Glucagon-like Peptide-1 Secretion Research Articles

Intestinal distension induced by luminal D-allulose promotes GLP-1 secretion in male rats.

The secretion of glucagon-like peptide-1 (GLP-1) is promoted by various nutrients, and glucose and fructose stimulate GLP-1 secretion via intracellular metabolism. D-Allulose (allulose), a non-metabolizable epimer of D-fructose, is also effective in stimulating GLP-1 secretion, although its underlying mechanism remains unclear. We previously observed intestinal distension after the oral administration of allulose, accompanied by increased GLP-1 secretion in rats, possibly because of the low or slow absorbability of allulose. In this study, we sought to determine whether intestinal distension caused by allulose and other factors gives rise to GLP-1 secretion in rats. We found that the oral co-administration of carbonated water enhanced allulose-induced GLP-1 secretion. Polyethylene glycol 1000 and D-mannitol, which are water-soluble and poorly absorbable, stimulated GLP-1 secretion. However, cellulose (insoluble), and tetra ethylene glycol (water-soluble and absorbable) did not. The secretion of GLP-1 increased as the absolute amount of allulose increased, independent of the concentration. The extent of the GLP-1 secretory response was positively correlated with the intestinal content volume and diameter after allulose administration. Furthermore, the intra-ileal administration of air expanded the intestine-induced secretion of GLP-1. Our results demonstrate that allulose promotes GLP-1 secretion, at least in part, via intestinal distension as a novel GLP-1 secretory mechanism. Physical stimulation may also contribute to the postprandial GLP-1 secretion.

Chemerin loss-of-function attenuates glucagon-like peptide-1 secretion in exercised obese mice.

To investigate the role of chemerin reduction in mediating exercise-induced Glucagon-like peptide-1 (GLP-1) secretion and the amelioration of pancreatic β-cell function in obesity. Obesity models were established using wild-type and chemerin systemic knockout mice, followed by 8 weeks of moderate-intensity continuous aerobic exercise training. Serum chemerin levels, GLP-1 synthesis, glucose tolerance, pancreatic β-cell function, structure, and apoptosis were assessed. In vitro experiments were conducted on STC-1 cells, derived from murine intestinal endocrine cells, to evaluate GLP-1 secretion following exogenous chemerin treatment. Additionally, colonic tissue inflammation and apoptosis were analyzed using qPCR and TUNEL staining. In obese wild-type mice, moderate-intensity aerobic exercise significantly reduced serum chemerin levels, enhanced GLP-1 secretion, and improved glucose tolerance, pancreatic β-cell structure, function, and apoptosis. These effects were absent in obese chemerin knockout mice. Exogenous chemerin treatment reduced GLP-1 secretion in STC-1 cells. Furthermore, the beneficial effects of exercise on colonic inflammation and apoptosis observed in wild-type mice were abolished in chemerin knockout mice. Reduction of chemerin is crucial for the beneficial effects of aerobic exercise on GLP-1 secretion and pancreatic β-cell function in obesity. The mechanisms behind these effects may involve improvements in colonic inflammation and apoptosis. These findings offer new insights into the molecular mechanisms through which exercise improves obesity-related metabolic dysfunction.

Dose-related effects of calcium to enhance the effects of L-tryptophan on gut hormones and energy intake in obesity.

In males of normal weight, intraduodenal administration of calcium enhances the effects of the amino acid, L-tryptophan (Trp), to suppress energy intake, associated with greater stimulation of cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1) and peptide tyrosine-tyrosine (PYY) secretion (key mechanisms underlying the regulation of pyloric motility and gastric emptying), but not gastrin or glucose-dependent insulinotropic polypeptide (GIP). Given the implications for the management of obesity, the current study evaluated the effects of calcium, when administered alone and in combination with Trp, on gut hormone secretion, antropyloroduodenal motility and energy intake in males with obesity. Fifteen males with obesity and without type 2 diabetes (mean±SD; age: 27±8 years; body mass index: 30±2 kg/m2; HbA1c: 5.3±0.2%), received 150-min intraduodenal infusions of 0, 500 or 1000 mg calcium, each combined with Trp (load: 0.1 kcal/min, known to have submaximal energy intake-suppressant effects) from t=75-150 min, on three separate occasions, in a randomized, double-blind, cross-over order. Plasma concentrations of gastrin, CCK, GIP, GLP-1, PYY, and pyloric pressures were measured during the infusions. Immediately post-infusion (t=150-180 min), energy intake at a standardized buffet-style lunch was quantified. Calcium, in a dose of 1000 mg, stimulated GLP-1, PYY and pyloric pressures alone (all P<0.05), and enhanced the effects of Trp to stimulate CCK, GLP-1 and PYY (all P<0.05), associated with greater suppression of energy intake (P=0.01). Energy intake (R=-0.64; P=0.001) was inversely related to the dose of calcium, while plasma concentrations of CCK (R=0.44; P=0.05), GLP-1 (R=0.60; P=0.01) and PYY (R=0.83; P=0.01) were directly related. Intraduodenal calcium enhances the effect of intraduodenal Trp to stimulate CCK, GLP-1 and PYY, and suppress energy intake, in males with obesity.

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.

G Protein-Coupled Receptor 17 Inhibits Glucagon-like Peptide-1 Secretion via a Gi/o-Dependent Mechanism in Enteroendocrine Cells

Gut peptides, including glucagon-like peptide-1 (GLP-1), regulate metabolic homeostasis and have emerged as the basis for multiple state-of-the-art diabetes and obesity therapies. We previously showed that G protein-coupled receptor 17 (GPR17) is expressed in intestinal enteroendocrine cells (EECs) and modulates nutrient-induced GLP-1 secretion. However, the GPR17-mediated molecular signaling pathways in EECs have yet to be fully deciphered. Here, we expressed the human GPR17 long isoform (hGPR17L) in GLUTag cells, a murine EEC line, and we used the GPR17 synthetic agonist MDL29,951 together with pharmacological probes and genetic approaches to quantitatively assess the contribution of GPR17 signaling to GLP-1 secretion. Constitutive hGPR17L activity inhibited GLP-1 secretion, and MDL29,951 treatment further inhibited this secretion, which was attenuated by treatment with the GPR17 antagonist HAMI3379. MDL29,951 promoted both Gi/o and Gq protein coupling to mediate cyclic AMP (cAMP) and calcium signaling. hGPR17L regulation of GLP-1 secretion appeared to be Gq-independent and dependent upon Gi/o signaling, but was not correlated with MDL29,951-induced whole-cell cAMP signaling. Our studies revealed key signaling mechanisms underlying the role of GPR17 in regulating GLP-1 secretion and suggest future opportunities for pharmacologically targeting GPR17 with inverse agonists to maximize GLP-1 secretion.

Intestinal butyric acid-mediated disruption of gut hormone secretion and lipid metabolism in vasopressin receptor-deficient mice.

Arginine vasopressin (AVP), known as an antidiuretic hormone, is also crucial in metabolic homeostasis. Although AVP receptor-deficient mice exhibit various abnormalities in glucose and lipid metabolism, the mechanism underlying these symptoms remains unclear. This study aimed to explore the involvement of the gut hormones including glucagon-like peptide-1 (GLP-1) and microbiota as essential mediators. We used the mouse GLP-1-secreting cell line, GLUTag, and performed live cell imaging to examine the contribution of V1a and V1b vasopressin receptors (V1aR and V1bR, respectively) to GLP-1 secretion. We next investigated the hormone dynamics of V1aR-deficient mice (V1aR-/- mice), V1bR-deficient mice (V1bR-/- mice), and V1aR/V1bR-double deficient mice (V1aR-/-V1bR-/-mice). AVP induced the increase in intracellular Ca2+ levels and GLP-1 secretion from GLUTag cells in a V1aR and V1bR-dependent manner. AVP receptor-deficient mice, particularly V1aR-/-V1bR-/- mice, demonstrated impaired secretion of GLP-1 and peptide YY secreted by enteroendocrine L cells. V1aR-/-V1bR-/-mice also exhibited abnormal lipid accumulation in the brown adipose tissue and skeletal muscle. We discovered that V1aR-/-V1bR-/- mice showed increased Paneth cell-related gene expression in the small intestine, which was attributed to increased fecal butyric acid levels. Exposure to butyric acid reduced GLP-1 secretion in L cell line. Additionally, human Paneth cell-related gene expressions negatively correlated with that of V1 receptor genes. The deficiency in V1 receptor genes may increase gut butyric acid levels and impair the function of L cells, thus dysregulating lipid homeostasis in the brown adipose tissue and skeletal muscle. This study highlights the importance of appropriate control of the gut microbiota and its metabolites, including butyric acid, for the optimum functioning of enteroendocrine cells.

Targeting the Gut Microbiota for Prevention and Management of Type 2 Diabetes.

Type 2 diabetes (T2D) is a chronic metabolic disorder with a heterogeneous etiology encompassing societal and behavioral risk factors in addition to genetic and environmental susceptibility. The cardiovascular consequences of diabetes account for more than two-thirds of mortality among people with T2D. Not only does T2D shorten life expectancy, but it also lowers quality of life and is associated with extremely high health expenditures since diabetic complications raise both direct and indirect healthcare costs. An increasing body of research indicates a connection between T2D and gut microbial traits, as numerous alterations in the intestinal microorganisms have been noted in pre-diabetic and diabetic individuals. These include pro-inflammatory bacterial patterns, increased intestinal permeability, endotoxemia, and hyperglycemia-favoring conditions, such as the alteration of glucagon-like peptide-1 (GLP-1) secretion. Restoring microbial homeostasis can be very beneficial for preventing and co-treating T2D and improving antidiabetic therapy outcomes. This review summarizes the characteristics of a "diabetic" microbiota and the metabolites produced by microbial species that can worsen or ameliorate T2D risk and progression, suggesting gut microbiota-targeted strategies to restore eubiosis and regulate blood glucose. Nutritional supplementation, diet, and physical exercise are known to play important roles in T2D, and here their effects on the gut microbiota are discussed, suggesting non-pharmacological approaches that can greatly help in diabetes management and highlighting the importance of tailoring treatments to individual needs.

Increased gallbladder emptying and reduced GLP-1 response in pregnancy with and without gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) has been associated with reduced postprandial glucagon-like peptide 1 (GLP-1) responses. As pregnancy induces changes in gallbladder motility and bile acids stimulate GLP-1 secretion, we investigated postprandial gallbladder emptying and GLP-1 responses in women with GDM. Women with and without GDM underwent two 240-min mixed meal tests; one during third trimester of pregnancy and one 3-6 months postpartum. We evaluated ultrasonography-assessed gallbladder emptying, plasma concentrations of glucometabolic hormones including GLP-1, paracetamol absorption (proxy for gastric emptying) and circulating factors known to affect gallbladder dynamics. Fifteen women with GDM and 15 pregnant women with normal glucose tolerance (NGT) (baseline median age 31 (interquartile range 29;33) versus 32 (28;33) years, body mass index (BMI) 27.2 (24.7;30.7) versus 28.4 (26.2;31.0) kg/m2, HbA1c 30 (29;32) versus 30 (28;31) mmol/mol) were included. No differences in postprandial gallbladder emptying or GLP-1 responses were observed between women with and without GDM, neither during pregnancy nor postpartum. Pregnancy increased fasting gallbladder volumes by 69 (30;122)% and 103 (59;156)% and postprandial gallbladder emptying by 77 (28;236)% and 99 (37;190)% compared with postpartum in women with and without GDM, respectively. Postprandial GLP-1 responses were reduced by 60 (3;82)% and 81 (11;90)% during pregnancy compared with postpartum in women with and without GDM, respectively. Pregnancy-induced changes in gallbladder motility seem to play no or a limited role in previously reported GDM-associated reduced postprandial GLP-1 responses as gallbladder emptying was greater and postprandial GLP-1 response was lower in pregnancy than postpartum regardless of GDM status.

G protein-coupled receptor 17 inhibits glucagon-like peptide-1 secretion via a Gi/o-dependent mechanism in enteroendocrine cells.

Gut peptides, including glucagon-like peptide-1 (GLP-1), regulate metabolic homeostasis and have emerged as the basis for multiple state-of-the-art diabetes and obesity therapies. We previously showed that G protein-coupled receptor 17 (GPR17) is expressed in intestinal enteroendocrine cells (EECs) and modulates nutrient-induced GLP-1 secretion. However, the GPR17-mediated molecular signaling pathways in EECs have yet to be fully deciphered. Here, we expressed the human GPR17 long isoform (hGPR17L) in GLUTag cells, a murine EEC line, and we used the GPR17 synthetic agonist MDL29,951 together with pharmacological probes and genetic approaches to quantitatively assess the contribution of GPR17 signaling to GLP-1 secretion. Constitutive hGPR17L activity inhibited GLP-1 secretion, and MDL29,951 treatment further inhibited this secretion, which was attenuated by treatment with the GPR17 antagonist HAMI3379. MDL29,951 promoted both Gi/o and Gq protein coupling to mediate cyclic AMP (cAMP) and calcium signaling. hGPR17L regulation of GLP-1 secretion was Gq-independent and dependent upon Gi/o signaling, but was not correlated with MDL29,951-induced whole-cell cAMP signaling. Our studies revealed key signaling mechanisms underlying the role of GPR17 in regulating GLP-1 secretion and suggest future opportunities for pharmacologically targeting GPR17 with inverse agonists to maximize GLP-1 secretion.

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.

Symbiotic probiotic communities with multiple targets successfully combat obesity in high-fat-diet-fed mice

ABSTRACT Probiotics hold great potential for treating metabolic diseases such as obesity. Given the complex and multifactorial nature of these diseases, research on probiotic combination with multiple targets has become popular. Here, we choose four obesity-related targets to perform high-throughput screening, including pancreatic lipase activity, bile salt hydrolase activity, glucagon-like peptide-1 secretion and adipocyte differentiation. Then, we obtained 649 multi-strain combinations with the requirement that each must cover all these targets in principle. After in vitro co-culture and in vivo co-colonization experiments, only four (<0.7%) combinations were selected as symbiotic probiotic communities (SPCs). Next, genome-scale metabolic model analysis revealed that these SPCs showed lower metabolic resource overlap and higher metabolic interaction potential involving amino acid metabolism (Ammonium, L−Lysine, etc.) and energy metabolism (Phosphate, etc.). Further animal experiments demonstrated that all SPCs exhibited a good safety profile and excellent effects in improving obesity and associated glucose metabolism disruptions and depression-like behaviors in high-fat-diet-fed mice. This anti-obesity improvement was achieved through reduced cholesterol level, fat accumulation and inhibited adipocyte differentiation. Taken together, our study provides a new perspective for designing multi-strain combinations, which may facilitate greater therapeutic effect on obesity and other complex diseases in the future.

Amelioration of Type 2 Diabetes Mellitus Using Rapeseed (Brassica napus)-Derived Peptides through Stimulating Calcium-Sensing Receptor: Effects on Glucagon-Like Peptide-1 Secretion and Hepatic Lipid Metabolism.

The potential of rapeseed-derived peptides (RDPs) in the amelioration of type 2 diabetes mellitus (T2DM) has been hypothesized. However, the mechanisms of the intestinal endocrine hormones activated by RDPs have not been fully understood. This study aimed to explore the amelioration of T2DM and associated hepatic lipid metabolism disorders using RDPs by affecting glucagon-like peptide-1 (GLP-1) secretion. Eight RDPs were prepared by different stepwise enzymatic hydrolysis, wherein RCPP-3 (sequential using alcalase/flavourzyme) and RNPP-1 (sequential using alcalase/trypsin) maintained the normal blood glucose level, significantly increased the body weight (27.17 ± 0.19%) in T2DM mice compared to the positive group (p < 0.05). Western blotting and immunofluorescence experiments indicated that RCPP-3 and RNPP-1 regulated the intestinal endocrine hormones GLP-1 secretion through the calcium-sensing receptor (CaSR). Additionally, the PI3K-Akt pathway was significantly activated by GLP-1, leading to marked improvements in hepatic lipid parameters (TC, TG, LDL-c, and HDL-c) and mitigated fat accumulation (p < 0.05). Notably, the stimulating effect of RCPP-3 on GLP-1 was 10.05% ± 0.71% higher than RNPP-1. G2-R3, a fraction separated from RCPP-3, which contained 14 peptides with the best capacity to stimulate GLP-1 secretion, was identified using HPLC-QTOF-MS/MS. This study suggests the potential of RDPs as novel functional food supplements for ameliorating T2DM.

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.

Targeted discovery of pea protein-derived GLP-1-secreting peptides by CaSR activation-based molecular docking and their digestive stability

Dietary proteins could stimulate Glucagon-like peptide 1 (GLP-1) secretion. However, only a few food-derived GLP-1-secreting peptides have been identified. Herein, three GLP-1-secreting peptides were identified from pea protein hydrolysate (PPH) by calcium-sensing receptor (CaSR) activation-based molecular docking. PPH-triggered GLP-1 secretion was mediated by CaSR activation. A total of 4221 peptides were sequenced from PPH through peptidomic analysis. Subsequently, three GLP-1-secreting peptides, including RFY, FEPF, and FLFK, were screened by CaSR activation-based molecular docking, and peptide-induced GLP-1 secretion were mediated by CaSR activation. More importantly, FEPF and FLFK exhibited good digestive stability. The molecular docking suggested that binding energy between peptides and CaSR was negatively correlated with their ability to stimulate GLP-1 secretion, and some binding sites in CaSR, such as Asn102 and Tyr218, play a crucial role in stimulating GLP-1 secretion. Our findings suggest that the targeted discovery of pea protein-derived GLP-1-secreting peptides through CaSR activation-based molecular docking is an effective strategy.

Anekomochi glutinous rice provides low postprandial glycemic response by enhanced insulin action via GLP-1 release and vagal afferents activation

Glutinous rice (mochi rice), compared to non-glutinous rice (uruchi rice), exhibits a wide range of glycemic index (GI) values, from low to high. However, the underlying mechanisms behind the variation in GI values remain poorly understood. In this study, we aimed to identify rice cultivars with a low postprandial glycemic response and investigate the mechanisms, focusing on insulin and incretin hormones. We examined seven glutinous rice cultivars and three non-glutinous rice cultivars. We discovered that Anekomochi, a glutinous rice cultivar, has the lowest postprandial glycemic response. Anekomochi significantly enhanced glucagon-like peptide-1 (GLP-1) secretion while suppressing insulin secretion. These effects were completely blunted by inhibiting GLP-1 receptor signaling and denervating the common hepatic branch of vagal afferent nerves that are crucial for sensing intestinal GLP-1. Our findings demonstrate that Anekomochi markedly enhances insulin action via GLP-1 release and vagal afferent neural pathways, thereby leading to a lower postprandial glycemic response.

Lipopolysaccharide accelerates peristalsis by stimulating glucagon-like peptide-1 release from L cells in the rat proximal colon.

Upon epithelial barrier dysfunction, lipopolysaccharide (LPS) stimulates glucagon-like peptide-1 (GLP-1) secretion from enteroendocrine L cells by activating Toll-like receptor 4 (TLR4). Because GLP-1 accelerates peristalsis in the proximal colon, the present study aimed to explore whether LPS facilitates colonic peristalsis by stimulating L cell-derived GLP-1 release. In isolated segments of rat proximal colon that were serosally perfused with physiological salt solution and luminally perfused with 0.9% saline, peristaltic wall motion was video recorded and converted into spatio-temporal maps. Fluorescence immunohistochemistry was also carried out. Intraluminal administration of LPS (100 or 1µgmL-1 but not 100ngmL-1) increased the frequency of oro-aboral propagating peristaltic contractions. The LPS-induced acceleration of colonic peristalsis was blocked by TAK-242 (the TLR4 antagonist), exendin-3 (the GLP-1 receptor antagonist) or BIBN4096 (the calcitonin gene-related peptide receptor antagonist). GLP-1-positive epithelial cells co-expressed TLR4 immunoreactivity. In aspirin-pretreated preparations where epithelial barrier function had been impaired, a lower dose of LPS (100ngmL-1) became capable of accelerating peristalsis. By contrast, luminally applied dimethyl sulphoxide, a reactive oxygen species scavenger that protects epithelial integrity, attenuated the prokinetic effects of a higher dose of LPS (100µgmL-1). In colonic segments of a stress rat model leading to a leaky gut, LPS induced more pronounced prokinetic effects. Colonic L cells may well sense luminal LPS via TLR4 triggering the release of GLP-1 that stimulates calcitonin gene-related peptide-containing neurons. The resultant acceleration of peristalsis would facilitate excretion of Gram-negative bacteria from the intestine, and thus L cells may have a protective role against intestinal bacterial infections. KEY POINTS: Colonic epithelial cells form a barrier against bacterial invasion but also may contribute more actively to the exclusion of luminal pathogen by stimulating colonic motility. Luminal lipopolysaccharide (LPS) accelerated colonic peristalsis by stimulating calcitonin gene-related peptide-containing neurons. The prokinetic effect of LPS was mediated by the secretion of glucagon-like peptide-1 from enteroendocrine L cells in which Toll-like receptor 4 was expressed. The LPS-mediated acceleration of peristalsis depended on epithelial barrier integrity. L cells have a defensive role against Gram-negative bacterial infections by facilitating faecal excretion, and could be a potential therapeutic target for gastrointestinal infections.

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.

Metformin Improves Glycemic Control and Postprandial Metabolism and Enhances Postprandial Glucagon-Like Peptide 1 Secretion in Patients With Type 2 Diabetes and Heart Failure: A Randomized, Double-Blind, Placebo-Controlled Trial

This randomized trial tested the effect of metformin on glycemic control and cardiac function in patients with heart failure (HF) and type 2 diabetes while evaluating intestinal effects on selected gut microbiome products reflected by trimethylamine-N-oxide (TMAO) and gut-derived incretins. Metformin treatment improved glycemic control and postprandial metabolism and enhanced postprandial glucagon-like peptide 1 (GLP-1) secretion but did not influence cardiac function or the TMAO levels. Metabolic effects of metformin in HF may be mediated by an improvement in intestinal endocrine function and enhanced secretion of the gut-derived incretin GLP-1.