Plasma Glucagon-like Peptide-1 Concentrations Research Articles

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.

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.

Dipeptidyl peptidase 4 inhibitor reduces intimal hyperplasia in rabbit autologous jugular vein graft under poor distal runoff

Dipeptidyl peptidase 4 inhibitors are widely used in patients with type 2 diabetes mellitus to accomplish glycemic control through an increase in the blood glucagon-like peptide 1 (GLP-1) concentration. These agents also inhibit vascular inflammation (eg, in atherosclerosis). This study was undertaken to determine whether and how vildagliptin (a potent dipeptidyl peptidase 4 inhibitor) might reduce intimal hyperplasia in vein grafts. Twelve rabbits were randomly divided into two groups; one group received vildagliptin orally (10mg/kg/d; n= 6), whereas the control group (n= 6) did not. Vildagliptin administration was started 7days before rabbits underwent interposition reversed autologous jugular vein grafting and ended at graft harvesting (28days after the operation). Histochemical changes in the vascular wall were examined, as were changes in the acetylcholine-induced effects on the endothelial Ca(2+) concentration ([Ca(2+)]i) and endothelium-dependent relaxation. Under fasting conditions, vildagliptin increased the plasma GLP-1 concentration, without affecting plasma glucose or insulin. Acetylcholine induced endothelium-dependent relaxation only in the vildagliptin group, and this was blocked by the nitric oxide synthase inhibitor N(ω)-nitro-l-arginine. Acetylcholine did not modify the endothelial [Ca(2+)]i in either the control or vildagliptin group. Intimal hyperplasia was significantly less in the vildagliptin group (0.11± 0.02mm, n= 5) than in the controls (0.31± 0.06mm, n= 4; P< .01). Vildagliptin increased the plasma GLP-1 concentration. It also enhanced acetylcholine-induced [Ca(2+)]i-independent endothelial nitric oxide release and reduced vein graft intimal hyperplasia, independently of any glycemic control action.

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, improves recognition memory, oxidative stress and hippocampal neurogenesis and upregulates key genes involved in cognitive decline.

To examine whether prolonged dipeptidyl peptidase-4 (DPP-4) inhibition can reverse learning and memory impairment in high-fat-fed mice. High-fat-fed mice received oral sitagliptin (50 mg/kg body weight) once daily or saline vehicle over 21 days. An additional group of mice on standard chow received saline vehicle. Energy intake, body weight, glucose and insulin concentrations were measured at regular intervals. Glucose tolerance, insulin sensitivity, novel object recognition, DPP-4 activity, hormone analysis, hippocampal gene expression and histology were performed. Sitagliptin decreased circulating DPP-4 activity and improved glucose tolerance, glucose-stimulated insulin secretion and insulin sensitivity, and reduced plasma triglycerides and cholesterol levels. DPP-4 inhibition improved recognition memory (1.2-fold increase) without affecting hypermoteric activity or anxiety levels. Improvement in memory and learning was linked to reduced immunostaining for 8-oxoguanine and increased doublecortin staining in the hippocampus, which were indicative of reduced brain oxidative stress and increased hippocampal neurogenesis, respectively. These effects were associated with significant upregulation of hippocampal gene expression of glucagon-like peptide-1 (GLP-1) receptor, glucose-dependent insulinotropic polypeptide receptor, synaptophysin, sirtuin 1, glycogen synthase kinase 3β, superdioxide mutase 2, nuclear factor (erythroid-derived 2)-like 2 and vascular endothelial growth factor. Total plasma and brain GLP-1 concentrations were significantly increased after sitagliptin therapy, whereas DPP-4 activity in brain tissue was not altered. These studies show that sitagliptin can reverse memory impairment in high-fat-fed mice and is also associated with improved insulin sensitivity, enhanced hippocampal neurogenesis and reduced oxidative stress. DPP-4 inhibitors may therefore exhibit dual benefits by improving metabolic control and reducing the decline in cognitive function.

Diurnal rhythms of plasma GLP-1 levels in normal and overweight/obese subjects: lack of effect of weight loss.

Food intake is regulated by not only neurohormonal, but also social, educational, and even cultural factors. Within the former, there is a complex interaction between orexigenic (ghrelin) and anorexigenic (glucagon-like peptide-1 (GLP-1)) factors in order to adjust the food intake to caloric expenditure; however, the number of subjects that are unable to properly balance appetite and body weight is increasing continuously. A loss of circadian or diurnal coordination of any of these factors may be implied in this situation. Special attention has retrieved GLP-1 due to its usefulness as a therapeutic agent against obesity and related alterations. Thus, the objective of the present study was to compare GLP-1 diurnal synthesis between normal weight and overweight/obese subjects, and to evaluate whether weight loss can restore the synthesis rhythms of GLP-1. Three groups of 25 subjects were divided attending to their body mass index (BMI) in normal weight, overweight, or obese subjects. Diurnal (5 points) GLP-1 levels were analyzed. Secondly, an intervention (behavioral-dietary treatment) study was conducted to analyze the effect of weight loss on plasma GLP-1 concentrations. Our results showed that baseline GLP-1 level was significantly lower in normal weight subjects (p = 0.003); furthermore, our cosinor analysis revealed a higher amplitude (p = 0.040) and daily GLP-1 variation (47%) in these subjects. In fact, our ANOVA data showed a lack of rhythmicity in overweight/obese patients. Weight loss was not able to restore a diurnal rhythm of plasma GLP-1 levels. In summary, the present work shows a disruption of diurnal GLP-1 levels in overweight/obese subjects, which worsen as body fat progresses. The attenuation of the GLP-1 synthesis rhythms may be important to understand the impairment of food intake regulation in overweight/obese subjects.

Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults

ObjectiveThe colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite regulation. We...

Increased nutrient sensitivity and plasma concentrations of enteral hormones during duodenal nutrient infusion in functional dyspepsia.

Functional dyspepsia is predominantly attributed to gastric sensorimotor dysfunctions. The contribution of intestinal chemosensitivity to symptoms is not understood. We evaluated symptoms and plasma hormones during enteral nutrient infusion and the association with impaired glucose tolerance and quality-of-life (QOL) scores in patients with functional dyspepsia vs. healthy controls. Enteral hormonal responses and symptoms were measured during isocaloric and isovolumic dextrose and lipid infusions into the duodenum in 30 patients with functional dyspepsia (n=27) or nausea and vomiting (n=3) and 35 healthy controls. Infusions were administered in randomized order over 120 min each, with a 120-min washout. Cholecystokinin, glucose-dependent insulinotropic peptide, glucagon-like peptide 1 (GLP1), and peptide YY were measured during infusions. Moderate or more severe symptoms during lipid (4 controls vs. 14 patients) and dextrose (1 control vs. 12 patients) infusions were more prevalent in patients than controls (P≤0.01), associated with higher dyspepsia symptom score (P=0.01), worse QOL (P=0.01), and greater plasma hormone concentrations (e.g., GLP1 during lipid infusion). Moderate or more severe symptoms during enteral infusion explained 18%, and depression score explained 21%, of interpatient variation in QOL. Eight patients had impaired glucose tolerance, associated with greater plasma GLP1 and peptide YY concentrations during dextrose and lipid infusions, respectively. Increased sensitivity to enteral dextrose and lipid infusions was associated with greater plasma enteral hormone concentrations, more severe daily symptoms, and worse QOL in functional dyspepsia. These observations are consistent with the hypothesis that enteral hormones mediate increased intestinal sensitivity to nutrients in functional dyspepsia.

Effect of glucagon-like peptide-1 receptor antagonism on appetite and food intake in healthy men

Exogenous glucagon-like peptide-1 (GLP-1) inhibits eating in healthy, overweight, and diabetic subjects. The GLP-1 receptor antagonist exendin(9-39)NH2 (ex9-39) was used to further explore the role of GLP-1 as an endogenous satiation signal. Two double-blind, 4-way crossover studies were performed, each of which included 10 healthy men. In study A, subjects received an intravenous infusion of ex9-39 or saline plus an oral glucose preload and an intraduodenal infusion of saline or glucose for 60 min. In study B, intravenous infusions were identical, but an oral mixed-liquid meal preload and a 60-min intraduodenal infusion of saline or oleic acid were administered. Thirty minutes after oral preloads, subjects ate and drank ad libitum, and amounts ingested and the time to meal completion were quantified. In addition, appetite and plasma GLP-1, peptide YY (PYY), insulin, glucagon, and blood glucose concentrations were measured. In both studies, GLP-1, PYY, and glucagon were substantially higher with intravenous ex9-39 than with intravenous saline (P ≤ 0.001). Insulin was lower with intravenous ex9-39 during intraduodenal glucose (P ≤ 0.05). The decrease in prospective food consumption and desire to eat during ad libitum eating after glucose ingestion was slightly attenuated (P ≤ 0.05 and P ≤ 0.01, respectively) with ex9-39. However, with intravenous ex9-39, food and fluid intakes and eating duration were not changed in either study. GLP-1 receptor antagonism slightly modulates appetite during ad libitum eating, but food and fluid intakes and meal duration remain unchanged, suggesting that endogenous GLP-1 is a weak satiation signal. However, concomitant substantial increases in plasma PYY and glucagon may counteract a desatiating effect of ex9-39. The effect of ex9-39 on PYY secretion supports an autoinhibitory feedback mechanism that controls L cell secretion; the effect on insulin and glucagon confirms the role of GLP-1 in glycemic control through its action on pancreatic α and β cells.

Initial evidence that GLP-1 receptor blockade fails to suppress postprandial satiety or promote food intake in humans

Glucagon-like peptide 1 (GLP-1) has incretin effects that are well-documented, but the independent role of GLP-1 action in human satiety perception is debated. We hypothesized that blockade of GLP-1 receptors would suppress postprandial satiety and increase voluntary food intake. After an overnight fast, eight normal weight participants (seven men, BMI 19–24.7 kg/m2, age 19–29 year) were enrolled in a double-blind, placebo-controlled, randomized crossover study of the GLP-1 antagonist Exendin-[9-39] (Ex-9) to determine if the satiating effects of a meal are dependent on GLP-1 signaling in humans. Following a fasting blood draw, iv infusion of Ex-9 (600–750 pmol/kg/min) or saline began. Thirty minutes later, subjects consumed a standardized breakfast followed 90 min later (at the predicted time of maximal endogenous circulating GLP-1) by an ad libitum buffet meal to objectively measure satiety. Infusions ended once the buffet meal was complete. Visual analog scale ratings of hunger and fullness and serial assessments of plasma glucose, insulin, and GLP-1 concentrations were done throughout the experiment. Contrary to the hypothesis, during Ex-9 infusion subjects reported a greater decrease in hunger due to consumption of the breakfast (Ex-9 −62 ± 5; placebo −41 ± 9; P = 0.01) than during placebo. There were no differences in ad libitum caloric intake between Ex-9 and placebo. Ex-9 increased glucose, insulin, and endogenous GLP-1, which may have counteracted any effects of Ex-9 infusion to block satiety signaling. Blockade of GLP-1 receptors failed to suppress subjective satiety following a standardized meal or increase voluntary food intake in healthy, normal-weight subjects.

Incretin, insulinotropic and glucose-lowering effects of whey protein pre-load in type 2 diabetes: a randomised clinical trial.

Since protein ingestion is known to stimulate the secretion of glucagon-like peptide-1 (GLP-1), we hypothesised that enhancing GLP-1 secretion to harness its insulinotropic/beta cell-stimulating activity with whey protein pre-load may have beneficial glucose-lowering effects in type 2 diabetes. In a randomised, open-label crossover clinical trial, we studied 15 individuals with well-controlled type 2 diabetes who were not taking any medications except for sulfonylurea or metformin. These participants consumed, on two separate days, 50 g whey in 250 ml water or placebo (250 ml water) followed by a standardised high-glycaemic-index breakfast in a hospital setting. Participants were randomised using a coin flip. The primary endpoints of the study were plasma concentrations of glucose, intact GLP-1 and insulin during the 30 min following meal ingestion. In each group, 15 patients were analysed. The results showed that over the whole 180 min post-meal period, glucose levels were reduced by 28% after whey pre-load with a uniform reduction during both early and late phases. Insulin and C-peptide responses were both significantly higher (by 105% and 43%, respectively) with whey pre-load. Notably, the early insulin response was 96% higher after whey. Similarly, both total GLP-1 (tGLP-1) and intact GLP-1 (iGLP-1) levels were significantly higher (by 141% and 298%, respectively) with whey pre-load. Dipeptidyl peptidase 4 plasma activity did not display any significant difference after breakfast between the groups. In summary, consumption of whey protein shortly before a high-glycaemic-index breakfast increased the early prandial and late insulin secretion, augmented tGLP-1 and iGLP-1 responses and reduced postprandial glycaemia in type 2 diabetic patients. Whey protein may therefore represent a novel approach for enhancing glucose-lowering strategies in type 2 diabetes. Trial registration ClinicalTrials.gov NCT01571622 Funding The Israeli Ministry of Health and Milk Council funded the research.

Incretins: their physiology and application in the treatment of diabetes mellitus.

Therapies targeting the action of incretin hormones have been under close scrutiny in recent years. The incretin effect has been defined as postprandial enhancement of insulin secretion by gut-derived factors. Likewise, incretin mimetics and incretin effect amplifiers are the two different incretin-based treatment strategies developed for the treatment of diabetes. Although, incretin mimetics produce effects very similar to those of natural incretin hormones, incretin effect amplifiers act by inhibiting dipeptidyl peptidase-4 (DPP-4) enzyme to increase plasma concentration of incretins and their biologic effects. Because glucagon-like peptide-1 (GLP-1) is an incretin hormone with various anti-diabetic actions including stimulation of glucose-induced insulin secretion, inhibition of glucagon secretion, hepatic glucose production and gastric emptying, it has been evaluated as a novel therapeutic agent for the treatment of type 2 diabetes mellitus (T2DM). GLP-1 also manifests trophic effects on pancreas such as pancreatic beta cell growth and differentiation. Because DPP-4 is the enzyme responsible for the inactivation of GLP-1, DPP-4 inhibition represents another potential strategy to increase plasma concentration of GLP-1 to enhance the incretin effect. Thus, anti-diabetic properties of these two classes of drugs have stimulated substantial clinical interest in the potential of incretin-based therapeutic agents as a means to control glucose homeostasis in T2DM patients. Despite this fact, clinical use of GLP-1 mimetics and DPP-4 inhibitors have raised substantial concerns owing to possible side effects of the treatments involving increased risk for pancreatitis, and C-cell adenoma/carcinoma. Thus, controversial issues in incretin-based therapies under development are reviewed and discussed in this manuscript.

Intravenous glucagon like peptide-1 infusion does not affect dry matter intake or hypothalamic mRNA expression of neuropeptide Y, agouti related peptide and proopiomelatnocortin in wethers

Relling, A. E., Loerch, S. C. and Reynolds, C. K. 2014. Intravenous glucagon like peptide-1 infusion does not affect dry matter intake or hypothalamic mRNA expression of neuropeptide Y, agouti related peptide and proopiomelanocortin in wethers. Can. J. Anim. Sci. 94: 357–362. The objectives of the present study were to determine the effects of jugular vein infusions of glucagon like peptide-1 (GLP-1) and dietary fat inclusion on dry matter intake, nutrient digestibility and hypothalamic mRNA concentration of neuropeptide Y, agouti related peptide, and proopiomelanocortin in growing sheep. Thirty-six wethers were used (40.7±3.3 kg BW). Treatments were a control diet (n=11), dietary addition (6% of dry matter) of Ca salts of palm oil fatty acids (n=12), or 6-d jugular vein infusions of 0.155 µg kg−1 body weight/day of GLP-1 (n=11). Hormone concentrations were measured in jugular vein plasma from samples taken on days 1, 4 and 6. On day 7, the wethers were slaughtered for hypothalamus collection to measure mRNA concentration. The dietary addition of 6% of Ca salts of palm oil increased plasma GLP-1 concentration (P&lt;0.01) and decreased dry matter intake on day 1, but not on day 6 (time×treatment interaction, P&lt;0.05). The infusion of GLP-1 did not change dry matter intake (P&gt;0.20), but increased neutral detergent fibre digestibility (P&lt;0.01). In conclusion, glucagon like peptide-1 infusion or feeding fat did not decrease dry matter intake or affect hypothalamic neuropeptide mRNA concentrations of sheep.

Effect of increased physical activity on fructose-induced glycemic response in healthy individuals

The purpose of the current study was to determine whether increased physical activity (PA) altered glycemic control while ingesting an energy-balanced high-fructose diet. Twenty-two normal-weight men and women (age: 21.2±0.6 years; body mass index: 22.6 ±0.6 kg/m(2)) participated in a randomized, cross-over design study in which they ingested an additional 75 g of fructose for 14 days while either maintaining low PA (FR+inactive) (<4500 steps/day) or high PA (FR+active) (>12,000 steps/day). Before and following the 2-week loading period, a fructose-rich meal challenge was administered and blood was sampled at baseline and for 6 h after the meal and analyzed for glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), c-peptide, glucose and insulin concentrations. Plasma insulin, glucose, c-peptide, GIP and GLP-1 concentrations significantly increased in response to the test meal on all test visits (P<0.05). C-peptide incremental area under the curve (AUC) decreased by 10,208 ±120 pmol/l × min for 6 h from pre to post Fr+active intervention (P=0.02) leading to a decrease in plasma insulin total AUC (pre: 58,470.2±6261.0 pmol/l; post: 49,444.3±3883.0 pmol/l; P=0.04) resulting in a decrease Δpeak[Insulin] (P=0.009). Following the FR+active intervention, GIP total AUC significantly decreased (P=0.005) yet only males had a lower total GLP-1 AUC after both interventions (P=0.049). There were no sex differences in GIP levels. Increased PA attenuates the deleterious effects on glycemic control caused by a high-fructose diet. These changes in glycemic control with PA are associated with decreases in insulin and GIP concentrations.

Effects of sitagliptin on plasma incretin concentrations after glucose administration through an esophagostomy tube or feeding in healthy cats

We investigated the effect of sitagliptin, a dipeptidyl peptidase 4 inhibitor, on plasma incretin concentrations after glucose administration through an esophagostomy tube or feeding in healthy cats. Six cats were used for the glucose administration experiment and 5 cats were used for the feeding experiment. Glucose administration through an esophagostomy tube increased plasma glucagon-like peptide 1 (GLP-1) concentrations by 6-fold, whereas plasma glucose-dependent insulinotropic polypeptide (GIP) concentrations did not change. Feeding increased both plasma GLP-1 concentrations by 1.5-fold and GIP concentrations by 4.6-fold. Sitagliptin was administered through an esophagostomy tube (25 and 50 mg per cat) in the glucose administration experiment and orally (25 mg per cat) in the feeding experiment. Sitagliptin treatment potentiated the GLP-1 response to glucose by 1.5-fold (P < 0.05). In addition, postprandial plasma GLP-1 concentration was higher by 2-fold when sitagliptin was administered (P < 0.05). In contrast, administration of sitagliptin did not affect plasma GIP concentrations after glucose administration or feeding. Sitagliptin enhanced insulin secretion following glucose administration by 1.5-fold (P < 0.05); however, it did not influence the plasma glucose concentration. Furthermore, sitagliptin had no effect on the postprandial plasma glucose and insulin concentrations. In conclusion, this study provides no evidence that sitagliptin is beneficial for management of feline diabetes mellitus.

Tu2012 Impact of a 2-Week Very Low Calorie Diet (VLCD) on Glucose Sensing, Absorption, Transporters, Incretin Hormones and Glycemia in Morbidly Obese Humans

We showed that glucose absorption is accelerated in the proximal intestine of morbidly obese humans, associated with increased expression of sodium dependent glucose co-transporter 1 (SGLT1), an altered incretin profile, hyperinsulinemia and hyperglycemia. This study aimed to examine the effects of energy restriction on glucose absorption, expression of intestinal glucose transporters and sweet taste receptors (STR), incretin hormone responses and glycemia in the morbidly obese. Methods: 10 non-diabetic, morbidly obese subjects (2M:8F; 45±3yrs, BMI: 46±3kg/m2) were studied before and after a 2-week VLCD (750kcal/day). On each occasion, endoscopic duodenal biopsies were collected before and after intraduodenal glucose infusion (30g glucose over 30 min, with 3g 3-O-methylglucose (3-OMG) to estimate glucose absorption). Blood glucose and plasma concentrations of 3-OMG, glucosedependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and insulin were measured over 240 min. Absolute expression of SGLT-1, GLUT2 and STR (T1R2) transcripts was quantified by PCR. Results After 2 weeks of VLCD, body weight (-5.6±0.5kg, P<0.001), HbA1c (-0.32±0.08%, P=0.001), fasting blood glucose (-0.5±0.1mmol/L, P=0.02) and fasting expression of T1R2 (-54±22%, P=0.03), SGLT1 (-30±7%, P=0.004) and GLUT2 (-50±15%, P=0.008) were lower than at baseline. Prior to VLCD, intra-duodenal glucose had no impact onT1R2, SGLT-1 and GLUT2 expression, but after VLCD, intra-duodenal glucose stimulated increased expression of T1R2 (45±30%, P=0.03) and GLUT2 (57±14%, P=0.003). The blood glucose (P=0.002), plasma GIP (P=0.03) and plasma insulin (P=0.002) responses to intra-duodenal glucose were all reduced after VLCD, while plasma 3-OMG and GLP-1 concentrations were unchanged. CONCLUSIONS: The improvement in glycemic control after short-term VLCD in morbid obesity is most likely mediated by reduced insulin resistance from weight loss, but not via a reduction in intestinal glucose absorption or an increased incretin response. Although VCLD reduces the fasting expression of both STR and glucose transporters, these increase rapidly on exposure to glucose. Further studies with inhibitors of STR and/or glucose transporters are warranted to determine whether the changes in receptor expressional dynamics are responsible for the observed incretin responses.

Tu2013 A Short Bowel Syndrome Rodent Model Mimicking the Human Pathology Results in Increased AgRP/NPY and Decreased POMC/TRH Expression in the Hypothalamus

We showed that glucose absorption is accelerated in the proximal intestine of morbidly obese humans, associated with increased expression of sodium dependent glucose co-transporter 1 (SGLT1), an altered incretin profile, hyperinsulinemia and hyperglycemia. This study aimed to examine the effects of energy restriction on glucose absorption, expression of intestinal glucose transporters and sweet taste receptors (STR), incretin hormone responses and glycemia in the morbidly obese. Methods: 10 non-diabetic, morbidly obese subjects (2M:8F; 45±3yrs, BMI: 46±3kg/m2) were studied before and after a 2-week VLCD (750kcal/day). On each occasion, endoscopic duodenal biopsies were collected before and after intraduodenal glucose infusion (30g glucose over 30 min, with 3g 3-O-methylglucose (3-OMG) to estimate glucose absorption). Blood glucose and plasma concentrations of 3-OMG, glucosedependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and insulin were measured over 240 min. Absolute expression of SGLT-1, GLUT2 and STR (T1R2) transcripts was quantified by PCR. Results After 2 weeks of VLCD, body weight (-5.6±0.5kg, P<0.001), HbA1c (-0.32±0.08%, P=0.001), fasting blood glucose (-0.5±0.1mmol/L, P=0.02) and fasting expression of T1R2 (-54±22%, P=0.03), SGLT1 (-30±7%, P=0.004) and GLUT2 (-50±15%, P=0.008) were lower than at baseline. Prior to VLCD, intra-duodenal glucose had no impact onT1R2, SGLT-1 and GLUT2 expression, but after VLCD, intra-duodenal glucose stimulated increased expression of T1R2 (45±30%, P=0.03) and GLUT2 (57±14%, P=0.003). The blood glucose (P=0.002), plasma GIP (P=0.03) and plasma insulin (P=0.002) responses to intra-duodenal glucose were all reduced after VLCD, while plasma 3-OMG and GLP-1 concentrations were unchanged. CONCLUSIONS: The improvement in glycemic control after short-term VLCD in morbid obesity is most likely mediated by reduced insulin resistance from weight loss, but not via a reduction in intestinal glucose absorption or an increased incretin response. Although VCLD reduces the fasting expression of both STR and glucose transporters, these increase rapidly on exposure to glucose. Further studies with inhibitors of STR and/or glucose transporters are warranted to determine whether the changes in receptor expressional dynamics are responsible for the observed incretin responses.

GLP-1 at physiological concentrations recruits skeletal and cardiac muscle microvasculature in healthy humans

Muscle microvascular surface area determines substrate and hormonal exchanges between plasma and muscle interstitium. GLP-1 (glucagon-like peptide-1) regulates glucose-dependent insulin secretion and has numerous extrapancreatic effects, including a salutary vascular action. To examine whether GLP-1 recruits skeletal and cardiac muscle microvasculature in healthy humans, 26 overnight-fasted healthy adults received a systemic infusion of GLP-1 (1.2 pmol/kg of body mass per min) for 150 min. Skeletal and cardiac muscle MBV (microvascular blood volume), MFV (microvascular flow velocity) and MBF (microvascular blood flow) were determined at baseline and after 30 and 150 min. Brachial artery diameter and mean flow velocity were measured and total blood flow was calculated before and at the end of the GLP-1 infusion. GLP-1 infusion raised plasma GLP-1 concentrations to the postprandial levels and suppressed plasma glucagon concentrations with a transient increase in plasma insulin concentrations. Skeletal and cardiac muscle MBV and MBF increased significantly at both 30 and 150 min (P<0.05). MFV did not change in skeletal muscle, but decreased slightly in cardiac muscle. GLP-1 infusion significantly increased brachial artery diameter (P<0.005) and flow velocity (P=0.05) at 150 min, resulting in a significant increase in total brachial artery blood flow (P<0.005). We conclude that acute GLP-1 infusion significantly recruits skeletal and cardiac muscle microvasculature in addition to relaxing the conduit artery in healthy humans. This could contribute to increased tissue oxygen, nutrient and insulin delivery and exchange and therefore better prandial glycaemic control and tissue function in humans.

Effects of Aerobic Exercise with or without Metformin on Plasma Incretins in Type 2 Diabetes

Despite positive effects of incretins on insulin secretion, little is known about the effect of exercise on these hormones. Metformin can affect incretin concentrations and is prescribed to a large proportion of people with diabetes. We, therefore, examined the effects of aerobic exercise and/or metformin on incretin hormones. Ten participants with type 2 diabetes were recruited for this randomized crossover study. Metformin or placebo was given for 28 days, followed by the alternate treatment for 28 days. On the last 2 days of each condition, participants were assessed during a non-exercise day and a subsequent exercise day. Aerobic exercise took place in the morning and blood samples were taken in the subsequent hours (before and after lunch). Aerobic exercise did not increase total plasma glucagon-like peptide-1 (GLP-1) or glucose-dependent insulinotropic polypeptide (GIP) in the pre- or post-lunch periods (all p>0.1). GLP-1 was higher in the pre-lunch (p=0.016) and post-lunch (p=0.018) periods of the metformin conditions compared with the placebo. Total plasma GIP was higher in the pre-lunch period (p=0.05), but not in the post-lunch period (p=0.95), with metformin compared with placebo. In contrast to our hypothesis, aerobic exercise did not acutely increase total GLP-1 and GIP levels in patients with type 2 diabetes. Metformin, independent of exercise, significantly increased total plasma GLP-1 and GIP concentrations in these patients.

Ileal transposition surgery produces ileal length-dependent changes in food intake, body weight, gut hormones and glucose metabolism in rats

Enhanced stimulation of the lower gut is hypothesized to play a key role in the weight loss and resolution of diabetes following bariatric surgeries. Ileal transposition (IT) permits study of the effects of direct lower gut stimulation on body weight, glucose homeostasis and other metabolic adaptations without the confounds of gastric restriction or foregut exclusion. However, the underlying mechanisms and the length of the ileum sufficient to produce metabolic benefits following IT surgery remain largely unknown. To determine the effects of transposing varying lengths of the ileum to upper jejunum on food intake, body weight, glucose tolerance and lower gut hormones, and the expression of key markers of glucose and lipid metabolism in skeletal muscle and adipose tissue in rats. Adult male Sprague-Dawley rats (n=9/group) were subjected to IT surgery with translocation of 5, 10 or 20 cm of the ileal segment to proximal jejunum or sham manipulations. Daily food intake and body weight were recorded, and an intraperitoneal glucose tolerance test was performed. Blood samples were assayed for hormones and tissue samples for mRNA (RT-qPCR) and/or protein abundance (immunoblotting) of regulatory metabolic markers. We demonstrate that IT surgery exerts ileal length-dependent effects on multiple parameters including: (1) decreased food intake and weight gain, (2) improved glucose tolerance, (3) increased tissue expression and plasma concentrations of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), and decreased leptin concentrations and (4) upregulation of key markers of glucose metabolism (glucose transporter-4 (GLUT-4), insulin receptor substrate 1 (IRS-1), adenosine monophosphate-activated protein kinase (AMPK), hexokinase (HK) and phosphofructokinase (PFK)) together with a downregulation of lipogenic markers (fatty acid synthase (FAS)) in muscle and adipose tissue. Together, our data demonstrate that the reduction in food intake and weight gain, increase in lower gut hormones, glycemic improvements and associated changes in tissue metabolic markers following IT surgery are dependent on the length of the transposed ileum.