Glucagon-like Peptide-1 Concentrations Research Articles

The incretin hormone glucagon‐like peptide 1 increases mitral cell excitability by decreasing conductance of a voltage‐dependent potassium channel

Key points The gut hormone called glucagon‐like peptide 1 (GLP‐1) is a strong moderator of energy homeostasis and communication between the peripheral organs and the brain.GLP‐1 signalling occurs in the brain; using a newly developed genetic reporter line of mice, we have discovered GLP‐synthesizing cells in the olfactory bulb.GLP‐1 increases the firing frequency of neurons (mitral cells) that encode olfactory information by decreasing activity of voltage‐dependent K channels (Kv1.3).Modifying GLP‐1 levels, either therapeutically or following the ingestion of food, could alter the excitability of neurons in the olfactory bulb in a nutrition or energy state‐dependent manner to influence olfactory detection or metabolic sensing.The results of the present study uncover a new function for an olfactory bulb neuron (deep short axon cells, Cajal cells) that could be capable of modifying mitral cell activity through the release of GLP‐1. This might be of relevance for the action of GLP‐1 mimetics now widely used in the treatment of diabetes. The olfactory system is intricately linked with the endocrine system where it may serve as a detector of the internal metabolic state or energy homeostasis in addition to its classical function as a sensor of external olfactory information. The recent development of transgenic mGLU‐yellow fluorescent protein mice that express a genetic reporter under the control of the preproglucagon reporter suggested the presence of the gut hormone, glucagon‐like peptide (GLP‐1), in deep short axon cells (Cajal cells) of the olfactory bulb and its neuromodulatory effect on mitral cell (MC) first‐order neurons. A MC target for the peptide was determined using GLP‐1 receptor binding assays, immunocytochemistry for the receptor and injection of fluorescence‐labelled GLP‐1 analogue exendin‐4. Using patch clamp recording of olfactory bulb slices in the whole‐cell configuration, we report that GLP‐1 and its stable analogue exendin‐4 increase the action potential firing frequency of MCs by decreasing the interburst interval rather than modifying the action potential shape, train length or interspike interval. GLP‐1 decreases Kv1.3 channel contribution to outward currents in voltage clamp recordings as determined by pharmacological blockade of Kv1.3 or utilizing mice with Kv1.3 gene‐targeted deletion as a negative control. Because fluctuations in GLP‐1 concentrations monitored by the olfactory bulb can modify the firing frequency of MCs, olfactory coding could change depending upon nutritional or physiological state. As a regulator of neuronal activity, GLP‐1 or its analogue may comprise a new metabolic factor with a potential therapeutic target in the olfactory bulb (i.e. via intranasal delivery) for controlling an imbalance in energy homeostasis.

Short-term aerobic exercise training improves gut peptide regulation in nonalcoholic fatty liver disease

Obesity-related nonalcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease. Exercise and diet are uniformly prescribed treatments for NAFLD; however, there are limited empirical data on the effects of exercise training on metabolic function in these patients. The purpose of this study was to investigate the fasting and glucose-stimulated adaptation of gut peptides to short-term aerobic exercise training in patients with NAFLD. Twenty-two obese subjects, 16 with NAFLD [body mass index (BMI), 33.2 ± 1.1 (SE) kg/m(2)] and 6 obese controls (BMI, 31.3 ± 1.2 kg/m(2)), were enrolled in a supervised aerobic exercise program (60 min/day, 85% of their heart rate maximum, for 7 days). Fasting and glucose-stimulated glucagon-like peptide-1 (GLP-17-36) and peptide tyrosine tyrosine (PYYTotal) concentrations in plasma were assessed before and after the exercise program. Initially, the NAFLD group had higher fasting PYY (NAFLD = 117 ± 18.6, control = 47.2 ± 6.4 pg/ml, P < 0.05) and GLP-1 (NAFLD = 12.4 ± 2.2, control = 6.2 ± 0.2 pg/ml, P < 0.05) and did not significantly increase GLP-1 or PYY in response to glucose ingestion. After the exercise program, fasting GLP-1 was reduced in the NAFLD group (10.7 ± 2.0 pg/ml, P < 0.05). Furthermore, exercise training led to significant increase in the acute (0-30 min) PYY and GLP-1 responses to glucose in the NAFLD group, while the total area under the glucose-stimulated GLP-1 response curve was reduced in both NAFLD and controls (P < 0.05). In summary, 7 days of vigorous aerobic exercise normalized the dynamic PYY and GLP-1 responses to nutrient stimulation and reduced the GLP-1 response in NAFLD, suggesting that exercise positively modulates gut hormone regulation in obese adults with NAFLD.

Duodenal fatty acid sensor and transporter expression following acute fat exposure in healthy lean humans

Free fatty acids (FFAs) and their derivatives are detected by G-protein coupled receptors (GPRs) on enteroendocrine cells, with specific transporters on enterocytes. It is unknown whether acute fat exposure affects FFA sensors/transporters, and whether this relates to hormone secretion and habitual fat intake. We studied 20 healthy participants (10M, 10F; BMI: 22±1kg/m2; age: 28±2 years), after an overnight fast, on 2 separate days. On the first day, duodenal biopsies were collected endoscopically before, and after, a 30-min intraduodenal (ID) infusion of 10% Intralipid®, and relative transcript expression of FFA receptor 1 (FFAR1), FFA receptor 4 (FFAR4), GPR119 and the FFA transporter, cluster of differentiation-36 (CD36) was quantified from biopsies. On the second day, ID Intralipid® was infused for 120-min, and plasma concentrations of cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) evaluated. Habitual dietary intake was assessed using food frequency questionnaires (FFQs). ID Intralipid® increased expression of GPR119, but not FFAR1, FFAR4 and CD36, and stimulated CCK and GLP-1 secretion. Habitual polyunsaturated fatty acid (PUFA) consumption was negatively associated with basal GPR119 expression. GPR119 is an early transcriptional responder to duodenal lipid in lean humans, although this response appeared reduced in individuals with high PUFA intake. These observations may have implications for downstream regulation of gut hormone secretion and appetite. This study was registered as a clinical trial with the Australia and New Zealand Clinical Trial Registry (Trial number: ACTRN12612000376842).

Jejunal feeding is followed by a greater rise in plasma cholecystokinin, peptide YY, glucagon-like peptide 1, and glucagon-like peptide 2 concentrations compared with gastric feeding in vivo in humans: a randomized trial

Jejunal feeding is preferred instead of gastric feeding in patients who are intolerant to gastric feeding or at risk of aspiration. However, the impact of gastric feeding compared with that of jejunal feeding on postprandial circulating plasma glucose and amino acid concentrations and the associated endocrine response in vivo in humans remains largely unexplored. We compared the impact of administering enteral nutrition as either gastric feeding or jejunal feeding on endocrine responses in vivo in humans. In a randomized, crossover study design, 12 healthy young men (mean ± SD age: 21 ± 2 y) received continuous enteral nutrition that contained noncoagulating proteins for 12 h via a nasogastric tube or a nasojejunal tube placed 30-40 cm distal to the ligament of Treitz. Blood samples were collected during the 12-h postprandial period to assess the rise in plasma glucose, amino acid, and gastrointestinal hormone concentrations. No differences were observed in the postprandial rise in circulating plasma amino acid and glucose concentrations between regimens. Jejunal feeding resulted in higher peak plasma insulin concentrations than did gastric feeding (392 ± 53 compared with 326 ± 54 pmol/L, respectively; P < 0.05). The postprandial rise in plasma cholecystokinin, peptide YY (PYY), glucagon-like peptide 1 (GLP-1), and glucagon-like peptide 2 (GLP-2) concentrations was greater after jejunal feeding than after gastric feeding, with higher peak concentrations and a greater postprandial incremental AUC for GLP-1 and cholecystokinin (all P < 0.05). Plasma ghrelin concentrations did not differ between regimens. Enteral nutrition with gastric or jejunal feeding in healthy young men results in similar postprandial plasma amino acid and glucose concentrations. However, the endocrine response differs substantially, with higher peak plasma cholecystokinin, PYY, GLP-1, and GLP-2 concentrations being attained after jejunal feeding. This effect may result in an improved anabolic response, greater insulin sensitivity, and an improved intestinotropic effect. Nevertheless, it may also lead to delayed gastric emptying. This trial was registered at trialregister.nl as NTR2801.

Capsaicin-induced satiety is associated with gastrointestinal distress but not with the release of satiety hormones

Capsaicin, which is the major pungent principle in chili peppers, is able to induce satiety and reduce caloric intake. The exact mechanism behind this satiating effect is still unknown. We hypothesized that capsaicin induces satiety through the release of gastrointestinal peptides, such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), from enteroendocrine cells in the small intestine. We investigate the effects of an intraduodenal capsaicin infusion (1.5 mg pure capsaicin) in healthy volunteers on hunger, satiety, and gastrointestinal symptoms and the release of GLP-1 and PYY. Thirteen participants (7 women) [mean ± SEM age: 21.5 ± 0.6 y; body mass index (in kg/m(2)): 22.8 ± 0.6] participated in this single-blind, randomized, placebo-controlled crossover study with 2 different treatments. During test days, an intraduodenal infusion of either capsaicin or a placebo (physiologic saline) was performed with the use of a nasoduodenal catheter over a period of 30 min. Visual analog scale scores were used to measure hunger, satiety, and gastrointestinal symptoms. Blood samples were drawn at regular intervals for GLP-1 and PYY. Gallbladder volumes were measured with the use of real-time ultrasonography. The intraduodenal capsaicin infusion significantly increased satiety (P-treatment effect < 0.05) but also resulted in an increase in the gastrointestinal symptoms pain (P-treatment × time interaction < 0.0005), burning sensation (P-treatment × time interaction < 0.0001), nausea (P-treatment × time interaction < 0.05), and bloating (P-treatment × time interaction < 0.001) compared with the effects of the placebo infusion. Satiety scores had a positive correlation with all gastrointestinal symptoms. No differences in GLP-1 and PYY concentrations and gallbladder volumes were observed after the capsaicin infusion compared with after the placebo infusion. An intraduodenal infusion of capsaicin significantly increases satiety but does not affect plasma concentrations of GLP-1 and PYY. Rather, the effect on satiety seems related to gastrointestinal stress as shown by the associations with pain, burning sensation, nausea, and bloating scores. This trial was registered at clinicaltrials.gov as NCT01667523.

Effects of endogenous GLP-1 and GIP on glucose tolerance after Roux-en-Y gastric bypass surgery.

Exaggerated secretion of glucagon-like peptide 1 (GLP-1) is important for postprandial glucose tolerance after Roux-en-Y gastric bypass (RYGB), whereas the role of glucose-dependent insulinotropic polypeptide (GIP) remains to be resolved. We aimed to explore the relative importance of endogenously secreted GLP-1 and GIP on glucose tolerance and β-cell function after RYGB. We used DPP-4 inhibition to enhance concentrations of intact GIP and GLP-1 and the GLP-1 receptor antagonist exendin-(9-39) (Ex-9) for specific blockage of GLP-1 actions. Twelve glucose-tolerant patients were studied after RYGB in a randomized, placebo-controlled, 4-day crossover study with standard mixed-meal tests and concurrent administration of placebo, oral sitagliptin, Ex-9 infusion, or combined Ex-9-sitagliptin. GLP-1 receptor antagonism increased glucose excursions, clearly attenuated β-cell function, and aggravated postprandial hyperglucagonemia compared with placebo, whereas sitagliptin had no effect despite two- to threefold increased concentrations of intact GLP-1 and GIP. Similarly, sitagliptin did not affect glucose tolerance or β-cell function during GLP-1R blockage. This study confirms the importance of GLP-1 for glucose tolerance after RYGB via increased insulin and attenuated glucagon secretion in the postprandial state, whereas amplification of the GIP signal (or other DPP-4-sensitive glucose-lowering mechanisms) did not appear to contribute to the improved glucose tolerance seen after RYGB.

Plasma Free Amino Acid Responses to Intraduodenal Whey Protein, and Relationships with Insulin, Glucagon-Like Peptide-1 and Energy Intake in Lean Healthy Men.

This study determined the effects of increasing loads of intraduodenal (ID) dairy protein on plasma amino acid (AA) concentrations, and their relationships with serum insulin, plasma glucagon-like peptide-1 (GLP-1) and energy intake. Sixteen healthy men had concentrations of AAs, GLP-1 and insulin measured in response to 60-min ID infusions of hydrolysed whey protein administered, in double-blinded and randomised order, at 2.1 (P2.1), 6.3 (P6.3) or 12.5 (P12.5) kJ/min (encompassing the range of nutrient emptying from the stomach), or saline control (C). Energy intake was quantified immediately afterwards. Compared with C, the concentrations of 19/20 AAs, the exception being cysteine, were increased, and this was dependent on the protein load. The relationship between AA concentrations in the infusions and the area under the curve from 0 to 60 min (AUC0–60 min) of each AA profile was strong for essential AAs (R2 range, 0.61–0.67), but more variable for non-essential (0.02–0.54) and conditional (0.006–0.64) AAs. The AUC0–60 min for each AA was correlated directly with the AUC0–60 min of insulin (R2 range 0.3–0.6), GLP-1 (0.2–0.6) and energy intake (0.09–0.3) (p < 0.05, for all), with the strongest correlations being for branched-chain AAs, lysine, methionine and tyrosine. These findings indicate that ID whey protein infused at loads encompassing the normal range of gastric emptying increases plasma concentrations of 19/20 AAs in a load-dependent manner, and provide novel information on the close relationships between the essential AAs, leucine, valine, isoleucine, lysine, methionine, and the conditionally-essential AA, tyrosine, with energy intake, insulin and GLP-1.

Acute Exercise and Appetite-Regulating Hormones in Overweight and Obese Individuals: A Meta-Analysis.

In lean individuals, acute aerobic exercise is reported to transiently suppress sensations of appetite, suppress blood concentrations of acylated ghrelin (AG), and increase glucagon-like peptide-1 (GLP-1) and peptide-YY (PYY). Findings in overweight/obese individuals have yet to be synthesised. In this systematic review and meta-analysis, we quantified the effects that acute exercise has on AG and total PYY and GLP-1 in overweight/obese individuals. The potential for body mass index (BMI) to act as a moderator for AG was also explored. Six published studies (73 participants, 78% male, mean BMI: 30.6 kg·m−2) met the inclusion criteria. Standardised mean differences (SMDs) and standard errors were extracted for AG and total PYY and GLP-1 concentrations in control and exercise trials and synthesised using a random effects meta-analysis model. BMI was the predictor in metaregression for AG. Exercise moderately suppressed AG area-under-the-curve concentrations (pooled SMD: −0.34, 95% CI: −0.53 to −0.15). The magnitude of this reduction was greater for higher mean BMIs (pooled metaregression slope: −0.04 SMD/kg·m−2 (95% CI: −0.07 to 0.00)). Trivial SMDs were obtained for total PYY (0.10, 95% CI: −0.13 to 0.31) and GLP-1 (−0.03, 95% CI: −0.18 to 0.13). This indicates that exercise in overweight/obese individuals moderately alters AG in a direction that could be associated with decreased hunger and energy intake. This trial is registered with PROSPERO: CRD42014006265.

Model-Based Quantification of Glucagon-Like Peptide-1–Induced Potentiation of Insulin Secretion in Response to a Mixed Meal Challenge

Glucagon-like peptide-1 (GLP-1) is a powerful insulin secretagogue that is secreted in response to meal ingestion. The ability to quantify the effect of GLP-1 on insulin secretion could provide insights into the pathogenesis and treatment of diabetes. We used a modification of a model of GLP-1 action on insulin secretion using data from a hyperglycemic clamp with concomitant GLP-1 infusion. We tested this model using data from a mixed meal test (MMT), thereby measuring GLP-1-induced potentiation of insulin secretion in response to a meal. The GLP-1 model is based on the oral C-peptide minimal model and assumes that over-basal insulin secretion depends linearly on GLP-1 concentration through the parameter Π, representing the β-cell sensitivity to GLP-1. The model was tested on 62 subjects across the spectrum of glucose tolerance (age, 53 ± 1 years; body mass index, 29.7 ± 0.6 kg/m(2)) studied with an MMT and provided a precise estimate of both β-cell responsivity and Π indices. By combining Π with a measure of L-cell responsivity to glucose, one obtains a potentiation index (PI) (i.e., a measure of the L-cell's function in relation to prevailing β-cell sensitivity to GLP-1). Model-based measurement of GLP-1-induced insulin secretion demonstrates that the PI is significantly reduced in people with impaired glucose tolerance, compared with those with normal glucose tolerance. We describe a model that can quantitate the GLP-1-based contribution to insulin secretion in response to meal ingestion. This methodology will allow a better understanding of β-cell function at various stages of glucose tolerance.

Supplementation with a fish protein hydrolysate (Micromesistius poutassou): effects on body weight, body composition, and CCK/GLP-1 secretion

BackgroundFish protein hydrolysates (FPHs) have been reported as a suitable source of proteins for human nutrition because of their balanced amino acid composition and positive effect on gastrointestinal absorption.ObjectiveHere, we investigated the effect of a FPH, Slimpro®, obtained from blue whiting (Micromesistius poutassou) muscle by enzymatic hydrolysis, on body composition and on stimulating cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) secretion.DesignA randomized clinical study was carried out on 120, slightly overweight (25 kg/m2 ≤ BMI<30 kg/m2), male (25%) and female (75%) subjects. FPH was tested in a food supplement at two doses (1.4 and 2.8 g) to establish if a dose–effect relationship exists. Product use was associated with a mild hypocaloric diet (−300 kcal/day). Body composition (body weight; fat mass; extracellular water; and circumference of waist, thighs, and hips) and CCK/GLP-1 blood levels were measured at the beginning of the study and after 45 and 90 days of product use. CCK/GLP-1 levels were measured since they are involved in controlling food intake.ResultsTreated subjects reported an improvement of body weight composition and an increased blood concentration of both CCK and GLP-1. No differences were found between the 1.4 and 2.8 g FPH doses, indicating a plateau effect starting from 1.4 g FPH.ConclusionsBoth 1.4 and 2.8 g of FPH were effective in improving body composition and in increasing CCK and GLP-1 blood levels.

Administration of resveratrol for 5 wk has no effect on glucagon-like peptide 1 secretion, gastric emptying, or glycemic control in type 2 diabetes: a randomized controlled trial

Resveratrol has been reported to lower glycemia in rodent models of type 2 diabetes associated with the stimulation of glucagon-like peptide 1 (GLP-1), which is known to slow gastric emptying, stimulate insulin secretion, and suppress glucagon secretion and energy intake. We evaluated the effects of 5 wk of resveratrol treatment on GLP-1 secretion, gastric emptying, and glycemic control in type 2 diabetes. Fourteen patients with diet-controlled type-2 diabetes [mean ± SEM glycated hemoglobin (HbA1c): 6.4 ± 0.2% (46.4 ± 2.2 mmol/mol)] received resveratrol (500 mg twice daily) or a placebo over two 5-wk intervention periods with a 5-wk washout period in between in a double-blind, randomized, crossover design. Before and after each intervention period (4 visits), body weight and HbA1c were measured, and patients were evaluated after an overnight fast with a standardized mashed-potato meal labeled with 100 μg (13)C-octanoic acid to measure blood glucose and plasma GLP-1 concentrations and gastric emptying (breath test) over 240 min. Daily energy intake was estimated from 3-d food diaries during the week before each visit. Fasting and postprandial blood glucose and plasma total GLP-1 as well as gastric emptying were similar at each assessment, and the change in each variable from weeks 0 to 5 did not differ between resveratrol and placebo groups. Similarly, changes in HbA1c, daily energy intake, and body weight after 5 wk did not differ between the 2 treatments. In patients with diet-controlled type 2 diabetes, 5 wk of twice-daily 500 mg-resveratrol supplementation had no effect on GLP-1 secretion, glycemic control, gastric emptying, body weight, or energy intake. Our observations do not support the use of resveratrol for improving glycemic control. This trial was registered at www.anzctr.org.au as ACTRN12613000717752.

Stromal Derived Factor 1 alpha (SDF-1a) in a Dual Therapy with the DPP-4 Inhibitor 1 Vildagliptin does not Enhance Beta Cell Function but Improves Glucose Clearance after Oral Glucose in Streptozotocin Diabetic Mice

Pancreatic alpha cells secrete glucagon-like peptide 1 (GLP-1), the production of which is enhanced by the chemokine stromal derived factor 1 (SDF-1). Since SDF-1, like GLP-1, is a substrate of dipeptidyl peptidase-4 (DPP-4), we examined whether dual therapy with SDF-1 and a DPP-4 inhibitor would preserve beta cell function and mass in diabetes. Diabetes was induced by daily injections of streptozotocin for 5 days. One diabetic group was treated with daily injections of SDF-1 alpha or vehicle for 5 days. These mice were concurrently treated with either the DPP-4 inhibitor vildagliptin or vehicle and they remained on vildagliptin or vehicle for an additional 3 weeks. Glucose clearance and beta cell function was evaluated from glucose and insulin data during OGTTs performed after 0, 2 and 4 weeks of treatment. Beta cell mass was determined histologically. Body weight did not differ between diabetic groups during the study. OGTT data showed that diabetic mice treated with SDF-1 alpha in combination with vildagliptin had increased glucose clearance which was not observed with vildagliptin alone. In contrast, vildagliptin alone enhanced beta cell function with no further enhancement by the combination with SDF-1 alpha. Beta cell mass and islet GLP-1 content were not altered by the treatments. In conclusion, SDF-1 alpha and vildagliptin combination therapy improves glucose clearance in streptozotocin induced diabetes in the mouse by an effect which seems independent from enhanced beta cell function.

Esophageal and Gastric Dysmotilities are Associated with Altered Glucose Homeostasis and Plasma Levels of Incretins and Leptin.

Gastrointestinal complications in diabetes may affect glucose and endocrine homeostasis. Glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1), and leptin regulate glucose homeostasis, food intake, and gastric emptying. The aim was to investigate associations between diabetes complications and glucose homeostasis and plasma levels of GIP, GLP-1, and leptin. Sixteen diabetes patients (seven men) were examined with gastric emptying scintigraphy and 72-h continuous subcutaneous glucose monitoring, 14 with the deep-breathing test, and 12 with esophageal manometry. A fiber-rich breakfast was given during the second day of glucose registration. Blood samples were taken 10 min and right before a fat-rich breakfast, as well as 10, 20, 30, 45, 60, 90, 120, 150, and 180 min afterwards. 20 healthy volunteers acted as controls. Plasma was analyzed regarding GIP, GLP-1, and leptin by Luminex. Gastroparesis lowered maximal concentration (c-max) (p = 0.003) and total area under the curve (tAUC) (p = 0.019) of glucose levels as well as d-min (p = 0.043) of leptin levels. It tended to lower baseline (p = 0.073), c-max (p = 0.066), change from baseline (d-max) (p = 0.073), and tAUC (p = 0.093) of GLP-1 concentrations. Esophageal dysmotility tended to lower tAUC of glucose levels (p = 0.063), and c-min (p = 0.065) and tAUC (p = 0.063) of leptin levels. Diabetes patients had a higher baseline concentration of glucose (p = 0.013), GIP (p = 0.023), and leptin (p = 0.019) compared with healthy subjects. Gastric and esophageal dysmotility are associated with both lesser increases in postprandial glucose elevations and decreased postprandial changes in GLP-1 and leptin.

Improved glucose metabolism following bariatric surgery is associated with increased circulating bile acid concentrations and remodeling of the gut microbiome.

Clinical studies have indicated that circulating bile acid (BA) concentrations increase following bariatric surgery, especially following malabsorptive procedures such as Roux-en-Y gastric bypasses (RYGB). Moreover, total circulating BA concentrations in patients following RYGB are positively correlated with serum glucagon-like peptide-1 concentrations and inversely correlated with postprandial glucose concentrations. Overall, these data suggest that the increased circulating BA concentrations following bariatric surgery - independently of calorie restriction and body-weight loss - could contribute, at least in part, to improvements in insulin sensitivity, incretin hormone secretion, and postprandial glycemia, leading to the remission of type-2 diabetes (T2DM). In humans, the primary and secondary BA pool size is dependent on the rate of biosynthesis and the enterohepatic circulation of BAs, as well as on the gut microbiota, which play a crucial role in BA biotransformation. Moreover, BAs and gut microbiota are closely integrated and affect each other. Thus, the alterations in bile flow that result from anatomical changes caused by bariatric surgery and changes in gut microbiome may influence circulating BA concentrations and could subsequently contribute to T2DM remission following RYGB. Research data coming largely from animal and cell culture models suggest that BAs can contribute, via nuclear farnezoid X receptor (FXR) and membrane G-protein-receptor (TGR-5), to beneficial effects on glucose metabolism. It is therefore likely that FXR, TGR-5, and BAs play a similar role in glucose metabolism following bariatric surgery in humans. The objective of this review is to discuss in detail the results of published studies that show how bariatric surgery affects glucose metabolism and subsequently T2DM remission.

Plasma Concentrations of GLP-1 and PYY in Rats Fed Dietary Fiber Depend on the Fermentability of Dietary Fiber and Respond to an Altered Diet

Background: It was reported to be associated with intake of dietary fiber and gut hormone. We compared the effect of dietary fiber on the plasma concentration of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). Methods: Firstly, male Wistar rats (10 wk old) were fed a fiber-free diet (FF diet, AIN-93G-based diet without cellulose) or one of nine FF diets with 5% dietary fiber for 21 days. Cellulose, guar gam (GG), partially hydrolyzed guar gum (PHGG), sugar beet fiber (BF), konjac mannnan (KM), raffinose (RF), hydroxypropyl starch (HPS), hydroxypropyl distarch phosphate (HPDP) and Akamoku (AK) were used as dietary fiber sources. Secondly, we then determined whether the concentrations of GLP-1 and PYY in portal and aorta plasma and microbiota in cecal contents responded to an altered diet. Male Wistar rats (10 wk old) were fed the PHGG diet for 20 days before being changed to the FF diet. Results: The amount of short chain fatty acids (SCFA) in the cecal contents markedly increased in rats fed the GG, PHGG, BF, KM, RF, HPS or HPDP diets compared with SCFA in rats fed the FF, CL or AK diets. The concentrations of GLP-1 and PYY in portal plasma positively correlated with the concentration of SCFA in the cecal contents and cecal tissue weight. The concentrations of GLP-1 and PYY, in the altered diet group decreased to the same concentration as that measured in the FF group. However, it was low the similarities in the cecal bacteria population. Conclusion: The plasma concentrations of GLP-1 and PYY increased with increasing the amounts of SCFA, the products of DF fermentation, in the cecal contents. GLP-1 and PYY plasma concentrations and SCFA concentrations in the cecal contents rapidly responded to the altered diet, but the cecal bacteria population did not.

Efficacy and safety of liraglutide for overweight adult patients with type 1 diabetes and insufficient glycaemic control (Lira-1): a randomised, double-blind, placebo-controlled trial

The combination of insulin and glucagon-like peptide-1 (GLP-1) receptor agonist therapy improves glycaemic control, induces weight loss, and reduces insulin dose needed in type 2 diabetes. We assessed the efficacy and safety of the GLP-1 receptor agonist liraglutide as an add-on therapy to insulin for overweight adult patients with type 1 diabetes. We did a randomised, double-blind, placebo-controlled trial at Steno Diabetes Center (Gentofte, Denmark). Patients aged 18 years or older with type 1 diabetes, insufficient glycaemic control (HbA1c >8% [64 mmol/mol]), and overweight (BMI >25 kg/m(2)) were randomly assigned (1:1) to receive insulin treatment plus either liraglutide or placebo (saline solution) by subcutaneous injection once per day. Randomisation was done in blocks of four. Treatment assignment was masked to investigators and patients. Treatment lasted 24 weeks and liraglutide was started at a dose of 0·6 mg per day, escalated to 1·2 mg per day after 1 week, and then again to 1·8 mg per day after another week. Intervals between dose increments could be extended at the discretion of the investigator. The primary endpoint was change in HbA1c from baseline to week 24. Secondary endpoints were changes in hypoglycaemic events, glycaemic variability, glycaemic excursions, insulin dose, bodyweight, postprandial plasma concentrations of glucagon and GLP-1, gastric emptying, blood pressure, heart rate, patient-reported outcome measures, time spent in hypoglycaemia, near-normoglycaemia, and hyperglycaemia, plasma fasting glucose, mean glucose, and cholesterol. Efficacy analyses were calculated by use of a mixed model, whereby a patient's data are used as long as the patient is in the study. The safety analyses were done in the intention-to-treat population, which consisted of all patients who received at least one dose of their randomly assigned study drug. This study is registered with ClinicalTrials.gov, number NCT01612468. Between July 10, 2012, and May 30, 2014, we enrolled 100 patients with type 1 diabetes, with 50 patients allocated liraglutide and 50 to placebo. Four patients from the liraglutide group and six patients from the placebo group discontinued treatment before 24 weeks. At the end of treatment, change in HbA1c from baseline did not differ between groups (-0·5%, 95% CI -0·8 to -0·4 [-6·0 mmol/mol, 95% CI -8·7 to -4·4] with liraglutide vs -0·3%, -0·6 to -0·2 [-4·0 mmol/mol, -6·6 to -2·3] with placebo; between-group difference -0·2% [-0·5 to 0·1; 2·2 mmol/mol, -5·5 to 1·1], p=0·1833). The number of hypoglycaemic events was reduced with liraglutide, with an incident rate ratio of 0·82 (95% CI 0·74 to 0·90). However, we detected no changes in glycaemic variability (continuous overall net glycaemic action per 60 min from 10·3 [95% CI 9·8 to 10·8] to 9·9 [9·2 to 10·6] in the liraglutide treated patients vs 10·2 [9·7 to 10·7] to 9·7 [9·1 to 10·3] in the placebo treated patients). Both bolus insulin (difference -5·8 IU, 95% CI -10·7 to -0·8, p=0·0227) and bodyweight (difference -6·8 kg, 95% CI -12·2 to -1·4, p=0·0145) decreased with liraglutide treatment compared with placebo. Heart rate increased with liraglutide, with a difference between groups of 7·5 bpm (95% CI 2·8-12·2, p=0·0019). Postprandial plasma glucagon and GLP-1 concentrations did not differ between groups (difference between groups at end of treatment: -408 mmol/L per 240 min [95% CI -941 to 125, p=0·1309] for glucagon and -266 mmol/L per 240 min [-1034 to 501, p=0·4899] for GLP-1). Gastric emptying was delayed after 3 weeks of treatment with liraglutide (19·9 min, 95% CI 0·8 to 39·0, p=0·0412), but we detected no difference after 24 weeks of treatment (-1·5 min, -20·5 to 17·6, p=0·8793). Patient-reported outcome measures differed between groups only with respect to perceived frequency of hypoglycaemia, which was higher with placebo, with a difference between groups of -0·6 (95% CI -1·1 to -0·07, p=0·0257). Liraglutide was associated with more frequent nausea (29 [58%] patients with liraglutide vs five [10%] with placebo), dyspepsia (11 [22%] patients with liraglutide vs one [2%] with placebo), diarrhoea (ten [20%] patients with liraglutide vs one [2%] with placebo), decreased appetite (seven patients [14%] with liraglutide vs none with placebo), and vomiting (seven [14%] patients with liraglutide vs one [2%] with placebo). In patients with type 1 diabetes, overweight, and insufficient glycaemic control, the reduction in HbA1c did not differ between insulin plus placebo and insulin plus liraglutide treatment. Liraglutide was associated with reductions in hypoglycaemic events, bolus and total insulin dose, and bodyweight, and increased heart rate. Novo Nordisk.

The effect of glucose when added to a fat load on the response of glucagon-like peptide-1 (GLP-1) and apolipoprotein B-48 in the postprandial phase.

Increased and prolonged postprandial lipemia has been identified as a risk factor of cardiovascular disease. However, there is no consensus on how to test postprandial lipemia, especially with respect to the composition of an experimental meal. To address this question of how glucose, when added to a fat load, affects the selected parameters of postprandial lipemia, we carried out a study in 30 healthy male volunteers. Men consumed an experimental meal containing either 75 g of fat + 25 g of glucose (F+G meal) or 75 g of fat (F meal) in a control experiment. Blood was taken before the meal and at selected time points within the following 8 h. Glucose, when added to a fat load, induced an increase of glycemia and insulinemia and, surprisingly, a 20 % reduction in the response of both total and active glucagon-like peptide-1 (GLP-1) concentration. The addition of glucose did not affect the magnitude of postprandial triglyceridemia and TRL-C and TRL-TG concentrations but stimulated a faster response of chylomicrons to the test meal, evaluated by changes in apolipoprotein B-48 concentrations. The addition of glucose induced the physiological response of insulin and the lower response of GLP-1 to the test meal during the early postprandial phase, but had no effect on changes of TRL-cholesterol and TRL-TG within 8 h after the meal.

A Randomised Crossover Trial: The Effect of Inulin on Glucose Homeostasis in Subtypes of Prediabetes

Background: Fermentable carbohydrates (FCHO) have been shown to improve insulin sensitivity in normoglycaemic and insulin-resistant subjects. However, there are no data on subjects with prediabetes. We aimed to investigate the effect of the FCHO inulin, on glucose homeostasis in subjects with prediabetes. Methods: In a double-blind and placebo-controlled crossover study, 40 volunteers with prediabetes were randomly allocated to take 30 g/day of inulin or cellulose for 2 weeks in a crossover trial, following a 4-week dose-escalation run-in. Fasting insulin and glucose were measured for all subjects. Fifteen of the 40 subjects also underwent a meal tolerance test to assess insulin sensitivity, free fatty acids and glucagon-like peptide-1 concentrations. A subanalysis was carried out to examine any differences between the prediabetes subtypes. Results: Inulin was associated with a significant increase in _{(0-30 min)}incremental AUC (iAUC) for insulin (treatment: p < 0.04) and _{(0-60 min)}iAUC for insulin (treatment: p < 0.04) compared to control. There was a significant reduction in insulin resistance measured by the homeostatic model assessment in the isolated-impaired fasting glucose (p < 0.05) but not in the isolated-impaired glucose tolerance groups (p = 0.59). Conclusion: The FCHO, inulin, may have unique metabolic effects that are of particular benefit to people at risk of diabetes, which warrant further investigation.

The effect of encapsulated glutamine on gut peptide secretion in human volunteers

ContextWeight loss and improved blood glucose control after bariatric surgery have been attributed in part to increased ileal nutrient delivery with enhanced release of glucagon-like peptide 1 (GLP-1). Non-surgical strategies to manage obesity are required. The aim of the current study was to assess whether encapsulated glutamine, targeted to the ileum, could increase GLP-1 secretion, improve glucose tolerance or reduce meal size. MethodsA single-center, randomised, double blind, placebo-controlled, cross-over study was performed in 24 healthy volunteers and 8 patients with type 2 diabetes. Fasting participants received a single dose of encapsulated ileal-release glutamine (3.6 or 6.0g) or placebo per visit with blood sampling at baseline and for 4h thereafter. Glucose tolerance and meal size were studied using a 75g oral glucose tolerance test and ad libitum meal respectively. ResultsIn healthy volunteers, ingestion of 6.0g glutamine was associated with increased GLP-1 concentrations after 90min compared with placebo (mean 10.6pg/ml vs 6.9pg/ml, p=0.004), increased insulin concentrations after 90min (mean 70.9 vs 48.5, p=0.048), and increased meal size at 120min (mean 542g eaten vs 481g, p=0.008). Ingestion of 6.0g glutamine was not associated with significant differences in GLP-1, glucose or insulin concentrations after a glucose tolerance test in healthy or type 2 diabetic participants. ConclusionsSingle oral dosing of encapsulated glutamine did not provoke consistent increases in GLP-1 and insulin secretion and was not associated with beneficial metabolic effects in healthy volunteers or patients with type 2 diabetes.

Protective Role of Glucagon-Like Peptide-1 Against High-Glucose-Induced Endothelial Oxidative Damage

To investigate the protective effect of glucagon-like peptide-1 (GLP-1) against cell damage induced by high glucose.Human umbilical vein endothelial cells (HUVECs) were divided into control group (5.5 mmol/L) and high glucose groups (19, 33, or 47 mmol/L), which were cultured with different concentrations of glucose for 48 hours, respectively. Cell viability was measured with MTT assay. Levels of intracellular reactive oxygen species (ROS) were monitored by flow cytometry and apoptotic cell death was measured by staining with Annexin V-FITC and propidium iodide. Cultured cells were detected with intercellular adhesion molecule 1 (ICAM-1), VCAM-1, and JNK on protein.Compared with the control group, cell viability was decreased by 20% and 37%, respectively, when cultured under 33 and 47 mM, while increased in different GLP-1-treated groups (0.01 L, 0.1, 1, and 10 nmol/L). The GLP-1 treatment significantly reduced the ROS level of high glucose treatment group but not impact on the control group. Meanwhile, the level of apoptosis was elevated in the high glucose treatment group. Early apoptosis was significantly reversed in the GLP-1-treated group (0.1, 1, and 10 nmol/L). Late apoptosis was uniquely decreased in the GLP-1 concentrations of 10 nmol/L. Furthermore, GLP-1 could also reduce the protein levels of ICAM-1, VCAM-1, and phospho JNK in the endothelial cells with high glucose treatment.GLP-1 could inhibit cell apoptosis and reduce ROS generation and JNK-Bax signaling pathway activation, which were induced by high glucose treatment.