The presence of nutrients in the small intestine slows gastric emptying and suppresses appetite and food intake; these effects are partly mediated by the release of gut hormones, including CCK. We investigated the hypothesis that the modulation of antropyloroduodenal motility, suppression of appetite, and stimulation of CCK and glucagon-like peptide-1 secretion by intraduodenal fat are dependent on triglyceride hydrolysis by lipase. Sixteen healthy, young, lean men were studied twice in double-blind, randomized, crossover fashion. Ratings for appetite-related sensations, antropyloroduodenal motility, and plasma CCK and glucagon-like peptide-1 concentrations were measured during a 120-min duodenal infusion of a triglyceride emulsion (2.8 kcal/min) on one day with, on the other day without, 120 mg tetrahydrolipstatin, a potent lipase inhibitor. Immediately after the duodenal fat infusion, food intake at a buffet lunch was quantified. Lipase inhibition with tetrahydrolipstatin was associated with reductions in tonic and phasic pyloric pressures, increased numbers of isolated antral and duodenal pressure waves, and stimulation of antropyloroduodenal pressure-wave sequences (all P < 0.05). Scores for prospective consumption and food intake at lunch were greater, and nausea scores were slightly less, and the rises in plasma CCK and glucagon-like peptide-1 were abolished (all P < 0.05). In conclusion, lipase inhibition attenuates the effects of duodenal fat on antropyloroduodenal motility, appetite, and CCK and glucagon-like peptide-1 secretion.

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There is evidence that gastrointestinal function adapts in response to a high-fat (HF) diet. This study investigated the hypothesis that an HF diet modifies the acute effects of duodenal lipid on appetite, antropyloroduodenal pressures, plasma CCK and plasma glucagon-like peptide-1 (GLP-1) levels in humans. Twelve healthy men were studied twice in randomized, crossover fashion. The effects of a 90-min duodenal lipid infusion (6.3 kJ/min) on the above parameters were assessed immediately following 14-day periods on either an HF or a low-fat (LF) diet. After the HF diet, pyloric tonic and phasic pressures were attenuated, and the number of antropyloroduodenal pressure-wave sequences was increased when compared with the LF diet. Plasma CCK and GLP-1 levels did not differ between the two diets. Hunger was greater during the lipid infusion following the HF diet, but there was no difference in food intake. Therefore, exposure to an HF diet for 14 days attenuates the effects of duodenal lipid on antropyloroduodenal pressures and hunger without affecting food intake or plasma hormone levels.

The determinants of postprandial blood glycemia are controversial. We assessed the effects of variations in the initial rate of small intestinal glucose delivery on blood glucose, plasma insulin, and incretin responses in both health and type 2 diabetes. Eight controls and eight patients with type 2 diabetes managed by diet alone underwent paired studies. On both days subjects received an intraduodenal glucose infusion (t = 0-120 min); on one day the infusion rate was variable, being more rapid initially (3 kcal/min) between t = 0 and 15 min and slower (0.71 kcal/min) subsequently (t = 15-120 min), whereas on the other day, the infusion rate was constant (1 kcal/min) from t = 0 to 120 min (i.e. on both days 120 kcal of glucose were administered). Between t = 0-180 min blood glucose, plasma insulin and plasma glucose-dependent insulin-releasing polypeptide were greater with the variable, compared with the constant, infusion. Between t = 0 and 30 min the magnitude of the rise in plasma glucagon-like peptide-1 was greater with the variable, compared with the constant infusion (P < 0.01, both groups). We conclude that modest variations in the initial rate of duodenal glucose entry may have profound effects on subsequent glycemic, insulin, and incretin responses.

Previous observations suggest that glucagon-like peptide-1 (GLP-1) is released into the bloodstream only when dietary carbohydrate enters the duodenum at rates that exceed the absorptive capacity of the proximal small intestine to contact GLP-1 bearing mucosa in more distal bowel. The aims of this study were to determine the effects of modifying the length of small intestine exposed to glucose on plasma concentrations of GLP-1 and also glucose-dependent insulinotropic peptide (GIP), insulin, cholecystokinin (CCK) and ghrelin, and antropyloric pressures. Glucose was infused at 3.5 kcal/min into the duodenum of eight healthy males (age 18 -59 yr) over 60 min on the first day into an isolated 60-cm segment of the proximal small intestine ("shortsegment infusion"); on the second day, the same amount of glucose was infused with access to the entire small intestine ("long-segment infusion"). Plasma GLP-1 increased and ghrelin decreased (P Ͻ 0.05 for both) during the long-, but not the short-, segment infusion. By contrast, increases in plasma CCK and GIP did not differ between days. The rises in blood glucose and plasma insulin were greater during the long-than during the short-segment infusion (P Ͻ 0.05). During the long-but not the short-segment infusion, antral pressure waves (PWs) were suppressed (P Ͻ 0.05). Isolated pyloric PWs and basal pyloric pressure were stimulated on both days. In conclusion, the release of GLP-1 and ghrelin, but not CCK and GIP, is dependent upon Ͼ60 cm of the intestine being exposed to glucose.gastrointestinal hormone secretion; antropyloric motility; small intestinal nutrient exposure; glucagon-like peptide-1; glucose-dependent insulinotropic peptide; cholecystokinin THE KNOWN REGULATORY GUT PEPTIDES have differing distributions along the small intestine. For example, GIP is secreted from endocrine K cells (7) and CCK by endocrine I cells (33) in the proximal small intestine, whereas peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) are secreted from endocrine L cells in the distal small intestine (6, 28). Whether these peptides are released primarily, or exclusively, by direct local contact with specific nutrients in their regions of storage or are released reflexively from the distal small intestine by signals arising from the proximal small intestine, or vice versa, is still debatable. For example, in rats, intravenous infusion of GIP has been shown to stimulate the secretion of GLP-1 (34). In dogs, Lin and colleagues (18,19) demonstrated that cholecystokinin (CCK) was released equipotently whether fat contacted the proximal, or distal, small intestine and that the release of PYY was dependent, at least in part, on the stimulation of CCK by fat confined to proximal small intestine. On the other hand, Pilichiewicz et al. (31) concluded recently that, in humans, CCK was released only by fat in the proximal small intestine and PYY was much more potently released by fat locally in the distal small intestine than in the jejunum. These last observations suggest that the nutrient-stimulat...

Background: Dietary interventions represent a promising therapeutic strategy to optimize postprandial glycemia. The addition of protein to oral glucose has been reported to improve the glycemic profile. Objective: The aim of the current study was to evaluate the mechanisms by which protein supplementation lowers the blood glucose response to oral glucose. Design: Nine healthy men were studied on 3 d each in a random order. Subjects consumed 300-mL drinks containing either 50 g glucose (Glucose), 30 g gelatin (Protein), or 50 g glucose with 30 g gelatin (Glucose ѿ Protein) in water labeled with 150 mg [13 C]acetate. Blood and breath samples were subsequently collected for 3 h to measure blood glucose and plasma insulin, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) concentrations and gastric half-emptying time, which was calculated from 13 CO 2 excretion. Results: The blood glucose response was less after Glucose ѿ Protein than after Glucose (P 0.005); GIP was lower (P 0.005), and there were no significant differences in plasma insulin or GLP-1. Protein alone stimulated insulin, GLP-1, and GIP (P 0.05 for each) without elevating blood glucose. The gastric half-emptying time was greater after Glucose ѿ Protein than after Glucose (P 0.05) and tended to be greater for Glucose than for Protein (P ҃ 0.06). Conclusions: In healthy humans, the addition of protein to oral glucose lowers postprandial blood glucose concentrations acutely, predominantly by slowing gastric emptying, although protein also stimulates incretin hormones and non-glucose-dependent insulin release.Am J Clin Nutr 2007;86:1364 -8.

The effects of volume and posture on gastric emptying and intragastric distribution of a solid meal and appetite were evaluated. Eight normal volunteers were studied on four occasions, on each of which a meal comprising ground beef mixed with tomato sauce of either 650 g (“large”) or 217 g (“small”) was eaten. Two studies were performed while the subject was lying in the left lateral decubitus position, and two studies were performed while the subject was sitting so that in each subject data were available for both meals and in both postures. Hunger and fullness were evaluated using a visual analog questionnaire. In both postures and after both meals, gastric emptying approximated a linear pattern after an initial lag phase. The lag phase was shorter for the large meal when compared with the small meal [sitting: large 13 ± 5 vs. small 29 ± 7 min; left lateral: large 16 ± 3 vs. small 24 ± 3 min, F(1,7) = 46.3, P < 0.0005]. In both postures the contents of the total [ F(1,7) = 1794.5, P < 0.0001], proximal [ F(1,7) = 203.7, P < 0.0001], and distal [ F(1,7) = 231.5, P < 0.0001] stomach were greater after the large meal when compared with the small meal. Although the 50% emptying time was greater with the large than the small meal [ F(1,7) = 40.8, P < 0.001], the postlag emptying rate (g/min) was more rapid with the large meal [sitting: large 1.7 ± 0.2 vs. small 1.1 ± 0.1 g/min; left lateral: large 1.8 ± 0.1 vs. small 1.3 ± 0.04 g/min, F(1,7) = 44.7, P < 0.0005]. There was a significant interaction between meal volume and posture for retention in the distal stomach [ F(1,7) = 7.14, P < 0.05]. Contrasts were used to evaluate the effects of volume and posture between the four studies and demonstrated an effect of posture for the large [ F(1,21) = 18.7, P < 0.005] but not the small [ F(1,21) = 0.30, P = 0.60] meal so that the retention was greater in the sitting when compared with the left lateral position. The magnitude of the postprandial increase in fullness [ F(1,7) = 7.8, P < 0.05] and reduction in hunger [ F(1,7) = 5.9, P < 0.05] was greater with the large meal. We conclude that meal volume has a major effect on gastric emptying; in contrast posture has only a minor impact on intragastric meal distribution, which is observed only after a large meal, and no effect on gastric emptying.

Although the primary source of ghrelin is the gastric mucosa, these results suggest that small intestinal nutrient exposure is sufficient for food-induced plasma ghrelin suppression in humans, and that gastric nutrient exposure is not necessary for suppression.