Glucagon-like Peptide-1 Concentrations Research Articles

Peptide YY3-36 and glucagon-like peptide-1 in functional dyspepsia. Secretion and role in symptom generation

ABSTRACTObjective The role of peptide YY3-36 (PYY3-36), glucagon-like peptide-1 (GLP-1), and glucose homoeostasis in symptom development in functional dyspepsia (FD) is unclear. The aim was to investigate postprandial changes in plasma PYY3-36, GLP-1, glucose and insulin, and the relationship between PYY3-36, GLP-1, dyspeptic symptoms, and satiety measurements. Materials and methods Thirty-six patients with functional dyspepsia and 18 healthy controls consumed a liquid meal at two occasions. Firstly, a fixed amount of 250 mL (300 kcal) was consumed and gastric emptying was assessed using the paracetamol method. Secondly, participants drank 75 mL (90 kcal) per five min until maximal satiety. PYY3-36, GLP-1, glucose, and insulin concentrations were assessed. Satiety measures and dyspeptic symptoms were registered using visual analogue scales. Results Gastric emptying, glucose, PYY3-36, and GLP-1 concentrations were similar in patients and controls. Patients with epigastric pain syndrome had higher postprandial insulin levels. Patients reported more satiety, nausea, and pain. Area under the curve (AUC) for GLP-1 correlated positively to nausea in patients and negatively to nausea in controls during a single meal. AUC for PYY3-36 correlated similarly to sensation of fullness in the two groups; however, the correlation was negative for the single meal and positive for the satiety test. Conclusions In epigastric pain syndrome, postprandial insulin secretion seems to be increased. Neither GLP-1 nor PYY3-36 secretion is altered in functional dyspepsia, but postprandial GLP-1 secretion seems to correlate with nausea and PYY3-36 to the sensation of fullness, and therefore, these hormones might be involved in symptom generation.

ß-cell pancreatic dysfunction plays a role in hyperglycemic peaks observed after gastric bypass surgery of obese patients

BackgroundEarly and intense hyperglycemic peaks are observed after Roux-en-Y gastric bypass (RYGB). ObjectivesThe aim of this observational study was to compare the ß-cell pancreatic function of patients with (PEAK) and without hyperglycemic peaks (NOPEAK). SettingReferral bariatric surgery center. MethodsInsulin secretion rate, clearance, and sensitivity and ß-cell and rate sensitivities were computed after a 75-g oral glucose tolerance test in 42 patients who underwent RYGB. ResultsPEAK patients (n = 18; 30-min glycemia>10.4 mmol/L) did not differ from NOPEAK patients (n = 24) in their presurgery or weight loss characteristics. PEAK patients had significantly higher plasma concentrations of glucose and C-peptide than did NOPEAK patients, whereas insulin and glucagon-like peptide-1 concentrations did not differ. The insulin secretion rate and whole-body insulin clearance (208%) were significantly greater, but insulin sensitivity was significantly less (48%) in PEAK patients. Insulin secretion normalized to plasma glucose was significantly lower in PEAK patients, and the disposition index was reduced (35% to 41% of the values in NOPEAK patients). ConclusionWe conclude that RYGB reveals a series of dysfunctions leading to hyperglycemia in a subset of patients. In PEAK patients, an insufficient adaptation of ß-cell function to glycemia, an increased insulin clearance, and a decreased insulin sensitivity cumulated to contribute to hyperglycemic peaks.

Circulating concentrations of glucagon-like peptide 1, glucose-dependent insulinotropic peptide, peptide YY, and insulin in client-owned lean, overweight, and diabetic cats

Our objectives were to measure plasma concentrations of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) in client-owned newly diagnosed diabetic cats and nondiabetic lean or overweight cats and to determine whether circulating concentrations of these hormones differed between study groups and if they increased postprandially as seen in other species. A total of 31 cats were recruited and placed into 1 of 3 study groups: lean (body condition score 4–5 on a scale of 1–9; n = 10), overweight (body condition score 6–8; n = 11), or diabetic (n = 10). Diabetics were newly diagnosed and had not had prior insulin therapy. Preprandial (fasting) and postprandial (60 min after meal) plasma hormone and glucose concentrations were measured at baseline and 2 and 4 wk. All cats were exclusively fed a commercially available high-protein and low-carbohydrate diet commonly prescribed to feline diabetic patients for 2 wk before the 2-wk assessment and continued through the 4-wk assessment. Results showed that plasma concentrations of GLP-1, GIP, PYY, and insulin increased in general after a meal in all study groups. Plasma PYY concentrations did not differ (P > 0.10) between study groups. Diabetics had greater plasma concentrations of GLP-1 and GIP compared with the other study groups at baseline (P < 0.05), and greater preprandial and postprandial GLP-1 concentrations than lean cats at 2 and 4 wk (P < 0.05). Preprandial plasma GIP concentrations were greater in diabetics than obese and lean (P < 0.05) cats at week 4. Postprandial plasma GIP concentrations in diabetics were greater than lean (P < 0.05) at week 2 and obese and lean cats (P < 0.05) at week 4. Together, our findings suggest that diabetic status is an important determinant of circulating concentrations of GLP-1 and GIP, but not PYY, in cats. The role of GLP-1, GIP, and PYY in the pathophysiology of feline obesity and diabetes remains to be determined.

Intraduodenal infusion of a combination of tastants decreases food intake in humans

Taste receptors are expressed not only in taste buds but also in the gastrointestinal tract. It has been hypothesized that these receptors may play a role in satiety and food intake. This study investigated the effect of intraduodenal tastant infusions (bitter, sweet, and umami) on food intake, hunger and fullness, gastrointestinal symptoms, and gastrointestinal peptide release. Fifteen healthy volunteers [6 male; mean ± SEM age: 23.9 ± 2.0 y; mean ± SEM body mass index (in kg/m(2)): 22.4 ± 0.3] received 5 treatments in a double-blind, randomized, placebo-controlled crossover design. Test days started with the insertion of a nasoduodenal catheter followed by a standardized liquid breakfast. Participants received an intraduodenal infusion 150 min after breakfast, containing quinine (bitter), rebaudioside A (sweet), monosodium glutamate (umami), a combination of the 3 tastants, or placebo (tap water) over a period of 60 min. Food intake was measured during an ad libitum meal, and visual analog scales were used to monitor gastrointestinal complaints and hunger and fullness scores. Blood samples were drawn at regular intervals for cholecystokinin, glucagon-like peptide 1 (GLP-1), and peptide YY (PYY) analysis. Infusion of the combination of tastants substantially decreased food intake (422 ± 97 compared with 486 ± 104 kcal for placebo, P < 0.05), whereas both a combination of tastants and umami decreased hunger scores compared with placebo. No change in cholecystokinin, GLP-1, or PYY concentrations was observed during the infusions. Intraduodenal infusions of the tastants did not result in gastrointestinal symptoms. Intraduodenal infusion of umami and a combination of tastants inhibits feelings of hunger, but only the latter also reduces food intake. However, these alterations were not accompanied by changes in the plasma concentrations of the gut-derived peptides cholecystokinin, GLP-1, or PYY. This trial was registered at clinicaltrials.gov as NCT01956838.

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.

Gastrointestinal hormone secretion in women with polycystic ovary syndrome: an observational study.

Is the secretion of gastrointestinal hormones impaired in patients with polycystic ovary syndrome (PCOS)? Gastrointestinal hormone levels were abnormal in patients with PCOS. The hormones glucagon-like peptide-1 (GLP-1) and peptide tyrosine-tyrosine (PYY) are both involved in signaling satiety. Secretion of GLP-1 and PYY in response to nutrients in the small intestine plays an important role in energy metabolism. Most PCOS patients are overweight or obese, which suggests dysregulation of appetite. In order to evaluate levels of gastrointestinal hormones in PCOS, a cohort study was undertaken, involving 30 PCOS patients and 29 BMI-matched healthy women recruited from Shanghai Renji Hospital between 1 March 2013 and 30 May 2014. After an overnight fast, all participants underwent an oral glucose tolerance test. Blood was sampled frequently for measurement of blood glucose and plasma insulin, total GLP-1 and PYY concentrations. Fasting and postprandial insulin levels were significantly higher in patients with PCOS compared with the healthy controls (P < 0.05). Fasting and postprandial GLP-1 (t = 0 and 30 min; mean ± SEM) were also higher in PCOS group (17.5 ± 1.07 pM versus 14.1 ± 1.16 pM, P < 0.05; 29.7 ± 2.39 pM versus 22.8 ± 2.09 pM, P < 0.05). However, there were no differences in plasma PYY between patients with PCOS and healthy controls either fasting or postprandially. PYY levels were lower in obese PCOS patients than in lean PCOS patients (P < 0.05). The study involved a small number of subjects with PCOS, and examined hormone responses to oral glucose rather than a physiological meal. Deficient secretion of GLP-1 and PYY does not contribute to excessive food intake in the pathophysiology of PCOS.

New lessons from gastric bypass: Impact of glucose‐independent islet function

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Autonomic Diabetic Neuropathy Impairs Glucose and Dipeptidyl Peptidase 4 Inhibitor-Regulated Glucagon Concentration in Type 1 Diabetic Patients

Background: Dipeptidyl peptidase 4 inhibitors (DPP4i) could exert their glucagonostatic action through a functional autonomic nervous system independently from insulin secretion. We explored this hypothesis. Methods: We studied C-peptide negative type 1 diabetic patients (T1D) with (AN+) or without (AN-) autonomic neuropathy. Plasma glucagon, active and total glucagon-like peptide-1 (GLP-1), GIP, pancreatic polypeptide (PP), and glucose concentrations were quantified over 180 minutes following a meal test. Furthermore, to increase the plasma concentration of GLP-1 between groups and study its impact on glucagon secretion, 50 mg of vildagliptin and a second meal test were administered to the same patients. Results: The plasma concentration of glucagon was higher in AN+ patients than in AN- patients, which was associated with lower PP and active GLP-1 plasma concentrations. This first set of data suggest that AN, presumably involving parasympathetic activity, results in loss of glucose-regulated glucagon secretion. After DPP4i treatment, AN+ patients lost the ability to suppress plasma glucagon, and the low plasma PP responses were not restored. Conclusions: We here show that a functional autonomic nervous system is required for the proper control of glucagon secretion. The mechanism is insulin-independent. The glucagonostatic action of DPP4i also requires this mechanism. J Endocrinol Metab. 2015;5(4):229-237 doi: http://dx.doi.org/10.14740/jem289w

The role of apolipoprotein A-IV in regulating glucagon-like peptide-1 secretion.

Both glucagon-like peptide-1 (GLP-1) and apolipoprotein A-IV (apoA-IV) are produced from the gut and enhance postprandial insulin secretion. This study investigated whether apoA-IV regulates nutrient-induced GLP-1 secretion and whether apoA-IV knockout causes compensatory GLP-1 release. Using lymph-fistula-mice, we first determined lymphatic GLP-1 secretion by administering apoA-IV before an intraduodenal Ensure infusion. apoA-IV changed neither basal nor Ensure-induced GLP-1 secretion relative to saline administration. We then assessed GLP-1 in apoA-IV-/- and wild-type (WT) mice administered intraduodenal Ensure. apoA-IV-/- mice had comparable lymph flow, lymphatic triglyceride, glucose, and protein outputs as WT mice. Intriguingly, apoA-IV-/- mice had higher lymphatic GLP-1 concentration and output than WT mice 30 min after Ensure administration. Increased GLP-1 was also observed in plasma of apoA-IV-/- mice at 30 min. apoA-IV-/- mice had comparable total gut GLP-1 content relative to WT mice under fasting, but a lower GLP-1 content 30 min after Ensure administration, suggesting that more GLP-1 was secreted. Moreover, an injection of apoA-IV protein did not reverse the increased GLP-1 secretion in apoA-IV-/- mice. Finally, we assessed gene expression of GLUT-2 and the lipid receptors, including G protein-coupled receptor (GPR) 40, GPR119, and GPR120 in intestinal segments. GLUT-2, GPR40 and GPR120 mRNAs were unaltered by apoA-IV knockout. However, ileal GPR119 mRNA was significantly increased in apoA-IV-/- mice. GPR119 colocalizes with GLP-1 in ileum and stimulates GLP-1 secretion by sensing OEA, lysophosphatidylcholine, and 2-monoacylglycerols. We suggest that increased ileal GPR119 is a potential mechanism by which GLP-1 secretion is enhanced in apoA-IV-/- mice.

Glucagon-like peptide-1 preserves non-alcoholic fatty liver disease through inhibition of the endoplasmic reticulum stress-associated pathway.

Glucagon-like peptide-1 (GLP-1) has been increasingly recognized for treating diabetes mellitus, and for its potential to effectively treat non-alcoholic fatty liver disease (NAFLD). However, the mechanisms of GLP-1 induction in NAFLD are not completely known. We investigated whether GLP-1 can protect against NAFLD by alleviating endoplasmic reticulum (ER) stress. Male Sprague-Dawley rats were fed a high-fat diet and treated with a long-acting GLP-1 receptor agonist, liraglutide. Biochemical, morphological, genetic and protein expression of ER stress were investigated. In vitro, HepG2 cells were exposed to 0.4 mM palmitate fatty acid and treated with different concentrations of GLP-1, and ER protein 46 (ERp46) and ER stress pathways were analyzed. Cellular response to ER stress and apoptosis were determined upon transfection with either ERp46 siRNA or a negative control siRNA. In vivo, the treatment of GLP-1 attenuated the hepatic accumulation of lipids, reduced inflammation and improved metabolic parameters. GLP-1 treatment significantly upregulated the expression of ERp46 and downregulated the ER stress marker. Activation of ER pathways was restrained by GLP-1. Similar observations were made in vitro. Furthermore, inhibition of ERp46 expression by siRNA-mediated silencing increased the ER stress response and enhanced cell apoptosis rates. In addition, GLP-1 could not reduce the levels of ER stress and apoptosis in cells transfected with ERp46 siRNA compared with in negative control transfected cells after palmitate treatment. GLP-1 protected against NAFLD by inactivating the ER stress-associated apoptosis pathway. In addition, the effect was possibly related to the signaling pathway of ERp46.

Effects of prepartum fat supplementation on plasma concentrations of glucagon-like peptide-1, peptide YY, adropin, insulin, and leptin in periparturient dairy cows

Dietary fat supplementation during the periparturient period is one strategy to increase energy intake and attenuate the degree of negative energy balance during early lactation; however, little is known of the underlying hormonal and metabolic adaptations. We evaluated the effects of prepartum fat supplementation on energy-balance parameters and plasma concentrations of glucagon-like peptide-1, peptide tyrosine-tyrosine (PYY), adropin, insulin, leptin, glucose, nonesterified fatty acid, and β-hydroxybutyric acid in dairy cows. Twenty-four pregnant dairy cows were randomized to diets containing either rolled canola or sunflower seed at 8% of dry matter, or no oilseed supplementation, during the last 5 wk of gestation and then assigned to a common lactation diet postpartum. Blood samples were collected at −2, +2, and +14 h relative to feeding, at 2 wk after the initiation of the diets, and at 2 wk postpartum. Dietary canola and sunflower supplementation alone did not affect energy balance, body weight, and plasma concentrations of glucagon-like peptide-1, PYY, adropin, insulin, leptin, nonesterified fatty acid, and β-hydroxybutyric acid; however, canola decreased and sunflower tended to decrease dry matter intake. We also observed that the physiological stage had a significant, but divergent, effect on circulating hormones and metabolite concentrations. Plasma glucagon-like peptide-1, PYY, adropin, nonesterified fatty acid, and β-hydroxybutyric acid concentrations were greater postpartum than prepartum, whereas glucose, insulin, leptin, body weight, and energy balance were greater prepartum than postpartum. Furthermore, the interaction of treatment and stage was significant for leptin and adropin, and tended toward significance for PYY and insulin; only insulin exhibited an apparent postprandial increase. Postpartum PYY concentrations exhibited a strong negative correlation with body weight, suggesting that PYY may be associated with body weight regulation during the transition period. These novel findings demonstrate that the transition from pregnancy to lactation is a stronger determinant of circulating gut hormone concentrations than dietary lipid in transition dairy cows.

Prior exercise does not alter the incretin response to a subsequent meal in obese women

Prior research has shown an increase in GLP-1 concentrations during exercise but this exercise bout was conducted postprandially. The purpose of this study was to examine the incretin response to a meal following an exercise bout of different intensities in obese subjects. Eleven women (BMI>37.3±7.0kg/m2; Age 24.3±4.6year) participated in 3 counter- balanced study days, where a standardized meal was preceded by: (1) No exercise (NoEx), (2) ModEx (55% VO2max), and (3) IntEx (4min (80% VO2max)/3min (50% VO2max). Frequent blood samples were analyzed for glucose, lactate, insulin, glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and C-peptide concentrations throughout 280min of testing. Glucose concentrations were not different between conditions during exercise or meals. There were no differences between conditions in insulin levels during exercise and recovery, but postprandial insulin incremental area under the curve was lower in ModEx vs. NoEx (p<0.01). GIP and GLP-1 levels were not different between conditions during exercise, but during exercise recovery, GLP-1 concentrations were higher in ModEx vs. NoEx (p=0.03). The meal increased the incretin responses (p<0.01) but this response was not affected by prior exercise. Glucagon concentrations increased with exercise (p<0.05) and continued to be elevated during recovery, with the greatest increase with IntEx compared with NoEx (p<0.05). No differences between conditions were detected for hepatic insulin extraction, insulin secretion, or insulin sensitivity. Exercise prior to an evening meal has no impact on the incretin response to the subsequent meal, yet insulin concentrations were lower during the meals that followed exercise. Exercise intensity had no impact on this response.

Postprandial glucose, insulin, and glucagon-like peptide-1 responses of different equine breeds adapted to meals containing micronized maize.

The enteroinsular axis is a complex system that includes the release of incretin hormones from the gut to promote the absorption and utilization of glucose after a meal. The insulinogenic effect of incretin hormones such as glucagon-like peptide-1 (GLP-1) remains poorly characterized in the horse. The aim of this study was to compare postprandial glucose, insulin, and GLP-1 responses of different equine breeds adapted to twice-daily meals containing micronized maize. Four Standardbred horses, 4 mixed-breed ponies, and 4 Andalusian cross horses in moderate BCS (5.5 ± 0.2 out of 9) were fed meals at 0800 and 1600 h each day. The meals contained micronized maize (mixed with soaked soybean hulls and lucerne chaff), with the amount of maize gradually increased over 12 wk to reach a final quantity of 1.7 g/kg BW (1.1 g/kg BW starch) in each meal. Animals had ad libitum access to the same hay throughout. After 12 wk of acclimation, serial blood samples were collected from all animals over a 14-h period to measure concentrations of glucose, insulin, and GLP-1, with meals fed immediately after the 0 and 8 h samples. Glucose area under the curve (AUC) values were similar between breed groups (P = 0.41); however, ponies and Andalusian horses exhibited significantly higher insulin AUC values after both meals compared with Standardbred horses (both P < 0.005). Postprandial GLP-1 AUC values were also significantly higher in ponies and Andalusian horses compared with Standardbred horses (breed × time interaction; P < 0.001). Correlation analysis demonstrated a strong positive association between concentrations of insulin and GLP-1 over time (rs = 0.752; P < 0.001). The increased insulin concentrations in ponies and Andalusian horses may partly reflect lower insulin sensitivity but could also be attributed to increased GLP-1 release. Given that hyperinsulinemia is a recognized risk factor for the development of laminitis in domestic equids, this study provides evidence that the enteroinsular axis warrants further investigation.

Defective Glucagon-Like Peptide 1 Secretion in Prediabetes and Type 2 Diabetes Is Influenced by Weight and Sex. Chicken, Egg, or None of the Above?

Glucagon-like peptide 1 (GLP-1) is considered to be the primary incretin hormone, released in response to food ingestion and contributing to meal assimilation. GLP-1 is a powerful insulin secretagogue, stimulating insulin secretion and suppressing glucagon secretion in a glucose-dependent manner (1), and indeed, numerous pharmacologic agents use the GLP-1 pathway to produce effective glucose-lowering therapy (2). Given the antidiabetogenic actions of GLP-1, it is a reasonable question to wonder whether defects in GLP-1 secretion contribute to the pathogenesis of type 2 diabetes. Over the years, multiple studies have examined this question. However, the evidence to suggest decreased GLP-1 secretion in prediabetes and diabetes has been mixed at best, with decreased (3–5), normal (6,7), or increased (8) GLP-1 concentrations reported in subjects with prediabetes or type 2 diabetes. Subsequently, Nauck et al. (9) undertook a meta-analysis of studies comparing active and total GLP-1 in people with diabetes and weight-matched control subjects and concluded that after an oral glucose challenge or after a mixed meal, the integrated, incremental concentrations of GLP-1 did not differ between patients with type 2 diabetes and control subjects. GLP-1 concentrations were unaffected by weight or age. In addition, we examined active and total GLP-1 concentrations in 165 …

High-fat diet feeding significantly attenuates anagliptin-induced regeneration of islets of Langerhans in streptozotocin-induced diabetic mice.

BackgroundDPP-4 inhibitors reportedly exert effects on both alpha and beta cells, and promote the proliferation and survival of beta cells. We investigated the effects of anagliptin on structurally-impaired islets of Langerhans in streptozotocin (STZ)-treated mice, fed either a normal or a high-fat diet. Pdx-1 expression in the pancreas and serum insulin/glucagon concentrations were also examined.FindingsAnagliptin treatment significantly up-regulated pancreatic Pdx-1 expression, with elevated serum glucagon-like peptide-1 concentrations, regardless of whether the diet was normal or high-fat. However, interestingly, the beta cell regeneration, structural normalization of islets of Langerhans including alpha cell: beta cell area ratios, and serum insulin elevation, all observed with anagliptin administration in the animals fed a normal diet, were markedly suppressed in the high-fat fed group.ConclusionsHigh-fat diet feeding clearly weakened the regenerative effects of anagliptin on the islets of Langerhans in STZ-treated mice. Our findings suggest the importance of normalizing lipid metabolism for full manifestation of DPP-4 inhibitor effects on the islets of Langerhans.Electronic supplementary materialThe online version of this article (doi:10.1186/s13098-015-0047-y) contains supplementary material, which is available to authorized users.

Effects of Fat and Protein Preloads on Pouch Emptying, Intestinal Transit, Glycaemia, Gut Hormones, Glucose Absorption, Blood Pressure and Gastrointestinal Symptoms After Roux-en-Y Gastric Bypass.

The aim was to determine the effects of fat and protein preloads on pouch emptying (PE), caecal arrival time (CAT), glucose absorption, blood glucose (BSL), gut hormones, haemodynamics and gastrointestinal (GI) symptoms in subjects who had undergone Roux-en-Y gastric bypass (RYGB) >12 months previously. Ten RYGB subjects were studied on three occasions, in randomised order, receiving 200-ml preloads of either water, fat (30 ml olive oil) or whey protein (55 g), 30 min before a mixed meal. PE, CAT, BSL, plasma 3-O-methyl-D-glucopyranose (3-OMG), insulin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1) and glucagon, blood pressure (BP), heart rate (HR) and GI symptoms were assessed over 270 min. Although fat and protein preloads did not alter PE of either solids or liquids, the CAT of solids, but not liquids, was longer than that after the water preload (fat 68 ± 5 min and protein 71 ± 6 min vs. water 46 ± 5 min; P = 0.02). BSL elevated promptly after the meal on all days (P < 0.001), but after protein, the magnitude and integrated increases in the first 75 min were less than fat and water preloads (area under the curve (AUC(0-75 min)), 18.7 ± 18.2 vs. 107.2 ± 30.4 and 76.1 ± 19.3 mmol/L/min; P < 0.05). Compared to water preload, the protein and fat preloads were associated with greater increases in plasma insulin, GLP-1 and glucagon concentrations, a reduction in BP, and greater increases in HR, fullness, bloating and nausea. Plasma 3-OMG levels were lower after the protein than after the water and fat preloads (P < 0.001). Given its effects to attenuate post-prandial glycaemia, reduce intestinal glucose absorption and potentiate the "incretin response", without inducing more adverse post-prandial GI symptom, protein preload may prove clinically useful in RYGB patients and warrant further evaluation, particularly in those with type 2 diabetes (T2DM) and/or dumping syndrome.

Abstract 671: Glucagon-like Peptide-1 Inhibits Abdominal Aortic Aneurysm Development

Objective: It has been shown that glucagon-like peptide-1 (GLP-1) signaling is protective effect in cardiovascular system. Thus, it is important to elucidate the underlying molecular mechanisms to develop a pharmacological treatment. We examined the effect of DPP-4 inhibitor (Alogliptin) and GLP-1 receptor analog (Lixisenatide) on AAA development. Methods: Thirty AAA model rats were divided into 2 groups: a control group (water) and alogliptin group (3 mg/kg/day). Alogliptin administration by gastric gavage was started at 7 days after aneurysm preparation. On day 14, plasma GLP-1 concentrations were measured with an ELISA. Furthermore we investigated the effect of lixisenatide to elucidate the role of GLP-1 signaling on AAA development, 42 rats were divided into 3 groups: a control group (saline), a low-dose group (10 μg/kg/day), and a high-dose group (100 μg/kg/day). Lixisenatide subcutaneous injection was started at 7 days after aneurysm preparation. Reactive oxygen species (ROS) expression in all groups was evaluated by dihydroethidium staining, and 8-hydroxydeoxyguanosine (8-OHdG) the oxidation product of DNA by immunochemical staining. The effect of GLP-1 signaling on the inflammatory response was also analyzed. Histopathological examinations were performed on day 28 and the AAA dilatation ratio was calculated. Results: On day 14, plasma GLP-1 concentrations were significantly increased by alogliptin (6.3 ± 0.8 pmol/L in Control group, 7.6 ± 0.9 pmol/L in Alogliptin group, p &lt; 0.05). ROS expression and 8-OHdG-positive cells in aneurysm walls were significantly decreased by alogliptin and lixisenatide. They decreased ERK expression in Western blot analysis, and reduced mRNA expression of tumor necrosis factor-α and matrix metallo-proteinases. CD68 positive macrophages infiltration in aneurysm walls were also decreased with treatment. On day 28, alogliptin (199.2 ± 10.0 % in Control group, 155.1 ± 2.3 % in Alogliptin group, p &lt; 0.01) and lixisenatide (188.0 ± 5.6 % in Control, 162.0 ± 6.0 % in Low-dose, and 151.5 ± 4.9 % in High-dose, p &lt; 0.01) prevented aneurysm development. Conclusion: GLP-1 inhibits AAA development through anti-oxidant and anti-inflammatory effects, and it might be a potent pharmacological target for AAA treatment.

A double-blind randomised controlled trial testing the effect of a barley product containing varying amounts and types of fibre on the postprandial glucose response of healthy volunteers.

The aim of the present study was to determine if the consumption of barley tortillas varying in fibre and/or starch composition affected postprandial glucose, insulin, glucagon-like peptide-1 (GLP-1) or peptide YY concentrations. A double-blind, randomised, controlled trial was performed with twelve healthy adults. They each consumed one of five barley tortillas or a glucose drink on six individual visits separated by at least 1 week. Tortillas were made from 100% barley flour blends using five different milling fractions to achieve the desired compositions. All treatments provided 50 g of available carbohydrate and were designed to make the following comparisons: (1) low-starch amylose (0%) v. high-starch amylose (42%) with similar β-glucan and insoluble fibre content; (2) low β-glucan (4.5 g) v. medium β-glucan (7.8 g) v. high β-glucan (11.6 g) with similar starch amylose and insoluble fibre content; and (3) low insoluble fibre (7.4 g) v. high insoluble fibre (19.6 g) with similar starch amylose and β-glucan content. Blood was collected at fasting and at multiple intervals until 180 min after the first bite/sip of the test product. Amylose and insoluble fibre content did not alter postprandial glucose and insulin, but high-β-glucan tortillas elicited a lower glucose and insulin response as compared to the low-β-glucan tortillas. The tortillas with high insoluble fibre had a higher AUC for GLP-1 as compared to the tortillas with low insoluble fibre, whereas amylose and β-glucan content had no effect. Results show that processing methods can be used to optimise barley foods to reduce postprandial blood glucose responses and factors that may influence satiety.

Cardiovascular Changes After Gastric Bypass Surgery: Involvement of Increased Secretions of Glucagon-Like Peptide-1 and Brain Natriuretic Peptide.

Obesity induces cardiovascular alterations, including cardiac hypertrophy, impaired relaxation, and heart rate variability (HRV), which are associated with increased mortality. Gastric bypass surgery (GBP) reduces cardiovascular mortality, but the mechanisms involved are not clearly established. To date, the implication of postsurgical hormonal changes has not been tested. Our aim was to study the relationships between the evolution of cardiovascular functions after GBP and changes in metabolic and hormonal parameters, including glucagon-like peptide-1 (GLP-1) and brain natriuretic peptide (N-terminal pro-brain natriuretic peptide (NT-proBNP)). Echocardiographic parameters, 24-h rhythmic Holter recording, plasma concentrations of GLP-1 before and after a test meal, and fasting NT-proBNP were assessed in 34 patients (M/F 2/32, age 36 ± 11 years, BMI 46 ± 6 kg/m(2)), before and 1 year after GBP. After GBP, excess weight loss was 79 ± 20%. Blood pressure (BP), heart rate, and left ventricular mass decreased, while HRV and diastolic function (E/A ratio) improved. Plasma concentrations of NT-proBNP and postprandial (PP) GLP-1 increased. Changes in cardiovascular parameters were related to BMI and insulin sensitivity. Furthermore, the decrease in BP was independently associated with the increase of PP GLP-1 level and HRV was positively associated with NT-proBNP concentration after surgery. The increase in endogenous GLP-1 observed after GBP was associated with decreased BP but not with improvement of other cardiovascular parameters, whereas the increase in NT-proBNP, within the physiological range, was associated with improved HRV.

Slow potentials encode intercellular coupling and insulin demand in pancreatic beta cells.

Ion fluxes constitute a major integrative signal in beta cells that leads to insulin secretion and regulation of gene expression. Understanding these electrical signals is important for deciphering the endogenous algorithms used by islets to attain homeostasis and for the design of new sensors for monitoring beta cell function. Mouse and human islets were cultured on multielectrode arrays (MEAs) for 3-13days. Extracellular electrical activities received on each electrode were continuously amplified and recorded for offline characterisation. Differential band-pass filtering of MEA recordings of mouse islets showed two extracellular voltage waveforms: action potentials (lasting 40-60ms) and very robust slow potentials (SPs, lasting 800-1,500ms), the latter of which have not been described previously. The frequency of SPs directly correlated with glucose concentration, peaked at 10mmol/l glucose and was further augmented by picomolar concentrations of glucagon-like peptide-1. SPs required the closure of ATP-dependent potassium channels as they were induced by glucose or glibenclamide but were not elicited by KCl-induced depolarisation. Pharmacological tools and the use of beta cell specific knockout mice showed that SPs reflected cell coupling via connexin 36. Moreover, increasing and decreasing glucose ramps showed hysteresis with reduced glucose sensitivity during the decreasing phase. SPs were also observed in human islets and could be continuously recorded over 24h. This novel electrical signature reflects the syncytial function of the islets and is specific to beta cells. Moreover, the observed hysteresis provides evidence for an endogenous algorithm naturally present in islets to protect against hypoglycaemia.