbiota metabolites, thereby exerting its anti-diabetic effects.

Imeglimin enhances glucagon secretion through an indirect mechanism and improves fatty liver in high-fat, high-sucrose diet-fed mice.

Imeglimin is a recently approved oral antidiabetic agent that improves insulin resistance, and promotes insulin secretion from pancreatic β-cells. Here, we investigated the effects of imeglimin on glucagon secretion from pancreatic α-cells. Experiments were carried out in high-fat, high-sucrose diet-fed mice. The effects of imeglimin were examined using insulin and glucose tolerance tests, glucose clamp studies, and measurements of glucagon secretion from isolated islets. Glucagon was measured using both the standard and the sequential protocol of Mercodia sandwich enzyme-linked immunosorbent assay; the latter eliminates cross-reactivities with other proglucagon-derived peptides. Plasma glucagon, insulin and glucagon-like peptide-1 levels were increased by imeglimin administration in high-fat, high-sucrose diet-fed mice. Glucose clamp experiments showed that the glucagon increase was not caused by reduced blood glucose levels. After both single and long-term administration of imeglimin, glucagon secretions were significantly enhanced during glucose tolerance tests. Milder enhancement was observed when using the sequential protocol. Long-term administration of imeglimin did not alter α-cell mass. Intraperitoneal imeglimin administration did not affect glucagon secretion, despite significantly decreased blood glucose levels. Imeglimin did not enhance glucagon secretion from isolated islets. Imeglimin administration improved fatty liver by suppressing de novo lipogenesis through decreasing sterol regulatory element binding protein-1c and carbohydrate response element binding protein and their target genes, while enhancing fatty acid oxidation through increasing carnitine palmitoyltransferase I. Overall, the present results showed that imeglimin enhances glucagon secretion through an indirect mechanism. Our findings also showed that glucagon secretion promoted by imeglimin could contribute to improvement of fatty liver through suppressing de novo lipogenesis and enhancing fatty acid oxidation.