GLP-1 Concentrations Research Articles

The consumption of protein and fiber‐matched beef vs. soy lunch meals on appetite control, satiety, and subsequent food intake in healthy adults (381.3)

Background: Although the satiety effects of protein quantity are well‐documented, the effects of protein quality (source) on satiety are limited. Purpose: To examine the effects of consuming beef vs. soy‐based protein foods on appetite control, satiety, and subsequent food intake. Methods: Using a randomized, crossover design, 23 healthy adults (age 23 ± 1 y; BMI: 23.4 ± 0.6 kg/m2) consumed, on separate days, 400 kcal lunch meals that were identical in protein (24 g), CHO (44 g), fat (11 g), and fiber (2 g) content but varied in protein source, with one containing beef protein (BEEF) and one containing soy protein (SOY). Pre and post‐lunch appetite questionnaires and repeated blood samples were collected throughout the day until dinner was voluntarily requested. An ad libitum dinner was provided. Results: The consumption of BEEF led to increased post‐lunch fullness vs. SOY (p<0.05) but had no effect on post‐lunch ghrelin, PYY, and GLP‐1 concentrations. Dinner was voluntarily requested at 260 ± 15min post‐lunch with no differences observed between the BEEF vs. SOY lunch meals. Lastly, no differences in dinner energy or macronutrient content were observed following the BEEF vs. SOY lunches. Conclusions: When comparing two high quality protein sources, such as beef and soy, the type of protein consumed within a mixed‐meal elicited very little effect on appetite control, satiety, and subsequent food intake in healthy adults.Grant Funding Source: Supported by The Beef Checkoff

Mapping glucose-mediated gut-to-brain signalling pathways in humans

ObjectivesPrevious fMRI studies have demonstrated that glucose decreases the hypothalamic BOLD response in humans. However, the mechanisms underlying the CNS response to glucose have not been defined. We recently demonstrated that the slowing of gastric emptying by glucose is dependent on activation of the gut peptide cholecystokinin (CCK1) receptor. Using physiological functional magnetic resonance imaging this study aimed to determine the whole brain response to glucose, and whether CCK plays a central role. Experimental designChanges in blood oxygenation level-dependent (BOLD) signal were monitored using fMRI in 12 healthy subjects following intragastric infusion (250ml) of: 1M glucose+predosing with dexloxiglumide (CCK1 receptor antagonist), 1M glucose+placebo, or 0.9% saline (control)+placebo, in a single-blind, randomised fashion. Gallbladder volume, blood glucose, insulin, and GLP-1 and CCK concentrations were determined. Hunger, fullness and nausea scores were also recorded. Principal observationsIntragastric glucose elevated plasma glucose, insulin, and GLP-1, and reduced gall bladder volume (an in vivo assay for CCK secretion). Glucose decreased BOLD signal, relative to saline, in the brainstem and hypothalamus as well as the cerebellum, right occipital cortex, putamen and thalamus. The timing of the BOLD signal decrease was negatively correlated with the rise in blood glucose and insulin levels. The glucose+dex arm highlighted a CCK1-receptor dependent increase in BOLD signal only in the motor cortex. ConclusionsGlucose induces site-specific differences in BOLD response in the human brain; the brainstem and hypothalamus show a CCK1 receptor-independent reduction which is likely to be mediated by a circulatory effect of glucose and insulin, whereas the motor cortex shows an early dexloxiglumide-reversible increase in signal, suggesting a CCK1 receptor-dependent neural pathway.

Glucose metabolism and incretins level in morbidly obese patients and in patients after biliopancreatic diversion performed for morbid obesity

We’ve studied a carbohydrate metabolism in morbidly obese (MO) patients and the patients after bariatric surgery. The patients of the 1st group had BMI40 (n=22) and no history of diabetes mellitus. Patients after biliopancreatic diversion (BPD) performed for MO were included in the 2nd group (n=23). The 3rd group was a control group of normal weight healthy subjects (n=22). Blood glucose levels, insulin, GLP-1, GIP and glucagon during the OGTT (with 75 g of glucose) at 0, 30, 60 and 120 minutes were measured in all patients. In MO group fasting glucose levels were the highest. Impaired glucose metabolism was revealed in 68.2% of patients (n=10). Impaired fasting glucose (IFG) was diagnosed in 4 cases (18.2%), impaired glucose tolerance (IGT) in 11 patients (50%). In the BPD postprandial blood glucose levels (120 min) were lower if compared to the other groups. In 4 individuals (17.4%) we found postprandial hypoglycemia (2.8 mmol/l). Patients of the MO group had the highest fasting insulin levels and HOMA-IR (p0.001). The maximum of insulin concentration was seen on minute 30 of the OGTT in the 2nd and 3rd groups, and it was significantly higher in the post-bariatric patients (p=0.026). In MO group the maximum of the plasma insulin levels were on the 60th minute and were still elevated after 120 minutes. Fasting and stimulated (on the 30th minute) levels of GLP-1 were significantly higher after BPD (р=0.037 and p=0.022 at 0 and 30 min, respectively). Morbidly obese patients had higher fasting and stimulated GIP. Fasting glucagon concentrations were similar in the surgical and control groups, while the people with MO had higher initial levels of glucagon (p=0.013) and it was not suppressed during the OGTT (p=0.076). Glucose intolerance and insulin resistance incidence was higher in MO patients. Hyperglucagonemia, increased GIP and decreased GLP-1 levels are observed in MO patients. Stimulated plasma insulin and GLP-1 concentrations were significantly increased in patients who underwent BPD, and may cause postprandial hypoglycemia.

GLP-1 amidation efficiency along the length of the intestine in mice, rats and pigs and in GLP-1 secreting cell lines

xxxMeasurements of plasma concentrations of the incretin hormone GLP-1 are complex because of extensive molecular heterogeneity. This is partly due to a varying and incompletely known degree of C-terminal amidation. Given that virtually all GLP-1 assays rely on a C-terminal antibody, it is essential to know whether or not the molecule one wants to measure is amidated. We performed a detailed analysis of extractable GLP-1 from duodenum, proximal jejunum, distal ileum, caecum, proximal colon and distal colon of mice (n=9), rats (n=9) and pigs (n=8) and determined the degree of amidation and whether this varied with the six different locations. We also analyzed the amidation in 3 GLP-1 secreting cell lines (GLUTag, NCI-H716 and STC-1). To our surprise there were marked differences between the 3 species with respect to the concentration of GLP-1 in gut. In the mouse, concentrations increased continuously along the intestine all the way to the rectum, but were highest in the distal ileum and proximal colon of the rat. In the pig, very little or no GLP-1 was present before the distal ileum with similar levels from ileum to distal colon. In the mouse, GLP-1 was extensively amidated at all sampling sites, whereas rats and pigs on average had around 2.5 and 4 times higher levels of amidated compared to non-amidated GLP-1, although the ratio varied depending upon the location. GLUTag, NCI-H716 and STC-1 cells all exhibited partial amidation with 2–4 times higher levels of amidated compared to non-amidated GLP-1.

Postprandial effects on plasma lipids and satiety hormones from intake of liposomes made from fractionated oat oil: two randomized crossover studies

BackgroundThe composition and surface structure of dietary lipids influence their intestinal degradation. Intake of liposomes made of fractionated oat oil (LOO) is suggested to affect the digestion process and postprandial lipemia and also induce satiety.ObjectiveIn the present study, the metabolic effects on plasma lipids and gut hormones related to satiety were investigated in healthy individuals after intake of LOO, with dairy lipids as placebo.DesignTwo blinded randomized studies with crossover design were performed. In the first study, 19 subjects consumed 35 g lipids from LOO or yoghurt in a breakfast meal. In a follow-up study, 15 women consumed 14 or 1.8 g lipids from LOO mixed in yoghurt. Blood samples were analyzed for plasma lipids, insulin, glucose, and intestinal hormones CCK, PYY, GLP-1, and GLP-2 before and four times after the meal. Subjective analysis of satiety was measured using a visual analog scale questionnaire. Participants recorded their food intake during the rest of the day.ResultsIntake of 35 and 14 g lipids from LOO significantly increased plasma concentrations of CCK, GLP-1, GLP-2, and PYY postprandially. This coincided with a prolonged elevation of triglycerides and large cholesterol-containing particles. Non-esterified fatty acids decreased after intake of 14 and 1.8 g lipids from LOO. The subjective sensation of satiety in women was increased 7 h after intake of 35 g lipids from LOO without any difference in food intake. Our results indicate that intake of 14 g lipids from LOO at breakfast substantially reduced energy intake during the rest of the day.ConclusionsThis study suggests that intake of LOO prolong lipid digestion, affect postprandial plasma lipids and have an effect on satiety. The effect of LOO on GLP-2 indicates that intake of LOO also improve gut health.

Glucose promotes its own metabolism by acting on the cell-surface glucose-sensing receptor T1R3

A homodimer of taste type 1 receptor 3 (T1R3) functions as a sweet taste-sensing receptor in pancreatic β-cells. This receptor is activated by various sweet molecules including sugars such as glucose. To determine the role of this receptor in glucose-induced insulin secretion, we addressed whether or not this receptor modulates glucose metabolism in MIN6 cells. We measured changes in intracellular ATP ([ATP]i) in MIN6 cells expressing luciferase. Sucralose, an agonist of T1R3, induced immediate and sustained elevation of [ATP]i in the presence of 5.5 mM glucose. The effect of sucralose was dose-dependent and, at 5 mM, was greater than that induced by 25 mM glucose. In contrast, carbachol, GLP-1 or high concentration of potassium did not reproduce the sucralose action. Sucralose facilitated the increase in [ATP]i induced by a mitochondrial fuel methylsuccinate, and potentiated glucose-induced elevation of [ATP]i. Administration of a non-metabolizable glucose analogue, 3-O-methylglucose, which acts as an agonist of T1R3, induced a small and transient increase in [ATP]i. 3-O-Methylglucose augmented elevation of [ATP]i induced by methylsuccinate, and also enhanced glucose-induced increase in [ATP]i. Knock down of T1R3 by using shRNA attenuated [ATP]i-response to high concentration of glucose and also reduced the glucose-induced insulin secretion. These results indicate that activation of the homodimer of T1R3 facilitates the metabolic pathway in mitochondria and augments ATP production. The results obtained by using 3-O-methylglucose suggest that glucose, by acting on the homodimer of T1R3, promotes its own metabolism.

Real-time trafficking and signaling of the glucagon-like peptide-1 receptor

The glucagon-like peptide-1 incretin receptor (GLP-1R) of family B G protein-coupled receptors (GPCRs) is a major drug target in type-2-diabetes due to its regulatory effect on post-prandial blood-glucose levels. The mechanism(s) controlling GLP-1R mediated signaling are far from fully understood. A fundamental mechanism controlling the signaling capacity of GPCRs is the post-endocytic trafficking of receptors between recycling and degradative fates. Here, we combined microscopy with novel real-time assays to monitor both receptor trafficking and signaling in living cells. We find that the human GLP-1R internalizes rapidly and with similar kinetics in response to equipotent concentrations of GLP-1 and the stable GLP-1 analogues exendin-4 and liraglutide. Receptor internalization was confirmed in mouse pancreatic islets. GLP-1R is shown to be a recycling receptor with faster recycling rates mediated by GLP-1 as compared to exendin-4 and liraglutide. Furthermore, a prolonged cycling of ligand-activated GLP-1Rs was observed and is suggested to be correlated with a prolonged cAMP signal.

Anti–glucagon-like peptide-1 immunoreactivity in samples of blood and ileum obtained from neonatal and adult alpacas

To compare numbers of L cells in intestinal samples and blood concentrations of glucagon-like peptide (GLP)-1 between neonatal and mature alpacas. Intestinal samples from carcasses of 4 suckling crias and 4 postweaning alpacas for immunohistochemical analysis and blood samples from 32 suckling crias and 19 healthy adult alpacas for an ELISA. Immunohistochemical staining was conducted in accordance with Oregon State University Veterinary Diagnostic Laboratory standard procedures with a rabbit polyclonal anti-GLP-1 primary antibody. Stained cells with staining results in ileal tissue were counted in 20 fields by 2 investigators, and the mean value was calculated. For quantification of GLP-1 concentrations, blood samples were collected into tubes containing a dipeptidyl peptidase-4 inhibitor. Plasma samples were tested in duplicate with a commercial GLP-1 ELISA validated for use in alpacas. Counts of stained cells (mean ± SD, 50 ± 18 cells) and plasma GLP-1 concentrations (median, 0.086 ng/mL; interquartile range, 0.061 to 0.144 ng/mL) were higher for suckling alpacas than for postsuckling alpacas (stained cells, 26 ± 4 cells; plasma GLP-1 concentration, median, 0.034 ng/mL; interquartile range, 0.015 to 0.048 ng/mL). Older alpacas had lower numbers of L cells in intestinal tissues and lower blood concentrations of GLP-1 than those in neonates. These findings suggested that there may be a decrease in the contribution of GLP-1 to insulin production in adult alpacas, compared with the contribution in neonates.

Mechanism of action of pre-meal consumption of whey protein on glycemic control in young adults

Whey protein (WP), when consumed in small amounts prior to a meal, improves post-meal glycemic control more than can be explained by insulin-dependent mechanisms alone. The objective of the study was to identify the mechanism of action of WP beyond insulin on the reduction of post-meal glycemia. In a randomized crossover study, healthy young men received preloads (300 ml) of WP (10 and 20 g), glucose (10 and 20 g) or water (control). Paracetamol (1.5 g) was added to the preloads to measure gastric emptying. Plasma concentrations of paracetamol, glucose, and β-cell and gastrointestinal hormones were measured before preloads (baseline) and at intervals before (0–30 min) and after (50–230 min) a preset pizza meal (12 kcal/kg). Whey protein slowed pre-meal gastric emptying rate compared to the control and 10 g glucose (P<.0001), and induced lower pre-meal insulin and C-peptide than the glucose preloads (P<.0001). Glucose, but not WP, increased pre-meal plasma glucose concentrations (P<.0001). Both WP and glucose reduced post-meal glycemia (P=.0006) and resulted in similar CCK, amylin, ghrelin and GIP responses (P<.05). However, compared with glucose, WP resulted in higher post-meal GLP-1 and peptide tyrosine-tyrosine (PYY) and lower insulin concentrations, without altering insulin secretion and extraction rates. For the total duration of this study (0–230 min), WP resulted in lower mean plasma glucose, insulin and C-peptide, but higher GLP-1 and PYY concentrations than the glucose preloads. In conclusion, pre-meal consumption of WP lowers post-meal glycemia by both insulin-dependent and insulin-independent mechanisms.

Circulating concentrations of GLP-1 are associated with coronary atherosclerosis in humans

BackgroundGLP-1 is an incretine hormone which gets secreted from intestinal L-cells in response to nutritional stimuli leading to pancreatic insulin secretion and suppression of glucagon release. GLP-1 further inhibits gastric motility and reduces appetite which in conjunction improves postprandial glucose metabolism. Additional vasoprotective effects have been described for GLP-1 in experimental models. Despite these vasoprotective actions, associations between endogenous levels of GLP-1 and cardiovascular disease have yet not been investigated in humans which was the aim of the present study.MethodsGLP-1 serum levels were assessed in a cohort of 303 patients receiving coronary CT-angiography due to typical or atypical chest pain.ResultsGLP-1 was found to be positively associated with total coronary plaque burden in a fully adjusted model containing age, sex, BMI, hypertension, diabetes mellitus, smoking, triglycerides, LDL-C (low density lipoprotein cholesterol), hsCRP (high-sensitive C-reactive protein), and eGFR (estimated glomerular filtration rate) (OR: 2.53 (95% CI: 1.12 – 6.08; p = 0.03).ConclusionCirculating GLP-1 was found to be positivity associated with coronary atherosclerosis in humans. The clinical relevance of this observation needs further investigations.

Oral processing effort, appetite and acute energy intake in lean and obese adults

Chewing reportedly contributes to satiation and satiety signals. Attempts to document and quantify this have led to small and inconsistent effects. The present trial manipulated oral processing effort though required chewing of gums of different hardness and measured appetitive sensations, energy intake, gastric emptying, GI transit time, and concentrations of glucose, insulin, GLP-1, ghrelin and pancreatic polypeptide. Sixty adults classified by sex and BMI (15 each of lean females, obese females, lean males and obese males) were tested in a randomized, controlled, cross-over trial with three arms. They chewed nothing, soft gum or hard gum for 15min while sipping grape juice (10% of individual energy needs) containing acetaminophen and lactulose on one day each separated by 7days. Electromyographic recordings and self-reports were obtained during and after chewing to quantify oral processing effort. Blood was sampled through an indwelling catheter and appetite ratings were obtained at baseline and at 0, 15, 30, 45, 60, 90, 120, 180 and 240min after chewing initiation. Breath samples were collected at 10min intervals for the first 2h and at 30min intervals for the next 2h. No effects of chewing were observed for appetitive sensations or gut peptide concentrations. Energy intake tended to decline in lean and increase in obese participants so that daily energy intake differed significantly between the two groups when chewing either gum, while no difference was observed on the non-chewing day. Serum glucose and insulin were significantly lower at selected time points 90–240min after chewing compared to baseline and the non-chewing day. These data indicate chewing effort does not affect appetitive sensations or gut peptide secretion, but may exert a small differential effect on acute energy intake in lean and obese individuals and lead to greater post-prandial declines of serum glucose and insulin. The efficacy of gum chewing as a substitute for eating for weight management remains uncertain.

Incretin for the continuing treatment of secondary failure to metformin in Type 2 diabetes

SUMMARY For the treatment of Type 2 diabetes, incretin-based therapies have been an established treatment since their introduction in 2006. GLP-1 receptor agonists as an injectable therapy and DPP-4 inhibitors as oral antidiabetic agents have a strictly glucose-dependent action on insulin and glucagon secretion, resulting in a negligible intrinsic hypoglycemia risk. The GLP-1 receptor agonists only act by stimulating the GLP-1 receptor directly at receptor ligand concentrations in the pharmacological concentration range. They decelerate gastric emptying dependent on their duration of action and also act directly by stimulating satiety signals in the CNS. These effects lead to a loss of body weight. DPP-4 inhibitors primarily elevate endogenous active GLP-1 plasma concentrations by two- to three-fold. They are body weight neutral since only higher concentrations of GLP-1 than those elicited by DPP-4 inhibitors have direct effects on the CNS or on the retardation of gastrointestinal motility. Novel studies ...

The Role of Viscosity and Fermentability of Dietary Fibers on Satiety- and Adiposity-Related Hormones in Rats

Dietary fiber may contribute to satiety. This study examined the effect of two dietary fiber characteristics, small intestinal contents viscosity and large intestinal fermentability, on satiety-and adiposity-related hormones in rats. Diets contained fiber sources that were non-viscous, somewhat viscous, or highly viscous, and either highly fermentable or non-fermentable, in a 2 × 3 factorial design. In the fed state (2 h postprandial), rats fed non-fermentable fibers had significantly greater plasma GLP-1 concentration than fermentable fibers. In the fasted state, among non-fermentable fibers, viscosity had no effect on GLP-1 concentration. However, among fermentable fibers, greater viscosity reduced GLP-1 concentration. Plasma peptide tyrosine tyrosine (PYY) concentrations in the fasted state were not influenced by the fermentability of the fiber overall, however animals consuming a fructooligosaccharide greater PYY concentration. In both the fed and fasted states, rats fed non-fermentable fibers had a significantly lower plasma ghrelin concentration than rats fed fermentable fibers. In the fasted state, rats fed non-fermentable fibers had a significantly lower plasma leptin concentration than rats fed fermentable fibers. Thus, fermentability and viscosity of dietary fiber interacted in complex ways to influence satiety- and adiposity-related plasma hormone concentrations. However, the results suggest that highly viscous, non-fermentable fibers may limit weight gain and reduce adiposity and non-fermentable fibers, regardless of viscosity, may promote meal termination.

Characterisation of oral and i.v. glucose handling in truncally vagotomised subjects with pyloroplasty

ObjectiveGlucagon-like peptide 1 (GLP1) is rapidly inactivated by dipeptidyl peptidase 4 (DPP4), but may interact with vagal neurons at its site of secretion. We investigated the role of vagal innervation for handling of oral and i.v. glucose.Design and methodsTruncally vagotomised subjects (n=16) and matched controls (n=10) underwent 50 g-oral glucose tolerance test (OGTT)±vildagliptin, a DPP4 inhibitor (DPP4i) and isoglycaemic i.v. glucose infusion (IIGI), copying the OGTT without DPP4i.ResultsIsoglycaemia was obtained with 25±2 g glucose in vagotomised subjects and 18±2 g in controls (P<0.03); thus, gastrointestinal-mediated glucose disposal (GIGD) – a measure of glucose handling (100%×(glucoseOGTT−glucoseIIGI/glucoseOGTT)) – was reduced in the vagotomised compared with the control group. Peak intact GLP1 concentrations were higher in the vagotomised group. Gastric emptying was faster in vagotomised subjects after OGTT and was unaffected by DPP4i. The early glucose-dependent insulinotropic polypeptide response was higher in vagotomised subjects. Despite this, the incretin effect was equal in both groups. DPP4i enhanced insulin secretion in controls, but had no effect in the vagotomised subjects. Controls suppressed glucagon concentrations similarly, irrespective of the route of glucose administration, whereas vagotomised subjects showed suppression only during IIGI and exhibited hyperglucagonaemia following OGTT. DPP4i further suppressed glucagon secretion in controls and tended to normalise glucagon responses in vagotomised subjects.ConclusionsGIGD is diminished, but the incretin effect is unaffected in vagotomised subjects despite higher GLP1 levels. This, together with the small effect of DPP4i, is compatible with the notion that part of the physiological effects of GLP1 involves vagal transmission.

Calcium co-ingestion augments postprandial glucose-dependent insulinotropic peptide1–42, glucagon-like peptide-1 and insulin concentrations in humans

This study determined whether calcium co-ingestion potentiates postprandial GIP(1-42) and GLP-1 concentrations in humans and the concomitant impact on insulin, appetite sensations and substrate metabolism. Ten healthy males consumed two energy- and macronutrient-matched meals in a double-blind, randomized, crossover design. The calcium content of the control meal was 3 mg/kg body mass, which was increased to 15 mg/kg body mass with calcium co-ingestion. Circulating concentrations of GIP(1-42), GLP-1 and insulin were determined over a 180-min postprandial period, followed by 60 min of exercise. Visual analogue scales were used to determine subjective appetite sensations. Rates of energy expenditure and substrate (lipid and carbohydrate) oxidation were estimated using indirect calorimetry. Calcium co-ingestion resulted in a 47% increase in GIP(1-42), a 22% increase in GLP-1 and a 19% increase in insulin areas under the curve for the 120 min following consumption (all P < 0.05). Furthermore, appetite sensations were suppressed by calcium co-ingestion by 12% (P = 0.034). No differences, however, were observed in substrate metabolism (P > 0.05). Ingestion of a high-calcium meal potentiates postprandial GIP(1-42), GLP-1 and insulin concentrations in humans. Subjective appetite is also temporarily suppressed, although substrate metabolism is unaffected.

Circulating glucagon-like peptide-1 increases in response to short-term overfeeding in men

BackgroundGlucagon-like Peptide-1 (GLP-1) is an incretin hormone secreted from the gastrointestinal tract that facilitates the glucose-dependent insulin response. Additionally, GLP-1 is thought to be involved in energy homeostasis. Currently little is known about GLP-1’s responsiveness to an energy surplus, a fundamental cause of obesity and diabetes. Our objective was to examine the response of serum GLP-1 to short-term (7 day) overfeeding in young men.MethodsSeventy-two young men from the Canadian province of Newfoundland were recruited for the study. For 7-days, the subjects consumed 70% more calories than required at baseline.Various measurements including: anthropometrics, body composition, markers of glucose/lipid metabolism and serum total GLP-1, were taken at a fasted state before (day 1) and after (day 8) the challenge. Paired t-test analyses were used to assess the change in variables after the overfeeding period. Additionally, the relationship between serum GLP-1 and the measured variables at baseline and change due to overfeeding were analyzed.ResultsSerum GLP-1 was significantly increased in all groups in response to the 7-day energy surplus, indicating the increase was independent of adiposity status. There was no significant difference in fasting GLP-1 at baseline between the normal weight and overweight/obese groups. At baseline, GLP-1 concentration negatively correlated with HDL-cholesterol and positively correlated with triacylglycerols and markers of insulin resistance in the overweight/obese group. Also GLP-1 was negatively correlated with change in percent gynoid fat in the overweight/obese subjects. Percent change in GLP-1 was negatively associated with percent change in gynoid fat in the normal weight group and positively associated with percent change in cholesterol in the overweight/obese group. Percentage change of circulating triacylglycerols was positively associated with percent change in GLP-1 in both adiposity groups.ConclusionOur findings showed that GLP-1 serum concentration is not a significant factor in determining obesity status. The increase of GLP-1 in all subjects regardless of obesity status, suggest GLP-1 serves as a protective role, counteracting energy surplus.

Incretins: What is known, new and controversial in 2013?

Glucagon-like peptide (GLP)-1 action involves both endocrine and neural pathways to control peripheral tissues. In diabetes the impairment of either pathway may define different subsets of patients: some may be better treated with GLP-1 receptor agonists that are more likely to directly stimulate beta-cells and extrapancreatic receptors, while others may benefit from dipeptidyl peptidase (DPP)-4 inhibitor treatments that are more likely to increase the neural gut–brain–pancreas axis. Elevated plasma concentrations of GLP-1 associated with agonist treatment or bariatric surgery also appear to exert neuroprotective effects, ameliorate postprandial and fasting lipids, improve heart physiology and protect against heart failure, thereby expanding the possible positioning of GLP-1-based therapies. However, the mechanisms behind GLP-1 secretion, the role played by proximal and distal intestinal GLP-1-producing cells as well as the molecular basis of GLP-1 resistance in diabetes are still to be ascertained. The pharmacological features distinguishing GLP-1 receptor agonists from DPP-4 inhibitors are discussed here to address their respective positions in type 2 diabetes.

Acute peripheral administration of synthetic human GLP-1 (7–36 amide) decreases circulating IL-6 in obese patients with type 2 diabetes mellitus: A potential role for GLP-1 in modulation of the diabetic pro-inflammatory state?

BackgroundTo explore the effects of acute administration of GLP-1 and GIP on circulating levels of key adipocyte-derived hormones and gut-brain peptides with established roles in energy and appetite regulation, modulation of insulin sensitivity and inflammation. MethodsSix obese male patients with diet-treated type 2 diabetes (T2DM) and 6 healthy lean subjects were studied. The protocol included 4 experiments for each participant that were carried out in randomised order and comprised: GLP-1 infusion at a rate of 1pmol/kg/min for 4h, GIP at a rate of 2pmol/kg/min, GLP-1+GIP and placebo infusion. Plasma leptin, adiponectin, IL-6, insulin, ghrelin and obestatin were measured at baseline, 15, 60, 120, 180 and 240min following the start of infusion. ResultsPatients with T2DM had higher baseline IL-6 compared with healthy [day of placebo infusion: T2DM IL-6 mean (SEM) 1.3 (0.3)pg/ml vs 0.3 (0.1)pg/ml, p=0.003]. GLP-1 infusion in T2DM was associated with a significant reduction in circulating IL-6 [baseline IL-6 1.2pg/ml vs IL-6=0.7 at 120min, p=0.0001; vs IL-6=0.8 at 180min, p=0.001]. There was no significant change in leptin, adiponectin, ghrelin or obestatin compared to baseline on all 4 experimental days in both groups. ConclusionShort-term infusion of supraphysiological concentrations of GLP-1 in T2DM results in suppression of IL-6, a key inflammatory mediator strongly linked to development of obesity and T2DM-related insulin resistance. It remains to be confirmed whether GLP-1-based diabetes therapies can impact favourably on cardiovascular outcomes.

Chronobiology, endocrinology, and energy‐ and food‐reward homeostasis

Energy- and food-reward homeostasis is the essential component for maintaining energy balance and its disruption may lead to metabolic disorders, including obesity and diabetes. Circadian alignment, quality sleep and sleep architecture in relation to energy- and food-reward homeostasis are crucial. A reduced sleep duration, quality sleep and rapid-eye movement sleep affect substrate oxidation, leptin and ghrelin concentrations, sleeping metabolic rate, appetite, food reward, hypothalamic-pituitary-adrenal (HPA)-axis activity, and gut-peptide concentrations, enhancing a positive energy balance. Circadian misalignment affects sleep architecture and the glucose-insulin metabolism, substrate oxidation, homeostasis model assessment of insulin resistance (HOMA-IR) index, leptin concentrations and HPA-axis activity. Mood disorders such as depression occur; reduced dopaminergic neuronal signaling shows decreased food reward. A good sleep hygiene, together with circadian alignment of food intake, a regular meal frequency, and attention for protein intake or diets, contributes in curing sleep abnormalities and overweight/obesity features by preventing overeating; normalizing substrate oxidation, stress, insulin and glucose metabolism including HOMA-IR index, and leptin, GLP-1 concentrations, lipid metabolism, appetite, energy expenditure and substrate oxidation; and normalizing food reward. Synchrony between circadian and metabolic processes including meal patterns plays an important role in the regulation of energy balance and body-weight control. Additive effects of circadian alignment including meal patterns, sleep restoration, and protein diets in the treatment of overweight and obesity are suggested.

DIGESTIVE PHYSIOLOGY OF THE PIG SYMPOSIUM: Involvement of gut chemosensing in the regulation of mucosal barrier function and defense mechanisms1,2

Meal ingestion is followed by release of numerous hormones from enteroendocrine cells interspersed among the epithelial cells lining the intestine. Recently, the de-orphanization of G protein-coupled receptor (GPCR)-type nutrient receptors, expressed on the apical membranes of enteroendocrine cells, has suggested a plausible mechanism whereby luminal nutrients trigger the release of gut hormones. Activation of nutrient receptors triggers intracellular signaling mechanisms that promote exocytosis of hormone-containing granules into the submucosal space. Hormones released by foregut enteroendocrine cells include the glucagon-like peptides (GLP) affecting glycemic control (GLP-1) and releasing pro-proliferative, hypertrophy-inducing growth factors (GLP-2). The foregut mucosa, being exposed to pulses of concentrated HCl, is protected by a system of defense mechanisms, which includes epithelial bicarbonate and mucus secretion and augmentation of mucosal blood flow. We have reported that luminal co-perfusion of AA with nucleotides in anesthetized rats releases GLP-2 into the portal vein, associated with increased bicarbonate and mucus secretion and mucosal blood flow. The GLP-2 increases bicarbonate secretion via release of vasoactive intestinal peptide (VIP) from myenteric nerves. Luminal bile acids also release gut hormones due to activation of the bile-acid receptor known as G Protein-Coupled Receptor (GPR) 131, G Protein Bile Acid Receptor (GPBAR) 1, or Takeda G Protein-Coupled Receptor (TGR) 5, also expressed on enteroendocrine cells. The GLP are metabolized by dipeptidyl peptidase IV (DPPIV), an enzyme of particular interest to pharmaceutical, because its inhibition increases plasma concentrations of GLP-1 to treat diabetes. We have also reported that DPPIV inhibition enhances the secretory effects of nutrient-evoked GLP-2. Understanding the release mechanism and the metabolic pathways of gut hormones is of potential utility to the formulation of feedstuff additives that, by increasing nutrient absorption due to increased mucosal mass, can increase yields.