BACKGROUND: Previous studies have indicated that the secretion of the intestinal satiety hormone glucagon-like peptide-1 (GLP-1) is attenuated in obese subjects.
OBJECTIVE: To compare meal-induced response of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in obese and lean male subjects, to investigate the effect of a major weight reduction in the obese subjects, and to look for an association between these hormones and ad libitum food intake.
METHOD: Plasma concentrations of intestinal hormones and appetite sensations were measured prior to, and every 30 min for 180 min after, ingestion of a 2.5 MJ solid test meal. Gastric emptying was estimated scintigraphically. An ad libitum lunch was served 3 h after the test meal.
SUBJECTS: Nineteen non-diabetic obese (body mass index (BMI) 34.1–43.8 kg/m2) and 12 lean (BMI 20.4–24.7 kg/m2) males. All obese subjects were re-examined after a mean stabilised weight loss of 18.8 kg (95% CI 14.4–23.2).
RESULTS: Total area under the GLP-1 response curve (AUCtotal, GLP-1) was lower in obese before and after the weight loss compared to lean subjects (P<0.05), although weight loss improved the response from 80 to 88% of that of the lean subjects (P=0.003). The GIP response was similar in obese and lean subjects. However, after the weight loss both AUCtotal, GIP and AUCincremental, GIP were lowered (P<0.05). An inverse correlation was observed between AUCincremental, GIP and energy intake at the subsequent ad libitum meal in all groups. In lean subjects ad libitum energy intake was largely predicted by the insulin response to the preceding meal (r2=0.67, P=0.001).
CONCLUSION: Our study confirmed previous findings of a reduced postprandial GLP-1 response in severely obese subjects. Following weight reduction, GLP-1 response in the obese subjects apparently rose to a level between that of obese and lean subjects. The data suggests that postprandial insulin and GIP responses are key players in short-term appetite regulation.
Absorption, as well as the mere presence of nutrients in the small intestine, contributes to the meal induced satiety response.1 There is increasing evidence to indicate that glucagon-like peptide-1 (GLP-1) is one of the mediators, not only of the so-called ileal brake,2,3,4 but also of the post-meal satiety response. Infusion of GLP-1 in humans has been shown to increase the feeling of fullness and satiety after a meal.5,6,7 This effect is possibly mediated through inhibition of the gastric emptying,6,8 perhaps combined with a more direct effect of GLP-1 on areas of the central nervous system involved in appetite regulation.9,10 Previously, obesity has been shown to be associated with attenuation of the postprandial response of GLP-111,12,13 consistent with the previously reported reduced secretion of intestinal proglucagon products in obese subjects.14 The effect of weight reduction on meal induced GLP-1 response has only been investigated after jejunoileal bypass surgery, resulting in an increase in GLP-1 response to a level above that of lean subjects.11 However, jejunoileal bypass surgery may in itself induce a change in GLP-1 release, due to increased exposure of the terminal ileum to food components.15
Whether glucose-dependent insulinotropic polypeptide (GIP) has a role in appetite regulation is still unknown. In studies from our institute the postprandial GIP response was found to be inversely related to the subsequent feeling of satiety.16,17,18 Furthermore, higher postprandial GIP responses to a high-fat test meal were seen in post-obese women compared to lean controls.16 These findings suggest that GIP may promote hunger and that supra-normal GIP responses could be a contributing factor to the development of obesity.16
Recently, Speechly and Buffenstein described an inverse relationship between insulin concentration 5.5 h after a fixed meal and the subsequent food intake in lean subjects, but not in obese subjects.19 The notion that insulin promotes satiety is supported by previous studies.20 GIP and GLP-1 are known to be important incretin-hormones,21 and in theory the increase in satiety produced by the intestinal handling of nutrients might, in part, be mediated through an increased insulin response.
The primary aims of the present study were to compare the response of GLP-1 and GIP to a standardised test meal in obese and lean male subjects, and to re-examine the obese subjects after a major, diet-induced weight loss. We also wanted to examine the possible relationship between postprandial GLP-1, GIP and insulin responses on the one hand and gastric emptying rate and appetite regulation on the other.
Subjects and methods
Thirty-five healthy male subjects between the ages of 18 and 50 y were recruited by newspaper and television advertisements, or through personal contact. Twenty-three subjects were obese compared to 12 normal-weight controls. Four obese subjects did not complete the study and only data for the 19 completers are presented (Table 1). All subjects were Caucasian, non-diabetic, non-smokers, and none were competition athletes. The two groups were matched for height and age, and the obese subjects were controlled for weight stability as previously described.22
None of the subjects used medication and none had proteinuria, hematuria or glucosuria, as tested by sticks (Ecure4-test®, Boehringer Mannheim GnbH, Germany). Fasting plasma triglycerides, total cholesterol, high density lipoprotein, alanine aminotransferase, aspartate aminotransferase and glucose were within the normal ranges in the lean subjects. As expected, these values tended to be slightly increased in obese subjects.22
Weight loss and maintenance
The obese subjects were re-examined 6 months later, following a weight reduction of 18.8 kg (range 5.3–32.7 kg) or 14.8% (range 4.0–26.6%) of their initial body weight (Table 1). The weight reducing programme consisted of 8 weeks on a strictly controlled 4.2 MJ/day low calorie formula diet (GERLINÉA®, WASABRØD A/S, Skovlunde, Denmark), followed by 8 weeks on a self-composed, energy-restricted diet providing 6.3 MJ/day, and 8 weeks weight maintenance diet (for details see Verdich et al).22 Apart from weighing at the department every week during the first 8 weeks, and every second week during the rest of the intervention, we did not control for compliance.
One obese subject dropped out of the study after a weight loss of 25 kg during the first 8 weeks. His reason was that he was unable to adhere to the 6.3 MJ/day diet as he began to regain weight. Two subjects left the study immediately before the re-examination. Re-examination could not be completed in one subject due to severe migraine. As a group the four drop-outs did not differ from the 19 completers with respect to initial anthropometrical measures or weight loss.
All subjects adhered to a standardised isocaloric conventional diet as described previously on the day prior to the examination day.22
Meal-related hormone response, gastric emptying and subjective appetite rating
After 12 h fasting and abstinence from water since midnight the subjects arrived, using motorised transportation, at the Department of Clinical Physiology and Nuclear Medicine at around 8:30 a.m. Between 9:00 and 9:30 a standardised, solid test-meal, consisting of a sandwich of 135 g wheat bread with omelet as filling, with 200 ml tap water, was served. The 2.5 MJ meal consisted of 20 E% (percentage energy) protein, 50 E% carbohydrate and 30 E% fat, with an energy density of 9.0 kJ/g. To estimate the rate of gastric emptying approximately 60 Mbq of 99mTc-labeled sulfur colloid was added to the omelet immediately before cooking. Images were acquired for 120 s every 30 min during the following 3 h (for details see Verdich et al22).
Blood samples were taken in the fasting state and 15, 30, 45, 60, 90, 120, 150 and 180 min after consumption of the test meal. Visual analogue scales (VAS) were used to assess appetite sensations in the fasting state, at half-hour intervals throughout the 3 h post test meal and after termination of the ad libitum meal.7 Three hours and 10–15 min after the test meal the subjects were served an ad libitum lunch consisting of a homogeneous salad made from cold boiled pasta, sliced ham, cheese, red pepper, green peas and dressing, with an energy density of 7 kJ/g with 16.4 E% protein, 48.1 E% carbohydrate and 35.5 E% fat. The lunch was served in a separate room. The subjects were separated by screens so that they could not see each other. They were instructed not to speak to each other. A large bowl of pasta salad, a bottle of water, and an empty plate were placed in front of each subject. The subjects were instructed to drink as much as they wanted, to take as many helpings of the salad as they liked, and to stop eating when they felt pleasantly satiated. The subjects were fully aware of the purpose of the experiment.
The computer database of foods from the National Food Agency of Denmark (Dankost 2.0, Danish Food Tables 1989) was used to calculate the energy and nutrient composition of the meals and diets.
Dual energy X-ray absorptiometry (DEXA) scanning
To assess body composition the subjects were DEXA-scanned at the beginning of the study and the obese subjects were scanned again after 24 weeks of weight loss and weight maintenance. A Lunar DPX-IQ Image Densitometer (DPX, Lunar Corporation, Madison, USA) was used. Lean subjects were generally scanned in the apparatus' fast mode and obese subjects were scanned in slow mode at both examinations. There was, however, some deviation from this procedure because sagittal height was used as a guideline for the selection of scan mode.
Venous blood was drawn without stasis through an indwelling antecubital cannula into syringes (Vasculette®, Greiner Labortechnic). Samples to be analysed for non-esterified fatty acids (NEFA), GIP and GLP-1 were taken into iced syringes and were kept on ice until centrifugation. Syringes contained EDTA K3/sodium-fluoride for glucose samples, and EDTA and NEFA, GIP and GLP-1 samples. No anti-coagulants were added to the syringe for insulin samples. All samples were centrifuged for 10 min at 2800 g at 4°C. The supernatant was transferred into plastic tubes and kept at −20°C until analysis. This was performed within 30–60 min. Plasma NEFA was quantified by an enzymatic colorimetric method (Wako NEFA test kit, NEFA C, ACS-ACOD Method, code no. 994-75409 E). Plasma concentrations of glucose were determined by end point analysis with MPR3 Gluco-Quant®, Glucose/HK Kinetic 1442457 (Boehringer & Manheim GmbH) with the hexokinase/G6P-DH method, analysed on a Cobas Mira (Rosche Diagnostic System). Serum concentration of insulin was determined on an Auto Delfia Fluriometer 1332 by direct immunofluorimetric sandwich technique with Auto DELFIA (TM) insulin kit B080-101 (Wallac Denmark A/S). Plasma GIP and GLP-1 concentrations were measured after extraction of plasma with 70% ethanol (vol/vol, final concentration). For the GIP radioimmunoassay23 we used the C-terminally directed antiserum R65, which reacts fully with human GIP but not with the so-called GIP 8000, the chemical nature of which and its relationship to GIP secretion are uncertain. Human GIP and 125-I human GIP (70 MBq/nmol) were used for standards and tracer. The plasma concentrations of GLP-1 were measured24 against standards of synthetic GLP-1 (7-36) amide using antiserum code no. 89390, which is specific for the amidated C-terminus of GLP-1 and therefore does not react with GLP-1-containing peptides from the pancreas. The results of the assay accurately reflect the rate of secretion of GLP-1 because the assay measures the sum of intact GLP-1 and the primary metabolite, GLP-1 (9-36) amide, into which GLP-1 is rapidly converted.25 For both assays sensitivity was below 1 pmol/l, intra-assay coefficient of variation was below 6% at 20 pmol/l, and recovery of standard, added to plasma before extraction, was about 100% when corrected for losses inherent in the plasma extraction procedure. Determination of GLP-1 and GIP in blood samples was carried out in three separate runs over 15 months. For example, blood samples taken prior to the weight loss in obese subjects were analysed separately from the blood samples taken after the weight loss. In order to investigate the reproducibility between the two sets of results, we repeated analysis for GLP-1 in blood samples taken before the weight loss in 10 obese subjects together with blood samples taken after the weight loss. The values from the second analysis were not significantly lower than values from the first analysis ((P=0.11), in a two-factor repeated measurement ANOVA).
Informed, written consent was obtained from all subjects after the experimental protocol had been described to them in writing and orally. The study is in accordance with the Helsinki-II Declaration and was approved by the ethical committees of Copenhagen, Frederiksberg and Zealand (Registration no. 01-143/97).
The overall 3 h gastric emptying rate was calculated separately for each subject by linear regression on the six repeated measures of percentage of initial gastric content (StatView SE+Graphics™). Anthropometrical measures, fasting concentrations, total and incremental area under curve (AUC(0-180)) for hormones and metabolites, measures of appetite and initial and 3 h emptying rates were compared by t-test for independent samples (lean vs obese) and paired t-test (obese before and after weight loss) (SPSS 8.0, 9.0 and 10.0 for Windows). Finally, the hypothesis that postprandial AUCtotal, GLP-1 increases gradually when overweight is reduced (obese<reduced obese<lean) was tested by the non-parametric Jonckheere–Terpstra test. In this test it was not possible to take into account the fact that the obese and reduced obese were the same subjects. However, since the null-hypothesis (Ho) is that there is no difference between the two neighboring measurements this will increase the risk of a type II error. For all statistical tests the level of significance was set to P<0.05.
As compared to lean the obese subjects presented higher fasting and postprandial concentrations of insulin, glucose and NEFA (Figure 1, Table 2). Following a mean weight reduction of 18.8 kg concentrations of glucose, NEFA and insulin were reduced and concentrations of glucose and NEFA were similar to the concentrations seen in lean subjects, whereas the insulin concentrations were still augmented (Figure 1, Table 2).
Fasting concentrations of GLP-1 and GIP were similar in lean and obese subjects (Table 2, Figure 2). Fasting GIP concentration was significantly reduced following weight reduction, whereas the fasting concentration of GLP-1 remained unchanged (Table 2, Figure 2). Postprandial GIP response was similar between obese and lean subjects but was reduced following weight reduction. AUCtotal, GLP-1, 1 was lower in obese as compared to lean subjects. Using the Jonckheere–Terpstra test a sequential increase in AUCtotal, GLP-1 was found, so that the AUC increased in a stepwise manner from obese to reduced obese, and from reduced obese to lean subjects (P=0.003). AUCincremental, GLP-1 was found to be similar in lean and obese subjects, but 36% lower in reduced obese compared to lean subjects (P<0.05). However, this difference disappeared after exclusion of data from one reduced obese subject, who presented a fasting GLP-1 was 37 pmol/l, total GLP-1 response was 3780 pmol/l × 180 min and incremental GLP-1 response was −2.880 pmol/l × 180 min.
Appetite, energy intake and palatability
There was a significant difference in the feeling of hunger prior to the test meal between the two examinations of obese subjects (P<0.01) with a tendency to a higher feeling of hunger at the second examination. No differences were seen between lean and obese subjects with regard to the fasting level of the other appetite measures or delta peak, mean change over the post test meal period (20–170 min after the test meal), or AUC for appetite measures. In obese subjects there was a tendency for the change in hunger and prospective consumption over the post meal period to be higher before compared to after the weight loss (P=0.05 and P=0.09 respectively). Furthermore, changes in hunger and satiety over the post-meal period were less pronounced in the reduced obese subjects compared to the lean subjects (P<0.05 for both). Finally, reduced obese subjects tended to report a higher feeling of fullness after the ad libitum meal than at the first examination (P=0.08). Ad libitum energy intake was identical in all three groups (Table 2), despite the fact that one obese subject ate more than 1.4 kg of the pasta salad at the second examination compared to 0.66 kg prior to the weight loss. This single measurement was excluded from the correlation analysis.
Subjective ratings of the meals
Reduced obese subjects evaluated the aftertaste of the test meal to be greater than at the initial test day (P<0.03). The reduced obese group rated the smell of the test meal less positively than did the lean subjects (P<0.03). No differences were seen in the evaluations of the ad libitum meal.
Relationship between hormones and metabolites and gastric emptying
No correlation existed between responses of GIP, GLP-1, glucose or NEFA and either overall gastric emptying rate or percentage gastric emptying during the initial 30 min.
Intestinal hormones and appetite regulation
An inverse correlation between AUCincremental, GIP and subsequent energy intake at the ad libitum lunch was found in all three subject groups, although the relationship was only borderline significant for lean subjects (P=0.07; Figure 3). Further, in lean subjects, AUCincremental, GIP was inversely correlated with AUCprospective, consumption (r2=0.39, P<0.03) and AUChunger (r2=0.35, P<0.05) and positively correlated with AUCsatiety (r2=0.35, P<0.05) and AUCfullness (r2=0.33, P=0.05). Similar correlations were not found in the obese or reduced obese group. In obese subjects high AUCincremental, GLP-1 was related to a low reduction in the feeling of fullness over the post-meal period (r2=0.25, P<0.03). However, in lean subjects a positive correlation was seen between AUCincremental, GLP-1 and the increase in feeling of hunger over the post-meal period (r2=0.43, P=0.02).
Insulin and appetite regulation
In lean subjects energy intake at the ad libitum meal was inversely related to both fasting insulin concentration prior to the fixed test-meal (r2=0.52, P=0.008); insulin concentration immediately before the ad libitum meal (r2=0.30, P=0.06); AUCtotal, insulin and AUCincremental, insulin (r2=0.67, P=0.001; r2=0.62, P=0.002 respectively) (Figure 4). In a stepwise regression analysis AUCtotal,insulin was found to explain 67% of the variation in ad libitum energy intake, leaving no further contribution by other hormones.
Intestinal hormones and insulin response
In obese subjects an inverse correlation was seen between AUCincremental, GLP-1 and AUCtotal, insulin, as well as AUCincremental, insulin (r2=0.31, P<0.02; r2=0.31, P<0.02, respectively).
In agreement with previous studies an attenuated postprandial GLP-1 response was observed in the obese subjects. The response of the reduced obese subjects appears to be intermediate between the response for obese and lean subjects, which points towards some improvement of the GLP-1 response after the weight loss. The reduced weight stable obese subjects still had a mean BMI of 33 kg/m2 and had lost only 40% of their overweight, which suggests that postprandial GLP-1 response normalises gradually when overweight is reduced. These findings suggest that the previously described supra-normal GLP-1 response in weight-reduced obese subjects could possibly be ascribed to the weight loss intervention—jejunoileal bypass surgery—rather than the weight loss per se.11,15 When evaluating our findings it is important to note that the size of the test meal was the same in all subjects and that the gradual normalisation of the GLP-1 response with weight loss may simply reflect a stepwise decrease in daily energy requirement and a larger proportion of daily energy needs covered by the test meal when weight was reduced.
Increased plasma concentrations of NEFA and glucose have previously been suggested as inhibitors of the GLP-1 release in obesity.12,26 In the present study no correlations were seen between the GLP-1 response and either fasting concentrations or postprandial responses of glucose and NEFA. In reduced obese subjects the postprandial responses of NEFA and glucose were fully normalised, whereas the GLP-1 response was still low after the weight loss, suggesting that the increase of plasma NEFA or glucose concentrations is not the primary cause of reduced GLP-1 response in obese subjects.
The postprandial GIP response was found to be similar in obese and lean subjects but was reduced after the weight loss. Postprandial GIP response has previously been described as normal,27 augmented29 or attenuated30 in obese as compared to lean subjects. Furthermore, augmentation of the GIP response to a high fat meal has been described in post-obese and reduced obese subjects.16,28 These apparently contradictory findings may be attributable to differences in the methods used to determine plasma concentration of GIP.28,30 For example, the assay used in the present study does not cross-react with GIP 8000. The present findings suggest that an impaired postprandial GIP response may reflect a primary dysfunction preceding the obese state that contributes to the hyperphagia, which is the most important phenotypic trait of obesity. Another possibility is that postprandial GIP responses are influenced by the composition of the habitual diet and/or the energy balance.31,32,33 The obese subjects in the present study were on a low-fat diet throughout the 6 month period between the two examinations. This change in the habitual diet is likely to have affected the gastrointestinal handling of the test meal even though all subjects consumed a standardised diet on the day prior to examination.34 It is therefore possible that reduced intake of fat and added sugars and increased intake of fibre, which is thought to transfer the intestinal absorption to the lower part of the small intestine, could explain the observed decrease in GIP-response and increase in GLP-1 response.35,36
Another purpose of this study was to examine the role of the incretin hormones and insulin in the regulation of gastric emptying and appetite. In the lean subjects ad libitum energy intake was inversely related to fasting insulin concentration and to the insulin response to the preceding fixed test meal. In fact, 67% of the variation between subjects in the ad libitum intake could be accounted for by differences in the insulin response, whereas the glucose response was unrelated to intake. In a previous study Holt and co-workers have described a similar relationship, finding that 16% of variance in ad libitum energy intake could be accounted for by differences in the insulin response induced by the preceding test meal.20 Speechly and Buffenstein have recently reported in lean subjects that insulin concentration before an ad libitum lunch, was inversely correlated to the energy intake.19 In the present study an inverse correlation was found between responses of insulin and GLP-1 in obese subjects. It is well known that GLP-1 stimulates insulin release and we therefore suggest that this finding may reflect two independent effects of the obese state: reduction of meal induced GLP-1 release and increased insulin release. The lack of a positive relationship between insulin and incretin hormones supports the hypothesis that the correlation between insulin and ad libitum energy intake does, in fact, reflect a cause and effect relationship. Previously, euglycemic infusion of insulin in humans has been shown not to affect appetite regulation, suggesting that insulin does not enhance satiety under these circumstances.38 However, this does not exclude the possibility of an interactive effect on appetite regulation mediated by insulin in combination with post-meal increase in plasma glucose or the release of intestinal hormones. Nor can a hepatic effect induced by the high portal insulin concentration following meal ingestion be excluded.38 In addition, intracerebroventricular administration of insulin has been shown to reduce energy intake in baboons.39 The present observation strengthens the hypothesis that insulin plays an important role in appetite regulation. We found no correlation between ad libitum energy intake and insulin response in obese subjects, which is in agreement with the findings of Speechly and Buffenstein.19 Given that insulin is a satiety hormone, this part of the appetite regulation may be dysfunctional in obese subjects. It has previously been suggested that insulin resistance in obesity might work to protect the body against further weight gain.37 However, if insulin acts as a satiety factor it follows that insulin resistance might, in fact, promote further weight gain and hamper weight loss. Further studies are needed in order to investigate the role of insulin in appetite regulation in humans and to test the hypothesis that insulin resistance may be an important determinant of the hyperphagia in obese subjects.
Together with the relationship between insulin and ad libitum energy intake in lean subjects we found an inverse correlation between the incremental GIP response induced by the test meal and the subsequent energy intake at the ad libitum meal in all groups. A corresponding correlation was seen between incremental GIP response and VAS-scores for appetite measures in lean subjects. In a stepwise regression analysis including insulin response only the VAS-scores proved to be significant, while the relationship between GIP and ad libitum intake disappeared. However, responses of insulin and GIP were not found to be correlated, and we take the results as evidence of a possible role for both insulin and GIP in appetite regulation. Our present findings are in contrast to findings from earlier studies performed in this department, where an inverse relationship was found between GIP response to a fixed meal and subsequent parameters of satiety.13,14,15,16,17,18 These contradicting findings may stem from differences in experimental settings, whereas the assay was the same. However, from the finding of an impaired GIP response in reduced obese and a possible role of GIP in the post-meal satiety response, GIP may prove to be a central factor in the development of obesity and reduced GIP response following a weight loss might predispose to relapse. Studies examining the effect of infusion of GIP or GIP antagonists on appetite regulation are needed to test the hypothesis that GIP is a satiety hormone.
From human infusion studies it is known that peripherally infused GLP-1 inhibits gastric emptying and increases post-meal satiety.5,6,7,8 However, in the present study we found no consistent correlations between the GLP-1 response and gastric emptying and ad libitum energy intake at lunch, and only a weak correlation was seen between the GLP-1 response and subjective appetite measures. The lack of correlation may possibly be attributable to the fact that plasma concentration of GLP-1 may not reflect the concentration that acts on the effector organs. Firstly, the GLP-1 concentrations measured represent the sum of the active hormone and its primary inactive metabolite.40 Secondly, AUC is only a rough estimation of the integrated changes in plasma concentrations of GLP-1, because of the long intervals between blood sampling and the possible pulsatile release of GLP-1.41 Finally, it has been proposed that GLP-1 secreted from the intestinal L-cells may act through a direct stimulation of vagal nerve endings in the intestinal wall or in the hepatic circulation.42 Recent studies have shown that about 50% of the newly secreted GLP-1 is metabolised to its primary metabolite when passing from the intestinal stroma into the capillary bed.43 Peripheral plasma concentration of GLP-1 may not, therefore, be an adequate measure of the GLP-1 mediated neural signalling in the gut.
In conclusion, insulin and GIP may serve as mediators of the postprandial satiety response, and the insulin resistance in obesity may promote further weight gain. The attenuation of postprandial GLP-1 response in obesity is somewhat reversed in response to weight reduction. It is not clear whether the reduction in postprandial GIP response following a stabilised weight reduction reflects a dysfunction in the GIP secretion in humans prone to obesity or simply the change in habitual diet.
Read NW . Role of gastrointestinal factors in hunger and satiety in man Proc Nutr Soc 1992 51: 7–11.
Wettergren A, Schjoldager B, Mortensen PE, Myhre J, Christiansen J, Holst JJ . Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic function in man Dig Dis Sci 1993 38: 665–673.
Schjoldager BT, Mortensen PE, Christiansen J, Ørskov C, Holst JJ . GLP-1 (glucagon-like peptide 1) and truncated GLP-1, fragments of human proglucagon, inhibit gastric acid secretion in humans Dig Dis Sci 1989 34: 703–708.
Layer P, Holst JJ, Grandt D, Goebell H . Ileal release of glucagon-like peptide-1 (GLP-1). Association with inhibition of gastric acid secretion in humans Dig Dis Sci 1995 40: 1074–1082.
Gutzwiller JP, Göke B, Drewe J, Hildebrand P, Ketterer S, Handschin D, Winterhalder R, Conen D, Beglinger C . Glucagon-like peptide-1: a potent regulator of food intake in humans Gut 1999 44: 81–86.
Näslund E, Barkeling B, King N, Gutniak M, Blundell JE, Rössner S, Hellström . Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men Int J Obes Relat Metab Disord 1999 23: 304–311.
Flint A, Raben A, Astrup A, Holst JJ . Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans J Clin Invest 1998 101: 515–520.
Flint A, Raben A, Holst JJ, Astrup A . Glucagon-like peptide-1 suppresses energy expenditure in obese humans Int J Obes Relat Metab Disord 1999 23: S35.
Turton MD, O'Shea D, Gunn I, Beak SA, Edwards CMB, Meeran K, Choi SJ, Taylor GM, Heath MM, Lambert PD, Wilding JPH, Smith DM, Ghatei MA, Herbert J, Bloom SR . A role for glucagon-like peptide-1 in the central regulation of feeding Nature 1996 379: 69–72.
Ørskov C, Poulsen SS, Møller M, Holst JJ . Glucagon-like peptide 1 receptors in the subfornical organ and area postrema are accessible to circulating glucagon-like peptide-1 Diabetes 1996 45: 832–835.
Näslund E, Grybäck P, Backman L, Jacobsson H, Holst JJ, Thero-dorsson E, Hellström PM . Distal small bowel hormones: correlation with fasting antroduodenal motility and gastric emptying Dig Dis Sci 1998 43: 945–952.
Ranganath LR, Beety JM, Morgan LM, Wright JW, Howland R, Marks V . Attenuated GLP-1 secretion in obesity: cause or consequence? Gut 1996 38: 916–919.
Ranganath L, Norris F, Morgan L, Wright J, Marks V . Inhibition of carbohydrate-mediated glucagon-like peptide-1 (7-36)amide secretion by circulating non-estrified fatty acids Clin Sci 1999 96: 335–342.
Holst JJ, Schwartz TW, Lovgreen NA, Pedersen O, Beck-Nielsen H . Diurnal profile of pancreatic polypeptide, pancreatic glucagon, gut glucagon and insulin in human morbid obesity Int J Obes 1983 7: 529–538.
Holst JJ, Sørensen TIA, Andersen AH, Stadil F, Andersen B . Plasma enteroglucagon after jejunoileal bypass with 3:1 or 1:3 jejunoileal ratio Scand J Gastroenterol 1979 14: 205–207.
Raben A, Andersen HB, Christensen NJ, Madsen J, Holst JJ, Astrup A . Evidence for an abnormal postprandial response to a high-fat meal in women predisposed to obesity Am J Physiol 1994 267: E549–559.
Raben A, Tagliabue A, Christensen NJ, Madsen J, Holst JJ, Astrup A . Resistant starch: the effect on postprandial glycemia, hormonal response, and satiety Am J Clin Nutr 1994 60: 544–551.
Raben A, Andersen K, Karberg MA, Holst JJ, Astrup A . Acetylation of or β-cyclodextrin addition to potato starch: beneficial effect on glucose metabolism and appetite sensation Am J Clin Nutr 1997 66: 304–314.
Speechly DP, Buffenstein R . Appetite dysfunction in obese males: evidence for role of hyperinsulinaemia in passive overconsumption with a high fat diet Eur J Clin Nutr 2000 54: 225–233.
Holt SHA, Brand Miller JC, Petocz P . Interrelationship among postprandial satiety, glucose and insulin responses and changes in subsequent food intake Eur J Clin Nutr 1996 50: 788–797.
Fieseler P, Bridenbaugh S, Nustede R, Martell J, Ørskov C, Holst JJ, Nauck MA . Physiological augmentation of amino acid-induced insulin secretion by GIP and GLP-1 but not by CCK-8 Am J Physiol 1995 268: E949–955.
Verdich C, Lysgård Madsen J, Toubro S, Buemann B, Holst JJ, Astrup A . Effects of obesity and major weight reduction on gastric emptying Int J Obes Relat Metab Disord 2000 24: 899–905.
Krarup T, Madsbad S, Moody AJ, Regeur L, Faber OK, Holst JJ, Sestoft L . Diminished gastric inhibitory polypeptide (GIP) response to a meal in newly diagnosed type I (insulin dependent) diabetics J Clin Endocrinol Metab 1983 56: 1306–1312.
Ørskov C, Rabenhøj L, Kofod H, Wettergren A, Holst JJ . Production and secretion of amidated and glycine-extended glucagon-like peptide-1 (GLP-1) in man Diabetes 1994 43: 535–539.
Deacon CF, Pridal L, Klarskov L, Olesen M, Holst JJ . Glucagon-like peptide-1 under goes differential tissue-specific metabolism in the anaesthetised pig Am J Physiol 1996 271: E458–E464.
Ranganath L, Norris F, Morgan L, Wright J, Marks V . The effect of circulating non-esterified fatty acids on the entero-insular axis Eur J Clin Invest 1999 29: 27–32.
Sarson DL, Kopelman PG, Besterman HS, Pilkington TRE, Bloom SR . Disparity between glucose-dependent insulinotropic polypeptide and insulin response in obese man Diabetologia 1983 25: 386–391.
Jones IR, Owens DR, Luzio SD, Hayes TM . Obesity is associated with increased post-prandial GIP levels which are not reduced by dietary restriction and weight loss Diabetes Metab (Paris) 1989 15: 11–22.
Ebert R, Creutzfeldt W . Gastric inhibitory polypeptide (GIP) hypersecretion in obesity depends on meal size and is not related to hyperinsulinemia Acta Diabetol Lat 1992 26: 1–15.
Groop PH . The influence of body weight, age and glucose tolerance on the relationship between GIP secretion and beta-cell function in man Scand J Clin Lab Invest 1989 49: 367–379.
Morgan LM, Tredger JAT, Hampton SM, French AP, Peake JCF, Marks V . The effect of dietary modification and hyperglycaemia on gastric emptying and gastric inhibitory polypeptide (GIP) secretion Br J Nutr 1988 60: 29–37.
Mazzaferri EL, Starich GH, Jeor ST . Augmented gastric inhibitory polypeptide and insulin response to a meal after an increase in carbohydrate (sucrose) intake J Clin Endocrinol Metab 1984 58: 640.
Thomsen C, Rasmussen O, Lousen T, Holst JJ, Fendselau S, Schrezenmeir J, Hermansen K . Differential effects of saturated and monounsaturated fatty acids on postprandial lipemia and incretin responses in healthy subjects Am J Clin Nutr 1999 69: 1135–1143.
Cunningham K, Daly J, Horowitz M, Read NW . Gastrointestinal adaptation to diet of differing fat composition in human volunteers Gut 1991 32: 483–486.
Beck A, Villaume C, Bau HM, Garuot P, Chayvialle JA, Desalme A, Debray G . Long term influence of a wheat-bran supplemented diet on secretion of gastrointestinal hormones and on nutrient absorption in healthy man Hum Nutr Clin Nutr 1986 40C: 25–33.
Reimer RA, McBurney MI . Dietary fiber modulates intestinal proglucagon messenger ribonucleic acid and postprandial secretion of glucagon-like peptide-1 and insulin in rats Endocrinology 1996 137: 3948–3956.
Swinburn BA, Nyomba BL, Saad MF, Zurlo F, Raz I, Knowler WC, Lillioja S, Bogardus C, Ravussin E . Insulin resistance associated with lower rates of weight gain in Pima indians J Clin Invest 1991 88: 168–173.
Chapman IM, Goble EA, Wittert GA, Morley JE, Horowitz M . Effect of intravenous glucose and euglycemic insulin infusion on short-term appetite and food intake Am J Physiol 1998 274: R596–603.
Woods SC, Lotter EC, Mckay LD, Porter D Jr . Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons Nature 1979 282: 503–505.
Deacon CF, Johnsen AH, Holst JJ . Degradation of glucagon-like peptide-1 by human plasma in vitro Yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo J Clin Endocrinol Metab 1995 80: 952–957.
Balkes HJ, Holst JJ, Mühler A, Brabrant G . Rapid oscillations in plasma glucagon-like peptide-1 (GLP-1) in humans: cholinergic control of GLP-1 secretion via muscarinic receptors J Clin Endocrinol Metab 1997 85: 786–790.
Nakabayashi H, Nishizawa M, Nakagawa A, Takeda R, Niijima A . Vagal hepatopancreatic reflex effects evoked by intraportal appearance of tGLP-1 Am J Physiol 1996 271: E808–813.
Hansen L, Deacon CF, Ørskov C, Holst JJ . Glucagon-like peptide-1-(7-36)amide is transformed to glucagon-like peptide-1-(9-36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine Endocrinology 1999 141: 5356–5363.
The authors wish to thank Jens Bülow, Lene Simonsen and Ingrid Thorn at the Department of Clinical Physiology, Bispebjerg Hospital, Copenhagen and Martin Kreutzer at the Research Department of Human Nutrition for performing the DEXA-scannings. We also wish to thank Inge Timmermann, Jannie M Larsen, Kirsten B Rasmussen, Bente Knap, Lars Paaske, Ulla Pedersen, Anette Vedelspang and Charlotte Kostecki for expert technical assistance.
This study was supported by the Danish Medical Research Council. The low calorie formula diet GERLINÉA® was donated by WASABRØD A/S; Skovlunde; Denmark.
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Verdich, C., Toubro, S., Buemann, B. et al. The role of postprandial releases of insulin and incretin hormones in meal-induced satiety—effect of obesity and weight reduction. Int J Obes 25, 1206–1214 (2001). https://doi.org/10.1038/sj.ijo.0801655
- meal induced response
- gastric emptying rate
- weight loss
- dietary intervention
- ad libitum
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