Glucagon-like Peptide-1 Release Research Articles

Greater glucagon-like peptide-1 responses to oral glucose are associated with lower central and peripheral blood pressures

Background and aimCardiovascular diseases (CVDs) are globally the leading cause of death and hypertension is a significant risk factor. Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists has been associated with decreases in blood pressure and CVD risk. Our aim was to investigate the association between endogenous GLP-1 responses to oral glucose and peripheral and central haemodynamic measures in a population at risk of diabetes and CVD.MethodsThis cross-sectional study included 837 Danish individuals from the ADDITION-PRO cohort (52% men, median (interquartile range) age 65.5 (59.8 to 70.7) years, BMI 26.1 (23.4 to 28.5) kg/m2, without antihypertensive treatment and known diabetes). All participants received an oral glucose tolerance test with measurements of GLP-1 at 0, 30 and 120 min. Aortic stiffness was assessed by pulse wave velocity (PWV). The associations between GLP-1 response and central and brachial blood pressure (BP) and PWV were assessed in linear regression models adjusting for age and sex.ResultsA greater GLP-1 response was associated with lower central systolic and diastolic BP of − 1.17 mmHg (95% confidence interval (CI) − 2.07 to − 0.27 mmHg, P = 0.011) and − 0.74 mmHg (95% CI − 1.29 to − 0.18 mmHg, P = 0.009), respectively, as well as lower brachial systolic and diastolic BP of − 1.27 mmHg (95% CI − 2.20 to − 0.33 mmHg, P = 0.008) and − 1.00 (95% CI − 1.56 to − 0.44 mmHg, P = 0.001), respectively. PWV was not associated with GLP-1 release (P = 0.3). Individuals with the greatest quartile of GLP-1 response had clinically relevant lower BP measures compared to individuals with the lowest quartile of GLP-1 response (central systolic BP: − 4.94 (95% CI − 8.56 to − 1.31) mmHg, central diastolic BP: − 3.05 (95% CI − 5.29 to − 0.80) mmHg, brachial systolic BP: − 5.18 (95% CI − 8.94 to − 1.42) mmHg, and brachial diastolic BP: − 2.96 (95% CI − 5.26 to − 0.67) mmHg).ConclusionGreater glucose-stimulated GLP-1 responses were associated with clinically relevant lower central and peripheral blood pressures, consistent with beneficial effects on the cardiovascular system and reduced risk of CVD and mortality.Trial registration ClinicalTrials.gov Identifier: NCT00237549. Retrospectively registered 10 October 2005

Suppression of Glucagon-Like Peptide-1 Release by Inhibition of Intestinal NLRP3 Inflammasome Activation in Asc-/- and Nlrp3-/- Mice.

The glucagon-like peptide-1 (GLP-1) is an insulinotropic hormone secreted by intestinal enteroendocrine L-cells, which plays a crucial role in glucose control, regulation, and protection from different pathological conditions such as diabetes mellitus. The present study sought to test whether GLP-1 release increases gut injury with a high-fat diet (HFD) and whether this GLP-1 release is associated with NLRP3 inflammasome activation. Our results showed that the NLRP3 inflammasome is activated in the intestinal tissue of wild-type mice on a HFD, accompanied by GLP-1 overexpression. The number of intestinal L-cells and the GLP-1 level in serum are increased in WT mice with HFD. However, in the Asc–/– and Nlrp3–/– mice, these HFD-induced intestinal and serum GLP-1 changes were suppressed. Using confocal microscopy, the colocalization of GLP-1 and FLICA that labels activated caspase-1 in intestine was decreased in the Asc–/– and Nlrp3–/– mice compared to WT mice. Mechanistically, the inhibitor of caspase-1 or HMGB1 blocker is used to demonstrate the regulatory action of NRLP3 inflammasome in GLP-1 release. It was found that the level of GLP-1 and its colocalization with IL-1β were reduced by inhibition of the caspase-1 activity, but not altered by blockade of HMGB1 action. Our results suggest that NLRP3 inflammasome activation triggers GLP-1 production from the intestine, which is associated with IL-1β, but not with HMGB1. These findings for the first time provide evidence that the activation of NLRP3 inflammasome in the intestine increases GLP-1 release in mice, which may serve as an adaptive response to intestinal inflammation.

2322 Liraglutide-Induced Liver Injury With Superimposed Acute Pancreatitis

INTRODUCTION: Liraglutide, commercially known as Victoza is a glucagon-like peptide 1 (GLP-1) receptor agonist that was recently approved for the treatment of diabetes mellitus type 2. Due to its recent arrival in the realm of anti-diabetic medications, the side effects of GLP-1 receptor agonists are not fully established. It is thought that the release of GLP-1 is mediated by sensory neurons located in the intestine and in the liver. This is clinically significant as many of the reported side-effects occur in these sites, namely the liver as was the case with our patient. CASE DESCRIPTION/METHODS: A 64-year-old woman with a medical history of hypertension, diabetes mellitus, hyperlipidemia, and cholecystectomy presented to our emergency department complaining of diffuse abdominal pain for 4 days. The patient denied alcohol consumption, illicit drug use, recent travel or any recent changes in her diet. Laboratory workup included alanine aminotransferase (ALT) of 1359 IU/L, aspartate aminotransferase (AST) of 565 IU/L, alkaline phosphatase (ALP) of 405 IU/L, and lipase of 287 U/L. Physical examination was notable for epigastric tenderness. Of note the patient was seen at our outpatient clinic 6 months at which point she was started on Liraglutide. Liver function tests at that time were within normal limits. Upon hospital admission Liraglutide was held and the patient was promptly started on intravenous fluids and N-acetylcysteine protocol. During her admission markers for viral hepatitis and autoimmune hepatitis were negative. On her third hospital day after discontinuation of Liraglutide the patients symptoms completely resolved and her liver function tests trended down (ALT: 335, AST: 58, ALP: 386). The patient was then discharged home with outpatient follow up scheduled. DISCUSSION: Acute pancreatitis is an established possible complication of liraglutide therapy. The mechanism behind its development is likely attributable to a hypersensitivity or metabolic idiosyncratic reaction. Drug induced liver injury however, is an exceedingly rare complication of liraglutide therapy. Current theories suggest the development of anti-liraglutide antibodies as the main culprit. Liraglutide is a peptide that is 97% homologous with human GLP-1. This is problematic as the development of antibodies against liraglutide may also cross-react with the GLP-1 receptor found on human hepatocytes thus resulting in liver injury. We highlight a rare case of liraglutide induced liver injury with concurrent acute pancreatitis.

Expression patterns of L-amino acid receptors in the murine STC-1 enteroendocrine cell line.

Regulation of gut function depends on the detection and response to luminal contents. Luminal L-amino acids (L-AA) are detected by several receptors including metabotropic glutamate receptors 1 and 4 (mGluR1 and mGluR4), calcium-sensing receptor (CaSR), GPRC family C group 6 subtype A receptor (GPRC6A) and umami taste receptor heterodimer T1R1/T1R3. Here, we show that murine mucosal homogenates and STC-1 cells, a murine enteroendocrine cell line, express mRNA for all L-AA receptors. Immunohistochemical analysis demonstrated the presence of all L-AA receptors on STC-1 with CaSR being most commonly expressed and T1R1 least expressed (35% versus 15% of cells); mGluRs and GPRC6a were intermediate (~ 20% of cells). Regarding coexpression of L-AA receptors, the mGluRs and T1R1 were similarly coexpressed with CaSR (10-12% of cells) whereas GPRC6a was coexpressed least (7% of cells). mGluR1 was coexpressed with GPRC6a in 11% of cells whereas coexpression between other receptors was less (2-8% of cells). CaSR and mGluR1 were coexpressed with glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) in 20-25% of cells whereas T1R1 and GPRC6a were coexpressed with GLP-1 and PYY less (8-12% of cells). Only mGluR4 showed differential coexpression with GLP-1 (13%) and PYY (21%). L-Phenylalanine (10mM) caused a 3-fold increase in GLP-1 release, which was strongly inhibited by siRNA to CaSR indicating functional coupling of CaSR to GLP-1 release. The results suggest that not all STC-1 cells express (and coexpress) L-AA receptors to the same extent and that the pattern of response likely depends on the pattern of expression of L-AA receptors.

Inulin might exceed incretin based drugs in the treatment of type 2 diabetes mellitus

Glucagon hormone being catabolic and hyperglycemic, it acts in an opposite manner to insulin and adds to insulin resistance. The oligosaccharide inulin fructans is indigestible in the small bowel. When it reaches the large intestine, it encourages beneficial microbacteria strains. These latter produce certain peptides which when absorbed they reach the endlocrine L-cells of the small gut. These peptides stimulate L-cells to release glucagon like peptide 1 (GLP-1) which suppresses glucagon and stimulates insulin secretion in a glucose dependant manner. Our aim is to find how inulin suppresses glucagon and to what extent this improves insulin resistance. Fasting serum glucagon and homeostasis model assessment for insulin resistance (HOMA-IR) were estimated in 28 type 2 diabetic female patients before and after twenty one days of daily inulin intake. Fasting serum glucagon and HOMA-IR decreased significantly after the inulin intake period. In conclusion inulin stimulates the release of GLP-1. This acts in a glucose dependant manner thus simulating the novel incretin based drugs in reducing insulin resistance. However, owing to inulin other actions on insulin resistance, it might exceed these novel drugs.

Bacterial modulation of visceral sensation: mediators and mechanisms.

The potential role of the intestinal microbiota in modulating visceral pain has received increasing attention during recent years. This has led to the identification of signaling pathways that have been implicated in communication between gut bacteria and peripheral pain pathways. In addition to the well-characterized impact of the microbiota on the immune system, which in turn affects nociceptor excitability, bacteria can modulate visceral afferent pathways by effects on enterocytes, enteroendocrine cells, and the neurons themselves. Proteases produced by bacteria, or by host cells in response to bacteria, can increase or decrease the excitability of nociceptive dorsal root ganglion (DRG) neurons depending on the receptor activated. Short-chain fatty acids generated by colonic bacteria are involved in gut-brain communication, and intracolonic short-chain fatty acids have pronociceptive effects in rodents but may be antinociceptive in humans. Gut bacteria modulate the synthesis and release of enteroendocrine cell mediators, including serotonin and glucagon-like peptide-1, which activate extrinsic afferent neurons. Deciphering the complex interactions between visceral afferent neurons and the gut microbiota may lead to the development of improved probiotic therapies for visceral pain.

Gastric Emptying and Distal Gastrectomy Independently Enhance Postprandial Glucagon-Like Peptide-1 Release After a Mixed Meal and Improve Glycemic Control in Subjects Having Undergone Pancreaticoduodenectomy.

New-onset diabetes frequently resolves after pancreaticoduodenectomy (PD). Glucagon-like peptide-1 (GLP-1) conceivably is involved as its release is enhanced by rapid gastric emptying and distal bowel exposure to nutrients. We aimed at studying factors associated with GLP-1 release after PD. Fifteen PD subjects with distal gastrectomy (Whipple) and 15 with pylorus preservation were evaluated. A test meal containing 1 g paracetamol to measure gastric emptying was ingested. Blood for the measurement of paracetamol, glucose, insulin, and GLP-1 was drawn at baseline and 10, 20, 30, 60, 90, 120, 150, and 180 minutes thereafter. The Matsuda index of insulin sensitivity was calculated. In univariate analysis, gastric emptying correlated with GLP-1. Glucagon-like peptide-1 responses to the modes of operation did not differ. Multiple regression analysis confirmed gastric emptying and Whipple versus pylorus-preserving pancreaticoduodenectomy as independent predictors of GLP-1 release. The Matsuda index of insulin sensitivity correlated with GLP-1 concentrations and inversely with body mass index. Patients after Whipple procedure revealed lower glycated hemoglobin as compared with pylorus-preserving pancreaticoduodenectomy. Following PD, the postprandial GLP-1 release seems to be enhanced by rapid gastric emptying and to improve insulin sensitivity. Partial gastrectomy versus pylorus preservation enhanced the release of GLP-1, conceivably because of greater distal bowel exposure to undigested nutrients.

Vagal Nerve Stimulation for Glycemic Control in a Rodent Model of Type 2 Diabetes.

Vagal nerve stimulation (VNS) has been reported to reduce body weight and improve sympathovagal imbalance in both basic and clinical studies. Its effects on glycemic control were however unclear. The aims of this study were to investigate the effects of VNS with various parameters on blood glucose and its possible mechanisms in rats. A hyperglycemic rodent model induced by glucagon was used initially to optimize the VNS parameters; then, a type 2 diabetic rodent model induced by high-fat diet combined with streptozotocin was used to validate the VNS method. The VNS electrodes were implanted at the dorsal subdiaphragmatic vagus; three subcutaneous electrodes were implanted at the chest area for recording electrocardiogram in rats induced by glucagon. (1) VNS with short pulse width of 0.3ms but not 3ms reduced blood glucose during an oral glucose tolerance test (OGTT), with a 38.4% reduction at 15min and 26.9% at 30min (P < 0.05, vs. sham-VNS respectively). (2) VNS at low frequency of 5Hz but not 14Hz or 40Hz reduced blood glucose during the OGTT (P < 0.05, vs. sham-VNS). (3) Intermittent VNS was more potent than continuous VNS (P < 0.01). (4) No difference was found between unilateral VNS and bilateral VNS. (5) VNS enhanced vagal activity (P = 0.005). (6) The hypoglycemic effect of VNS was blocked by glucagon-like peptide-1 (GLP-1) antagonist exendin-4. VNS at 5Hz reduces blood glucose in diabetic rats by enhancing vagal efferent activity and the release of GLP-1.

SCO-267, a GPR40 Full Agonist, Improves Glycemic and Body Weight Control in Rat Models of Diabetes and Obesity.

The GPR40/FFA1 receptor is a G-protein-coupled receptor expressed in the pancreatic islets and enteroendocrine cells. Here, we report the pharmacological profiles of (3S)-3-cyclopropyl-3-{2-[(1-{2-[(2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl]-5-methoxyphenyl}piperidin-4-yl)methoxy]pyridin-4-yl}propanoic acid (SCO-267), a novel full agonist of GPR40. Ca2+ signaling and insulin and glucagon-like peptide-1 (GLP-1) secretion were evaluated in GPR40-expressing CHO, MIN6, and GLUTag cells. Hormone secretions and effects on fasting glucose were tested in rats. Single or repeated dosing effects were evaluated in neonatally streptozotocin-induced diabetic rats (N-STZ-1.5 rats), diet-induced obese (DIO) rats, and GPR40-knockout (Ffar1-/- ) mice. Treatment with SCO-267 activated Gq signaling in both high- and low-FFAR1-expressing CHO cells, stimulated insulin secretion in MIN6 cells, and induced GLP-1 release in GLUTag cells. When administered to normal rats, SCO-267 increased insulin, glucagon, GLP-1, glucose-dependent insulinotropic peptide, and peptide YY (PYY) secretions under nonfasting conditions. These results show the full agonistic property of SCO-267 against GPR40. Hypoglycemia was not induced in SCO-267-treated rats during the fasting condition. In diabetic N-STZ-1.5 rats, SCO-267 was highly effective in improving glucose tolerance in single and 2-week dosing studies. DIO rats treated with SCO-267 for 2 weeks showed elevated plasma GLP-1 and PYY levels, reduced food intake, and decreased body weight. In wild-type mice, SCO-267 induced GLP-1 secretion, food intake inhibition, and body weight reduction; however, these effects were abolished in Ffar1-/- mice, indicating a GPR40-dependent mechanism. In conclusion, SCO-267 stimulated islet and gut hormone secretion, improved glycemic control in diabetic rats, and decreased body weight in obese rats. These data suggest the therapeutic potential of SCO-267 for the treatment of diabetes and obesity.

Starch Digestion Products Activate Enteroendocrine L-cells and Their Ileal Delivery Through the Diet Contributes to Weight Management in Mice (P08-005-19)

ObjectivesOur laboratory has recently shown that slowly digestible starch (SDS) that locationally digests to the ileum activates the gut-brain axis and reduces food intake in obese animals. Glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY) are the main appetite-suppressing (anorexigenic) peptides of the intestinal enterendocrine L-cells that regulate postprandial insulin levels and satiety signals. We investigated the in vitro L-cell chemosensation of α-amylase starch digestion products, named maltooligosaccharides (MOS), and using SDS to deliver MOS in vivo. MethodsMouse (STC-1) and human (NCI-H716) cells were used to test chemosensation response and release of GLP-1, OXM and PYY after MOS treatment. Differential gene expression and comparable global protein profiling of STC-1 cell treated with MOS was tested using RNA sequencing and LC-MS/MS analysis. Alginate-entrapped SDS microspheres that digest distally into the ileum were used to examine the role of SDS in the intervention and prevention of obesity in C57BL/6 J obese and lean mice, respectively. Body weight, food intake and body composition were monitored periodically. ResultsMOS exhibited significantly higher stimulatory effect on GLP-1 and OXM secretion in mouse and human L-cells, respectively, compared to glucose. Multi-omics analysis showed that MOS induced exocytosis of GLP-1- and OXM-containing vesicles and did not induce positive regulation of the proglucagon gene suggesting that secretion, but not synthesis, of the proglucagon gene products was enhanced by MOS. In vivo Results showed that 20% SDS in low-fat diets significantly improved weight loss and food intake reduction in obese mice. Similarly, 15% SDS in high-fat diets showed significant reduction in body fat %, increase in lean body mass, and considerable reduction in weight gain rate and food intake in lean mice fed on high-fat diets. ConclusionsWe propose several insights into L-cell sensation of dietary starch-degraded MOS delivered by the consumption of slowly digestible starch. MOS exhibit unique influences on L-cell sensitivity and gut hormone productivity. The intricate role of dietary carbohydrates on gut physiological response, related to satiety and food intake could be a new approach for design of foods for obesity prevention. Funding SourcesWhistler Center for Carbohydrate Research, Purdue University. Supporting Tables, Images and/or Graphs▪▪

1974-P: Identification of a Dual-Action Small Molecule with Potent Antidiabetic Activity

Type 2 diabetes (T2D) is a result of insulin resistance and pancreatic β-cell dysfunction. Therefore, identifying agents that simultaneously reverse these two defects could be a novel strategy leading to more effective prevention and treatment of T2D. Recently, we generated a small molecule elenolic acid moiety (EA). Here, we report that oral administration of EA normalized glycemia, glucose tolerance, insulin sensitivity, and hepatic glucose production in high-fat diet (HFD)-induced obese mice. These metabolic and antihyperglycemic effects of EA treatment were associated with increased circulating GLP-1 and peptide YY concentrations, but reduced blood insulin, leptin, and lipid levels. In addition, EA slowed gastric emptying and reduced food intake, body weight, and fat mass in HFD-fed obese mice. In vitro, EA directly induces glucagon-like peptide-1 (GLP-1) release from intestinal L-cells via a Gαq/phospholipase C-mediated mechanism. It also suppresses glucose production from HepG2 cells and stimulates glucose uptake in primary human skeletal muscle cells. These data suggest that EA may be a novel agent for developing drug to treat T2D. Disclosure Y. Wang: None. J. Luo: None. H.A. Alkhalidy: None. B. Xu: None. D. Liu: None. Funding National Institutes of Health (1R01AT007077, 1R01AT007566)

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.

Postprandial glucose, insulin and incretin responses differ by test meal macronutrient ingestion sequence (PATTERN study)

Previous studies have shown that the sequential order of consuming different food components significantly impacts postprandial glucose and insulin excursions in prediabetes and type 2 diabetes, but the causative mechanisms in healthy humans remain ill-defined. Using a typical Asian meal comprising vegetables, protein (chicken breast), and carbohydrate (white rice), the aim of this study was to examine the effect of food intake sequence on postprandial glucose, insulin and incretin secretions in healthy adults. Sixteen healthy Chinese adults participated in a randomized, controlled, crossover meal trial. Subjects consumed in random order 5 experimental isocaloric meals that differed in the food intake sequence of vegetables, protein and carbohydrate. Glucose, insulin, incretins and satiety markers were measured over 3h. There were significant food intake sequence×time interaction effects on plasma glucose, insulin, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) concentrations (P<0.001). In comparison with rice consumed first followed by vegetable and meat (R-VM), the overall postprandial glucose response was significantly attenuated after the food intake sequence of vegetable first, followed by meat and rice (V-MR) or meat first, followed by vegetable and rice (M-VR) or vegetable first followed by meat and rice (V-M-R) or vegetable, meat and rice consumed together (VMR). The insulin iAUC (0-60) was significant lower after V-M-R than M-VR, VMR and R-VM. V-M-R food intake sequence stimulated higher GLP-1 release than other meal sequences. However, GIP response was lower after V-MR and V-M-R than M-VR and R-MR food intake sequences. Food macronutrient intake sequence can considerably influence its glycemic, insulinemic and incretin responses. V-M-R food intake sequence attenuates the glycemic response to a greater degree with accentuated GLP-1 stimulation without any increased demand for insulin. The sequence of food intake has great potential as a novel and simple behavioral strategy to modulate glycemic response in healthy adults. The trial was registered at clinicaltrials.gov as NCT03533738.

Chemogenetics defines receptor-mediated functions of short chain free fatty acids.

Differentiating actions of short chain fatty acids (SCFAs) at free fatty acid receptor 2 (FFA2) from other free fatty acid-responsive receptors and from non-receptor-mediated effects has been challenging. Using a novel chemogenetic and knock-in strategy, whereby an engineered variant of FFA2 (FFA2-DREADD) that is unresponsive to natural SCFAs but is instead activated by sorbic acid replaced the wild-type receptor, we determined that activation of FFA2 in differentiated adipocytes and colonic crypt enteroendocrine cells of mouse accounts fully for SCFA-regulated lipolysis and release of the incretin glucagon-like peptide-1 (GLP-1), respectively. In vivo studies confirmed the specific role of FFA2 in GLP-1 release and also demonstrated a direct role for FFA2 in accelerating gut transit. Thereby, we establish the general principle that such a chemogenetic knock-in strategy can successfully define novel G-protein-coupled receptor (GPCR) biology and provide both target validation and establish therapeutic potential of a 'hard to target' GPCR.

Effect of six Korean plants on glucagon like peptide-1 release.

Glucagon like peptide-1 (GLP-1) plays a major role in the regulation of energy homeostasis as it causes satiety and suppresses appetite. Angelica dahurica, Coreanomecon hylomeconoides, Chrysanthemum morifolium, Portulaca oleracea, Stellaria alsine, and Stellaria media have traditionally been used as famine relief foods in Korea. The aim of the present study was to determine whether the aqueous ethanolic extracts of the six plants stimulate GLP-1 secretion. The results demonstrated that each extract of the plants stimulated GLP-1 secretion from enteroendocrine NCI-H716 cells, respectively. Among the extracts examined, the extract of Portulaca oleracea showed the highest activity on GLP-1 release. The results may suggest that the GLP-1 secretion induced by the six plants is a possible mechanism for the six plants exerting effects on satiety increase and appetite suppression.

Let-7e-5p Regulates GLP-1 Content and Basal Release From Enteroendocrine L Cells From DIO Male Mice.

Characterization of enteroendocrine L cells in diabetes is critical for better understanding of the role of glucagon-like peptide-1 (GLP-1) in physiology and diabetes. We studied L-cell transcriptome changes including microRNA (miRNA) dysregulation in obesity and diabetes. We evaluated the regulation of miRNAs through microarray analyses on sorted enteroendocrine L cells from control and obese glucose-intolerant (I-HFD) and hyperglycemic (H-HFD) mice after 16 weeks of respectively low-fat diet (LFD) or high-fat diet (HFD) feeding. The identified altered miRNAs were studied in vitro using the mouse GLUTag cell line to investigate their regulation and potential biological functions. We identified that let-7e-5p, miR-126a-3p, and miR-125a-5p were differentially regulated in L cells of obese HFD mice compared with control LFD mice. While downregulation of let-7e-5p expression was observed in both I-HFD and H-HFD mice, levels of miR-126a-3p increased and of miR-125a-5p decreased significantly only in I-HFD mice compared with controls. Using miRNA inhibitors and mimics we observed that modulation of let-7e-5p expression affected specifically GLP-1 cellular content and basal release, whereas Gcg gene expression and acute GLP-1 secretion and cell proliferation were not affected. In addition, palmitate treatment resulted in a decrease of let-7e-5p expression along with an increase in GLP-1 content and release, suggesting that palmitate acts on GLP-1 through let-7e-5p. By contrast, modulation of miR-125a-5p and miR-126a-3p in the same conditions did not affect content or secretion of GLP-1. We conclude that decrease of let-7e-5p expression in response to palmitate may constitute a compensatory mechanism contributing to maintaining constant glycemia in obese mice.

The mixture of corn and wheat peptide prevent diabetes in NOD mice

Abstract Corn peptide promotes glucagon-like peptide-1 release in type 2 diabetic animals, while wheat peptide increases pro-inflammatory cytokine response in type 1 diabetic patients. However, the effect of a mixture of corn and wheat peptide on the initiation and the development of type 1 diabtes remains unclear. Corn peptide reduced the blood glucose in wheat peptide-evoked diabetic NOD mice. A mixture of corn and wheat peptide significantly delayed the initiation and decreased the incidence of diabetes in NOD mice. In addition to the improved oral glucose tolerance, level of interleukin (IL)-6 and the insulitis score were decreased, while β-cell areas and IL-10 gene expression were increased via treatment with this peptide mixture. Meanwhile, serine and histidine levels in the serum were significantly increased in this peptide mixture treated NOD mice. Our data suggested that a mixture of corn and wheat peptide could prevent diabetes in NOD mice.

Fat facts: An overview of adipose tissue and lipids

The term fat evokes a multitude of ideas, images, and prejudices. It encompasses the different types of adipose tissue (AT) and cellular components as well as the myriad of lipid molecules. The AT and lipid molecules throughout the body carry out scores of vital functions ranging from thermal insulation to energy homeostasis to signal transduction. A fact that is not generally appreciated is that in addition to its roles in energy balance and thermoregulation, the AT is also an integral part of both the endocrine and immune systems. Fatty acids (FAs) are the primary building blocks of most lipids. They serve as fuel, structural components, and regulatory molecules (mediators). Most of the free FAs in the body are either obtained from the diet or released by the AT (lipolysis). However, most of the short-chain FAs such as propionate and butyrate are generated in the colon by the fermentation of dietary fiber by the gut microbiota. In addition to providing fuel for the colon enterocytes, these molecules act on specific G protein-coupled receptors in the gut cells stimulating the release of glucagon-like peptide-1 and peptide YY simultaneously improving insulin sensitivity and curbing appetite. The essential FAs linoleic and α-linolenic give rise to two distinct classes of omega FAs, n-6 and n-3, respectively, and hence to more complex lipid derivatives (eicosanoids) which are involved in virtually all aspects of cellular function including immunomodulation and inflammation. These include prostacyclins, thromboxanes, leukotrienes, and epoxyeicosatrienoic acids.

Bile acids drive colonic secretion of glucagon-like-peptide 1 and peptide-YY in rodents.

A large number of glucagon-like-peptide-1 (GLP-1)- and peptide-YY (PYY)-producing L cells are located in the colon, but little is known about their contribution to whole body metabolism. Since bile acids (BAs) increase GLP-1 and PYY release, and since BAs spill over from the ileum to the colon, we decided to investigate the ability of BAs to stimulate colonic GLP-1 and PYY secretion. Using isolated perfused rat/mouse colon as well as stimulation of the rat colon in vivo, we demonstrate that BAs significantly enhance secretion of GLP-1 and PYY from the colon with average increases of 3.5- and 2.9-fold, respectively. Furthermore, we find that responses depend on BA absorption followed by basolateral activation of the BA-receptor Takeda-G protein-coupled-receptor 5. Surprisingly, the apical sodium-dependent BA transporter, which serves to absorb conjugated BAs, was not required for colonic conjugated BA absorption or conjugated BA-induced peptide secretion. In conclusion, we demonstrate that BAs represent a major physiological stimulus for colonic L-cell secretion. NEW & NOTEWORTHY By the use of isolated perfused rodent colon preparations we show that bile acids are potent and direct promoters of colonic glucagon-like-peptide 1 and peptide-YY secretion. The study provides convincing evidence that basolateral Takeda-G protein-coupled-receptor 5 activation is mediating the effects of bile acids in the colon and thus add to the existing literature described for L cells in the ileum.

GLP-1 mediated improvement of the glucose tolerance in the T2DM GK rat model after massive jejunal resection

ObjectiveThe aim of this study was to clarify the role of the middle gut in the entero-pancreatic axis modification that leads to glucose improvement in the Goto-Kakizaki (GK) rat as a non-obese T2DM model. BackgroundBariatric surgery is considered an assured solution for type 2 Diabetes (T2DM). Enterohormones such as ghrelin, gastric inhibitory polypeptide and mainly glucagon-like peptide-1 (GLP-1) were recognized as key players in the physiophathological mechanisms associated with entero-pancreatic axis regulation and glucose tolerance improvement. However, the influence of anatomical arrangements post-bariatric surgery on this axis is still debatable. MethodTo this purpose, 50% of small intestine resections were performed on GK rats (n = 6), preserving the proximal half of the jejunum and the ileum (IR50). Phenotypic and functional changes, such as performance in oral glucose tolerance tests, ileal release of GLP-1, beta-cell sensitivity to GLP-1, beta-cell mass, and turnover were characterized in IR50 and the surgical control group (Sham). ResultsThe glucose tolerance was improved and ileal release of GLP-1 was enhanced four weeks after IR50 versus the control group rats. Beta-cell mass, beta-cell proliferation, and beta-cell sensitivity to GLP-1 were also increased in the pancreas of IR50 versus the control group rats. Conclusionthe jejunal exclusion increases beta-cell-mass and improves glucose tolerance by increasing in GLP-1 expression and number of receptors via the entero-pancreatic axis.