Promotes Glucagon-like Peptide-1 Secretion Research Articles

Pea protein hydrolysate stimulates GLP-1 secretion in NCI-H716 cells via simultaneously activating the sensing receptors CaSR and PepT1.

Glucagon-like peptide-1 (GLP-1) plays a crucial role in regulating glucose homeostasis by stimulating insulin secretion and suppressing glucagon release. Our previous study observed that pea protein hydrolysate (PPH) exhibited the function of triggering GLP-1 secretion. However, the underlying mechanisms have not been revealed. Herein, the mechanisms of PPH-stimulated GLP-1 secretion were investigated in NCI-H716 cells. The PPH-induced GLP-1 secretion was reduced (p < 0.05) after adding the sensing receptor antagonists NPS-2143 and 4-AMBA, indicating that activation of both calcium-sensing receptor (CaSR) and peptide-transporter 1 (PepT1) was involved in PPH-triggered GLP-1 release. Moreover, the intracellular Ca2+ level increased by 2.01 times during the PPH-induced GLP-1 secretion. Similarly, the cAMP content also increased by 1.43 times after stimulation by PPH. The RT-qPCR results showed that PPH increased the gene expression of prohormone convertase 1/3 (PCSK-1) by 2.79-fold, which effectively promoted the conversion of proglucagon (GCG) to GLP-1. The specific pathway of PPH-induced GLP-1 secretion may involve both CaSR and PepT1 activation-induced Ca2+ influx and cAMP generation, which effectively enhanced the enzyme activity of prohormone convertase 1/3 (PCSK-1) and ultimately promoted GLP-1 secretion.

Curcumin Compensates GLP-1 Deficiency via the Microbiota-Bile Acids Axis and Modulation in Functional Crosstalk between TGR5 and FXR in ob/ob Mice.

Glucagon-like peptide-1 (GLP-1) deficiency occurs in obesity-related pathologies due to defects in the intestinal lumen. And expanding the L-cell population has emerged as a promising avenue to elevate GLP-1 secretion to tackle metabolic disorders. Curcumin (Cur), the principal active component of spice turmeric, possesses well-established anti-obesity properties. To clarify, the study investigates whether Cur promotes GLP-1 secretion built upon the L-cell expansion. Cur (60mgkg-1 ) is administered orally to male ob/ob mice for 8 weeks. Cur ameliorates obesity and impaires glucose tolerance through increasing energy expenditure in ob/ob mice, accompanied by the maintenance of crypt architecture and gut permeability. It refines the microbial structure and bile acid (BA) profiles, resulting in deoxycholic acid (DCA) accumulation by weakening the enrichment of Lactobacillus. Further analyses show radically different properties of Cur on the intestine function of TGR5 and FXR (i.e., activation and repression). Cur amplifies L-cell number to promote GLP-1 secretion in ob/ob mice. The findings suggest that Cur may act as a natural TGR5 agonist and FXR antagonist to improve obesity by enhancing GLP-1 release from L-cell expansion via the gut microbiota-BAs-TGR5/FXR axis, and it may serve as a promising therapeutic agent to compensate obesity-related metabolic disorders.

1656-P: Glucagon-Like peptide-1 (GLP-1) Secretion from Intestinal L-Cells Is Mediated by hERG Potassium Channels

The hERG protein is a member of voltage-gated potassium (Kv) channels. Previous reports showed that patients with long QT syndrome due to mutations in hERG channel had higher responsive glucagon-like peptide-1 (GLP-1) secretion. However, the role of hERG in GLP-1 secretion remains uncertain. Here we report that hERG is co-expressed in GLP-1-expressing L cells in rodent intestinal epithelium (Fig. 1). In a murine L-cell model, GLUTag cell line, downregulation of hERG significantly prolonged action potential duration, increased intracellular calcium concentration ([Ca2+]i), and promoted GLP-1 secretion (Fig. 2) after stimulation of nutrients. These results reveal a direct role of hERG in GLP-1 secretion in murine L-cells, suggesting intestinal hERG is a potential target for the treatment of diabetes. Disclosure J.Yang: None. C.Liu: None. H.Wang: None. Y.Yuan: None. Funding National Natural Science Foundation of China (82170809, 81930019)

Physicochemical property changes of Dendrobium officinale leaf polysaccharide LDOP-A and it promotes GLP-1 secretion in NCI-H716 cells by simulated saliva-gastrointestinal digestion.

A polysaccharide LDOP-A with a molecular weight of 9.9 kDa was isolated and purified from Dendrobium officinale leaves by membrane separation, cellulose column, and dextran gel column. The Smith degradable products, methylation products, and nuclear magnetic resonance analysis showed that LDOP-A may be composed of →4)-Glc-(1→, →3,6)-Man-(1→, and →6)-Glc-(1→sugar residues. In vitro, simulated digestion assays showed that LDOP-A could be partially digested in the stomach and small intestine, and produced a large amount of acetic acid and butyric acid during colonic fermentation. Further cell experiment results illustrated that LDOP-A-I (LDOP-A digested by gastrointestinal tract) could induce glucagon-like peptide-1 (GLP-1) secretion in NCI-H716 cells without showing any cytotoxicity.

Dimeric styrylpyrones with stimulating GLP-1 secretion activities from Alpinia kwangsiensis

Stimulating glucagon-like peptide-1 (GLP-1) secretion is an important approach for the treatment of type 2 diabetes. Chemical investigation of Alpinia kwangsiensis rhizomes produced six dimeric styrylpyrones (1–6), including two new degraded ones (1 and 2). Compounds 1–4 were identified as four pairs of enantiomers and successfully prepared by chiral HPLC separation. These compounds incorporate the distinctive cyclobutane moiety via [2 + 2] cycloaddition, a key step in the biosynthetic pathway. The bioactivities of isolates in stimulating GLP-1 secretion in STC-1 cells were evaluated. Results showed that compounds (+)-1, (+)-2, (−)-2, (−)-4, 5 and 6 significantly increased GLP-1 secretion, and compound (+)-1 exhibited the strongest activity with EC50 value of 6.51 μM. In addition, compounds (+)-2, (−)-4 and 5 promoted GLP-1 secretion by increasing intracellular calcium concentration dependent on the PKA pathway, which could provide a chemical basis for the development of diabetes drugs especially that directly promote GLP-1 secretion.

Identification of a regulatory pathway of L-phenylalanine-induced GLP-1 secretion in the enteroendocrine L cells

Glucagon like peptide-1 (GLP-1) is one of incretin hormone and is secreted when enteroendocrine L cells sense saccharides, amino acids, and fatty acids. Some amino acids have been shown to promote GLP-1 secretion from small intestinal enteroendocrine L cells. However, the molecular mechanisms that L-phenylalanine, a potent trigger of GLP-1 secretion, causes GLP-1 secretion from enteroendocrine L cells has not been elucidated. In this study, we used live-cell imaging to clarify the pathway by which L-phenylalanine activates enteroendocrine L cells. The results showed that L-phenylalanine was sensed by Gq-coupled receptor GPR142 and caused an increase in intracellular Ca2+ concentration. In addition, L-phenylalanine was taken up directly into the cell via Na+-dependent amino acid transporter, causing membrane depolarization and enhancing GLP-1 secretion. In summary, enteroendocrine L cells may regulate blood glucose levels in the body by detecting L-phenylalanine in the lumen and secreting GLP-1 via GPR142 and Na+-dependent amino acid transporters.

(-)-Epicatechin and Anthocyanins Modulate GLP-1 Metabolism: Evidence from C57BL/6JMice and GLUTag Cells.

Generated in intestinal L cells through cleavage of proglucagon (Gcg), glucagon-like peptide 1 (GLP-1) is secreted and rapidly inactivated by dipeptidyl peptidase IV (DPP-IV). GLP-1 regulates insulin secretion and overall glucose homeostasis. The capacity of dietary bioactives to increase GLP-1 circulating levels, and therefore increase insulin secretion and glucose metabolism, has gained significant interest of late. We evaluated the effects of (-)-epicatechin (EC) and different anthocyanins (ACs) and AC metabolites on GLP-1 metabolism in mice and on GLUTag cells. We fed 6-week-old C57BL/6Jmale mice a control diet or a control diet supplemented with either 40mg AC or 20mg EC/kg body weight for 14 weeks (AC) or 15 weeks (EC). Intestinal mRNA levels of Gcg and Dpp-iv were measured. In vitro, GLUTag cells were incubated in the presence or absence of different ACs, the AC metabolite protocatechuic acid (PCA), and EC. GLP-1 secretion and the main pathways involved in its release were assessed. Long-term supplementation with EC or AC increased mouse GLP-1 plasma concentrations (55% and 98%, respectively; P<0.05). In mice, 1) EC and AC increased Gcg mRNA levels in the ileum (91%) and colon (41%), respectively (P<0.05); and 2) AC lowered ileum Dpp-iv mRNA levels (35%), while EC decreased plasma DPP-IV activity (15%; P<0.05). In GLUTag cells, 1) cyanidin, delphinidin, PCA, and EC increased GLP-1 secretion (53%, 33%, 53%, and 68%, respectively; P<0.05); and 2) cyanidin, delphinidin, EC, and PCA increased cyclin adenosine monophosphate levels (25-50%; P<0.05) and activated protein kinase A (PKA; 100%, 50%, 80%, and 86%, respectively; P<0.05). In mice, EC and ACs regulated different steps in GLP-1 regulation, leading to increased plasma GLP-1. Cyanidin, delphinidin, PCA, and EC promoted GLP-1 secretion from GLUTag cells by activating the PKA-dependent pathway. These findings support the beneficial actions of these flavonoids in sustaining intestinal and glucose homeostasis through the modulation of the GLP-1 metabolism.

Flavone Hispidulin Stimulates Glucagon‐Like Peptide‐1 Secretion and Ameliorates Hyperglycemia in Streptozotocin‐Induced Diabetic Mice

Loss of functional β-cell mass is central for the deterioration of glycemic control in diabetes. The incretin hormone glucagon-like peptide-1 (GLP-1) plays a critical role in maintaining glycemic homeostasis via potentiating glucose-stimulated insulin secretion and promoting β-cell mass. Agents that can directly promote GLP-1 secretion, thereby increasing insulin secretion and preserving β-cell mass, hold great potential for the treatment of T2D. GluTag L-cells, INS832/13 cells, and mouse ileum crypts and islets are cultured for examining the effects of flavone hispidulin on GLP-1 and insulin secretion. Mouse livers and isolated hepatocytes are used for gluconeogenesis. Streptozotocin-induced diabetic mice are treated with hispidulin (20 mg kg-1 day-1 , oral gavage) for 6 weeks to evaluate its anti-diabetic potential. Hispidulin stimulates GLP-1 secretion from the L-cell line, ileum crypts, and in vivo. This hispidulin action is mediated via activation of cyclic adenosine monophosphate/protein kinase A signaling. Hispidulin significantly improves glycemic control in diabetic mice, concomitant with improved insulin release, and β-cell survival. Additionally, hispidulin decreases hepatic pyruvate carboxylase expression in diabetic mice and suppresses gluconeogenesis in hepatocytes. Furthermore, hispidulin stimulates insulin secretion from β-cells. These findings suggest that Hispidulin may be a novel dual-action anti-diabetic compound via stimulating GLP-1 secretion and suppressing hepatic glucose production.

Thymoquinone activates imidazoline receptor to enhance glucagon-like peptide-1 secretion in diabetic rats.

Thymoquinone (TQ) is one of the principal bioactive ingredients proven to exhibit anti-diabetic effects. Recently, glucagon-like peptide-1 (GLP-1) has been found to be involved in antidiabetic effects in rats. The aim of this study was to evaluate the mediation of GLP-1 in the antidiabetic effect of TQ and to understand the possible mechanisms. NCI-H716 cells and CHO-K1 cells were used to investigate the effects of TQ on GLP-1 secretion in vitro. In type 1 diabetic rats, the changes in plasma glucose and GLP-1 levels were evaluated with TQ treatment. The direct effect of TQ on imidazoline receptors (I-Rs) was identified in CHO-K1 cells overexpressing I-Rs. Additionally, in the intestinal NCI-H716 cells that may secrete GLP-1, TQ treatment enhanced GLP-1 secretion in a dose-dependent manner. However, these effects of TQ were reduced by ablation of I-Rs with siRNA in NCI-H716 cells. Moreover, these effects were inhibited by BU224, the imidazoline I2 receptor (I-2R) antagonist. In diabetic rats, TQ increased plasma GLP-1 levels, which were inhibited by BU-224 treatment. Functionally, TQ-attenuated hyperglycemia is also evidenced through GLP-1 using pharmacological manipulations. This report demonstrates that TQ may promote GLP-1 secretion through I-R activation to reduce hyperglycemia in type-1 diabetic rats.

1788-P: The Natural Product ZYM01 Exerts Antidiabetic and Islet-Protective Effects in Diabetic Mice and Promotes Glucagon-Like Peptide-1 Secretion

Over the last few years, incretin-based therapies have emerged as important agents in the treatment of type 2 diabetes (T2D). These agents exert their effect via the incretin system, specifically targeting the receptor for the incretin hormone glucagon-like peptide 1 (GLP-1). Two classes of incretin-based therapies are available: GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. However, there are currently no clinical drugs that directly increase endogenous GLP-1 secretion. Although several nutrients induce GLP-1 secretion, there is little evidence to suggest that non-nutritive compounds directly increase GLP-1 secretion. In the present study, we demonstrated that the natural product ZYM01 from the Bougainvillea glabraChoisy (which was used for hypoglycemic by the Dai ethnic group in China) had a good hypoglycemic effect and a significant islet protection function in diabetic mouse model. ZYM01 treatment (50 mg•kg-1 •day-1) decreased plasma levels of glucose, body weight and food intake; ameliorated OGT and plasma lipid profiles; augmented plasma insulin levels; alleviated islets pathological morphology; and reduced liver lipid accumulation in db/db diabetic mouse model. Furthermore, ZYM01 enhanced GLP-1 release in C57BL/6 mice and exerted an acute hypoglycemic effect through the secretion of GLP-1 in vivo since the exendin 9-39, a GLP-1R antagonist could completely block the acute hypoglycemic effect of ZYM01. Also, in cultured STC-1 cells, ZYM01 increased intracellular calcium and promoted GLP-1 secretion in a dose- dependent manner accompanied by elevated levels of phosphorylated Erk signaling. In summary, our study found that ZYM01 exerted the hypoglycaemic and islets protective effects, which were associated with an enhanced release of GLP-1 mediated by the activation of the Erk signaling. These findings firmly identified ZYM01 as a new viable therapeutic option for diabetes control. Disclosure Y. Sun: None. J. Li: None. J. Li: None.

Resistant Protein Promotes Glucagon-like Peptide-1 Secretion by Controlling the Cecal Fermentation in Rats Fed High Amylose Corn Starch

It was examined whether undigested protein, namely resistant protein, affects glucagon-like peptide-1 (GLP-1) secretion in rats fed high amylose corn starch (HACS). Rats were fed one of three experimental diets for 28 d: casein without HACS, casein with HACS or dashigara with HACS. Dashigara is produced from Katsuobushi (smoke-dried skipjack tuna) treated with microbial protease. The apparent digestibilities of casein and dashigara are 96.0% and 84.5%, respectively. The amount of rat cecal butyric acid and propionic acid were as follows: the dashigara with HACS group > the casein with HACS group > the casein without HACS group. The dashigara with HACS group had significantly greater cecal butyric acid and lower cecal succinic acid than the casein with HACS group. The GLP-1 concentration in portal vein blood increased as the amount of butyric acid and propionic acid in the cecal contents increased. Denaturing gradient gel electrophoresis of PCR-amplified 16S rRNA gene fragments showed that the composition of cecal microbiota differed among the three groups. These results suggest that resistant protein contained in dashigara promotes GLP-1 secretion by controlling fermentation efficiency as well as the fermentation profile of HACS through the changes in cecal microbiota in rats fed HACS.

Sodium butyrate reduces high-fat diet-induced non-alcoholic steatohepatitis through upregulation of hepatic GLP-1R expression

Glucagon-like peptide-1 (GLP-1) has a broad spectrum of biological activity by regulating metabolic processes via both the direct activation of the class B family of G protein-coupled receptors and indirect nonreceptor-mediated pathways. GLP-1 receptor (GLP-1R) agonists have significant therapeutic effects on non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) in animal models. However, clinical studies indicated that GLP-1 treatment had little effect on hepatic steatosis in some NAFLD patients, suggesting that GLP-1 resistance may occur in these patients. It is well-known that the gut metabolite sodium butyrate (NaB) could promote GLP-1 secretion from intestinal L cells. However, it is unclear whether NaB improves hepatic GLP-1 responsiveness in NAFLD. In the current study, we showed that the serum GLP-1 levels of NAFLD patients were similar to those of normal controls, but hepatic GLP-1R expression was significantly downregulated in NAFLD patients. Similarly, in the NAFLD mouse model, mice fed with a high-fat diet showed reduced hepatic GLP-1R expression, which was reversed by NaB treatment and accompanied by markedly alleviated liver steatosis. In addition, NaB treatment also upregulated the hepatic p-AMPK/p-ACC and insulin receptor/insulin receptor substrate-1 expression levels. Furthermore, NaB-enhanced GLP-1R expression in HepG2 cells by inhibiting histone deacetylase-2 independent of GPR43/GPR109a. These results indicate that NaB is able to prevent the progression of NAFL to NASH via promoting hepatic GLP-1R expression. NaB is a GLP-1 sensitizer and represents a potential therapeutic adjuvant to prevent NAFL progression to NASH.

Satiating effect of a sodium caseinate hydrolysate and its fate in the upper gastrointestinal tract

Previously we identified a sodium caseinate (NaCas) hydrolysate, LFC25, which significantly increased secretion of satiety hormone glucagon-like peptide-1 (GLP-1) in vitro and reduced food intake in mice when administered intraperitoneally. This study investigates whether LFC25, administered orally, promotes GLP-1 secretion and/or reduces food intake in vivo. Over an 8-hour period, mice received LFC25 by oral gavage had similar food intake to mice received NaCas. Postprandial blood glucose, plasma active GLP-1, amino acids, insulin and food consumed at the next meal were not significantly different in pigs that consumed LFC25 compared to NaCas in a dairy beverage, at a dosage relevant for human consumption. Simulated in vitro gastro-duodenal digestion of LFC25 revealed a significant reduction in bioactivity. In contrast, the harsh conditions of the upper gut appear to functionalize intact NaCas as a GLP-1 secretagogue. In conclusion, LFC25 will need enteric protection to be used as a food ingredient for satiety.

Insulin regulates glucagon-like peptide-1 secretion by pancreatic alpha cells.

Proglucagon is expressed in both pancreatic alpha cells and intestinal epithelial L cells and is cleaved into glucagon and glucagon-like peptide-1 (GLP-1) by different prohormone convertases (PCs). Recent studies have shown that α-cells can also secrete GLP-1, which may improve islet function. However, little is known about the factors influencing GLP-1 secretion by α cells. In this study, we investigated whether insulin promotes GLP-1 secretion by α cells, as well as the mechanisms underlying this phenomenon. We cultured the alpha-cell line In-R1-G9 in low- or high-glucose medium in the presence or absence of insulin to determine the influence of glucose concentrations on the actions of insulin. We also treated In-R1-G9 cells with insulin for different times and at different doses. Then GLP-1 and glucagon protein expression levels were estimated. Moreover, ERK and phosphatidylinositol-3-kinase/AKT (PI3K/AKT) pathway activity levels and prohormone convertase expression levels were evaluated to elucidate the mechanism underlying the effects of insulin on GLP-1 secretion by α-cells. Insulin promoted GLP-1 secretion in a time- and dose-dependent manner under high-glucose conditions. Inhibiting the PI3K/AKT pathway with LY294002 and the Ras/mitogen-activated protein kinase (RAS/MAPK) pathway with PD98059 reduced GLP-1 secretion, respectively, in inhibitor-treated cells compared with insulin-treated cells. Moreover, insulin increased prohormone convertase 1/3 expression levels in the corresponding group of IN-R1-G9 cells compared with the control group of cells. Insulin facilitates GLP-1 secretion by pancreatic alpha cells by inducing PC1/3 expression under high-glucose conditions, a phenomenon that may be associated mainly with PI3K/AKT pathway activation.

An Enteral Formula Containing Fermented Milk Products and Prebiotics Promotes Glucagon-Like Peptide-1 Secretion via Short Chain Fatty Acid Signaling

An enteral formula containing fermented milk products and prebiotics (prebiotic formula, PF) is known to promote the proliferation of Bifidobacterium and the production of short-chain fatty acids (SCFAs) in humans and rats. We studied the effect of PF on the secretion of glucagon-like peptide-1 (GLP-1) and the involvement of SCFAs in this process, using the knockout (KO) mice for the SCFA receptors G protein-coupled receptor 41 (GPR41) and G protein-coupled receptor 43 (GPR43). Wild type (WT) or KO mice were fed either a standard formula (SF) or PF for two weeks, and then were orally administered either PF or SF after overnight fasting and dissected after 0, 30, 60, and 240 minutes. Blood GLP-1 and glucose levels were measured (Experiment 1). Alternatively, mice fed SF or PF for two weeks were dissected after four hours of fasting, and their blood GLP-1 and cecal SCFAs levels were measured (Experiment 2). In Experiment 1, WT and GPR43KO mice showed a significant increase in GLP-1 concentration 30 and/or 60 minutes after formula administration in the PF group compared with that in the SF group. Similarly, WT and GPR43KO mice showed a significant suppression of the increase in glucose levels after formula administration in the PF group compared with that in the SF group. On the other hand, there was no significant difference in GLP-1 concentration or blood glucose levels between the two treatment groups in GPR41KO mice. In Experiment 2, there was a significant increase in cecal SCFA levels in the PF group compared with that in the SF group for all mice, as well as an increase in GLP-1 concentration. PF promotes GLP-1 secretion and SCFAs might contribute to the GLP-1 secretion that occurs directly after ingestion, through GPR41 signal transduction.

Recombinant Mouse Osteocalcin Secreted by Lactococcus lactis Promotes Glucagon-Like Peptide-1 Induction in STC-1 Cells.

An osteoblastic protein, osteocalcin (OC), exists in vivo in two forms: carboxylated OC, and uncarboxylated or low-carboxylated OC (ucOC). ucOC acts as a hormone to regulate carbon and energy metabolism. Recent studies demonstrated that ucOC exerts insulinotropic effects, mainly through the glucagon-like peptide 1 (GLP-1) pathway. GLP-1 is an insulinotropic hormone secreted by enteroendocrine L cells in the small intestine. Thus, efficient delivery of ucOC to the small intestine may be a new therapeutic option for metabolic diseases such as diabetes and obesity. Here, we genetically engineered a lactic acid bacterium, Lactococcus lactis, to produce recombinant mouse ucOC. Western blotting showed that the engineered strain (designated NZ-OC) produces and secretes the designed peptide (rOC) in the presence of nisin, an inducer of the recombinant gene. Highly-purified rOC was obtained from the culture supernatants of NZ-OC using immobilized metal affinity chromatography. An in vitro assay showed that purified rOC promotes GLP-1 secretion in a mouse intestinal neuroendocrine cell line, STC-1, in a dose-dependent manner. These results clearly demonstrate that NZ-OC secretes rOC, and that rOC can promote GLP-1 secretion by STC-1 cells. Genetically modified lactic acid bacteria (gmLAB) have been proposed over the last two decades as an effective and low-cost mucosal delivery vehicle for biomedical proteins. NZ-OC may be an attractive tool for the delivery of rOC to trigger GLP-1 secretion in the small intestine to treat diabetes and obesity.

Glycyrrhizic acid increases glucagon like peptide-1 secretion via TGR5 activation in type 1-like diabetic rats

Glycyrrhizic acid (GA) is belonged to triterpenoid saponin that is contained in the root of licorice and is known to affect metabolic regulation. Recently, glucagon like peptide-1 (GLP-1) has widely been applied in diabetes therapeutics. However, the role of GLP-1 in GA-induced anti-diabetic effects is still unknown. Therefore, we are interested in understanding the association of GLP-1 with GA-induced effects. In type 1-like diabetic rats induced by streptozotocin (STZ-treated rats), GA increased the level of plasma GLP-1, which was blocked by triamterene at a dose sufficient to inhibit Takeda G-protein-coupled receptor 5 (TGR5). The direct effect of GA on TGR5 has been identified using the cultured Chinese hamster ovary cells (CHO-K1 cells) transfected TGR5 gene. Moreover, in intestinal NCI-H716 cells that secreted GLP-1, GA promoted GLP-1 secretion with a marked elevation of calcium levels. However, both effects of GA were reduced by ablation of TGR5 with siRNA in NCI-H716 cells. Therefore, we demonstrated that GA can enhance GLP-1 secretion through TGR5 activation.

Laminarin counteracts diet-induced obesity associated with glucagon-like peptide-1 secretion.

Laminarin, a type of β-glucan isolated from brown seaweeds, exhibits verity of physiological activities, which include immunology modulation and antitumor function. To investigate the effect of laminarin on energy homeostasis, mice were orally administrated with laminarin to test food intake, fat deposition, and glucose homeostasis. Chronically, laminarin treatment significantly decreases high-fat-diet-induced body weight gain and fat deposition and reduces blood glucose level and glucose tolerance. Acutely, laminarin enhances serum glucagon-like peptide-1 (GLP-1) content and the mRNA expression level of proglucagon and prohormone convertase 1 in ileum. Subsequently, laminarin suppresses the food intake of mice, the hypothalamic AgRP neuron activity, and AgRP expression but activates pancreatic function. Furthermore, laminarin-induced appetite reduction was totally blocked by Exendin (9-39), a specific competitive inhibitor of GLP-1 receptor. Then, STC-1 cells were adopted to address the underlying mechanism, by which laminarin promoted GLP-1 secretion in vitro. Results showed that laminarin dose-dependently promoted GLP-1 secretion and c-Fos protein expression in STC-1 cells, which were independent of Dectin-1 and CD18. Interestingly, BAPTA-AM, a calcium-chelating agent, potently attenuated laminarin-induced [Ca2+]i elevation, c-Fos expression, and GLP-1 secretion. In summary, our data support that laminarin counteracts diet-induced obesity and stimulates GLP-1 secretion via [Ca2+]i; this finding provides an experimental basis for laminarin application to treat obesity and maintain glucose homeostasis.

Dissociation of GLP-1 and insulin association with food processing in the brain: GLP-1 sensitivity despite insulin resistance in obese humans.

ObjectiveGlucagon-like peptide-1 (GLP-1) is released into the bloodstream after food intake. In addition to stimulating insulin release, it causes satiety and contributes to the termination of food intake. In this study, we investigated whether endogenous GLP-1 affects food-related brain activity and hunger.MethodsTwenty-four volunteers (12 lean; 12 obese) underwent a 75 g oral glucose tolerance test that promotes GLP-1 secretion. Food cue-induced brain activity was assessed by functional magnetic resonance imaging and GLP-1 concentrations were measured before, 30, and 120 min after glucose intake.ResultsThe significant increase in GLP-1 levels negatively correlated with a change in the food cue-induced brain activity in the orbitofrontal cortex, a major reward area. This association was independent of simultaneous alterations in insulin and glucose concentrations. The association was present in lean and overweight participants. By contrast, postprandial insulin changes were associated with orbitofrontal activations in lean individuals only.ConclusionsThe postprandial release of GLP-1 might alter reward processes in the orbitofrontal cortex and might thereby support the termination of food intake and reduce hunger. While obese persons showed brain insulin resistance, no GLP-1 resistance was observed. Our study provides novel insight into the central regulation of food intake by the incretin hormone GLP-1.

Yhhu4488, a novel GPR40 agonist, promotes GLP-1 secretion and exerts anti-diabetic effect in rodent models

G protein-coupled receptor 40 (GPR40) is predominantly expressed in pancreatic β-cells and activated by long-chain fatty acids. GPR40 has drawn considerable interest as a potential therapeutic target for type 2 diabetes mellitus (T2DM) due to its important role in enhancing glucose-stimulated insulin secretion (GSIS). Encouragingly, GPR40 is also proven to be highly expressed in glucagon-like peptide-1 (GLP-1)-producing enteroendocrine cells afterwards, which opens a potential role of GPR40 in enhancing GLP-1 secretion to exert additional anti-diabetic efficacy. In the present study, we discovered a novel GPR40 agonist, yhhu4488, which is structurally different from other reported GPR40 agonists. Yhhu4488 showed potent agonist activity with EC50 of 49.96 nM, 70.83 nM and 58.68 nM in HEK293 cells stably expressing human, rat and mouse GPR40, respectively. Yhhu4488 stimulated GLP-1 secretion from fetal rat intestinal cells (FRIC) via triggering endogenous calcium store mobilization and extracellular calcium influx. The effect of yhhu4488 on GLP-1 secretion was further confirmed in type 2 diabetic db/db mice. Yhhu4488 exhibited satisfactory potency in in vivo studies. Single administration of yhhu4488 improved glucose tolerance in SD rats. Chronic administration of yhhu4488 effectively decreased fasting blood glucose level, improved β-cell function and lipid homeostasis in type 2 diabetic ob/ob mice. Taken together, yhhu4488 is a novel GPR40 agonist that enhances GLP-1 secretion, improves metabolic control and β-cell function, suggesting its promising potential for the treatment of type 2 diabetes.