Intraduodenal Nutrient Infusion Research Articles

Intraduodenal nutrient infusion differentially alters intestinal nutrient sensing, appetite, and satiety responses in lean and obese subjects

BackgroundIntestinal nutrient sensing regulates food intake and energy metabolism by acting locally and relaying nutritional status to the brain. It is unclear whether these mechanisms are altered in obese humans. ObjectivesWe aimed to investigate differences in duodenal nutrient sensing in humans with or without obesity and the effects of transiently blocking vagal transmission on nutrient sensing, hunger, and appetite. MethodsIn a single-blinded, randomized, cross-over design, subjects with or without obesity (n = 14 and n = 11, respectively) were infused intraduodenally with saline or a combination of glucose and oleic acid for 90 min (glucose load: 22.5 g, 1 kcal/min; oleic acid load: 10 g, 1 kcal/min) in the presence or absence of local anesthetic (benzocaine). Blood was sampled at 10-min intervals (120–240 min) and 15-min intervals until termination of the study for measurements of gut hormones, insulin, leptin, and C-peptide. Hunger and satiety sensations were scored using the visual analog scale, and hepatic glucose production and glucose oxidation rates were measured. ResultsDuodenal nutrient infusion in lean subjects led to a 65% drop in acyl ghrelin release and robustly increased cholecystokinin 8 (CCK-8) release (65%; P = 0.023); benzocaine infusion delayed this response (2-factor repeated-measures analysis of variance, P = 0.0065). In contrast, subjects with obesity had significantly blunted response to nutrient infusion, and no further effects were observed with benzocaine. Additionally, significant delays were observed in peptide YY (3-36), pancreatic polypeptide, glucose inhibitory peptide, and glucagon-like peptide 1 (7-36) response. No significant interactions were found between body mass index (BMI) or baseline hormone levels and areas under the curve for hormones except CCK-8 (BMI, P = 0.018; baseline CCK, P = 0.013). Nutrient-induced hunger and satiety sensations were impeded by benzocaine only in the lean cohort. Hunger and satiety sensations in subjects with obesity were not responsive to nutrient entry into the duodenum, and no additional effects were observed by blocking neural signaling. ConclusionNutrient-induced gut hormone release and response to transient vagal blockade are significantly blunted in subjects with obesity.This trial was registered at clinicaltrials.org as NCT02537314.

Regulation of gastric emptying rate and its role in nutrient-induced GLP-1 secretion in rats after vertical sleeve gastrectomy

Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) are effective weight loss surgeries that also improve glucose metabolism. Rapid, early rises of circulating insulin and glucagon-like peptide-1 (GLP-1) concentrations following food ingestion are characteristic of these procedures. The purpose of the current study was to test the hypothesis that postprandial hormone release is due to increased nutrient emptying from the stomach. Radioscintigraphy and chemical and radiolabeled tracers were used to examine gastric emptying in rat models of VSG and RYGB surgery. Intraduodenal nutrient infusions were used to assess intestinal GLP-1 secretion and nutrient sensitivity in VSG rats compared with shams. Five minutes after a nutrient gavage, the stomachs of RYGB and VSG rats were completely emptied, whereas only 6.1% of the nutrient mixture had emptied from sham animals. Gastric pressure was increased in VSG animals, and rats with this procedure did not inhibit gastric emptying normally in response to increasing caloric loads of dextrose or corn oil, and they did not respond to neural or endocrine effectors of gastric motility. Finally, direct infusion of liquid nutrients into the duodenum caused significantly greater GLP-1 release in VSG compared with shams, indicating that increases in GLP-1 secretion after VSG are the result of both greater gastric emptying rates and altered responses at the level of the intestine. These findings demonstrate greatly accelerated gastric emptying in rat models of RYGB and VSG. In VSG this is likely due to increased gastric pressure and reduced responses to inhibitory feedback from the intestine.

Intraduodenal milk protein concentrate augments the glycemic and food intake suppressive effects of DPP-IV inhibition

Glucagon-like peptide-1 (GLP-1) is an incretin hormone released from intestinal L-cells in response to food entering into the gastrointestinal tract. GLP-1-based pharmaceuticals improve blood glucose regulation and may hold promise for obesity treatment, as GLP-1 drugs reduce food intake and body weight in humans and animals. In an effort to improve GLP-1 pharmacotherapies, we focused our attention on macronutrients that, when present in the gastrointestinal tract, may enhance GLP-1 secretion and improve glycemic regulation and food intake suppression when combined with systemic administration of sitagliptin, a pharmacological inhibitor of DPP-IV (enzyme responsible for GLP-1 degradation). In particular, previous data suggest that specific macronutrient constituents found in dairy foods may act as potent secretagogues for GLP-1 and therefore may potentially serve as an adjunct dietary therapy in combination with sitagliptin. To directly test this hypothesis, rats received intraperitoneal injections of sitagliptin (6 mg/kg) or saline vehicle followed by intraduodenal infusions of either milk protein concentrate (MPC; 80/20% casein/whey; 4 kcal), soy protein (nondairy control infusate; 4 kcal), or 0.9% NaCl. Food intake was assessed 30 min postinfusion. In separate studies, regulation of blood glucose was examined via a 2-h oral glucose tolerance test (2 g/kg) following identical sitagliptin treatment and intraduodenal nutrient infusions. Collectively, results show that intraduodenal MPC, but not soy protein, significantly enhances both the food intake suppression and improved control of blood glucose produced by sitagliptin. These data support the hypothesis that dietary intake of dairy protein may be beneficial as an adjunct behavioral therapy to enhance the glycemic and food intake suppressive effects of GLP-1-based pharmacotherapies.

Endogenous leptin receptor signaling in the medial nucleus tractus solitarius affects meal size and potentiates intestinal satiation signals

Leptin receptor (LepRb) signaling in the hindbrain is required for energy balance control. Yet the specific hindbrain neurons and the behavioral processes mediating energy balance control by hindbrain leptin signaling are unknown. Studies here employ genetic [adeno-associated virally mediated RNA interference (AAV-RNAi)] and pharmacological methodologies to specify the neurons and the mechanisms through which hindbrain LepRb signaling contributes to the control of food intake. Results show that AAV-RNAi-mediated LepRb knockdown targeting a region encompassing the mNTS and area postrema (AP) (mNTS/AP LepRbKD) increases overall cumulative food intake by increasing the size of spontaneous meals. Other results show that pharmacological hindbrain leptin delivery and RNAi-mediated mNTS/AP LepRb knockdown increased and decreased the intake-suppressive effects of intraduodenal nutrient infusion, respectively. These meal size and intestinally derived signal amplification effects are likely mediated by LepRb signaling in the mNTS and not the AP, since 4th icv and mNTS parenchymal leptin (0.5 μg) administration reduced food intake, whereas this dose did not influence food intake when injected into the AP. Overall, these findings deepen the understanding of the distributed neuronal systems and behavioral mechanisms that mediate the effects of leptin receptor signaling on the control of food intake.

The effects of intraduodenal nutrient infusion on serum CCK, LES pressure, and gastroesophageal reflux

Fats cause reflux symptoms in many patients and cholecystokinin (CCK) may play a role. This study was designed to evaluate the effects of intraduodenal nutrient infusion on serum CCK levels, lower esophageal sphincter (LES) pressure, and gastroesophageal reflux (GER). Twenty-four asymptomatic volunteers were studied. A Dent sleeve catheter assessed LES function while an impedance-pH catheter measured reflux events. Participants were randomized to fat (F), carbohydrate (C) or protein (P) infusion. Serum CCK and LES pressures were measured at baseline and after nutrient infusion. Baseline LES pressures and CCK levels were similar in all three groups. A significant linear decrease was found in LES pressure during F, but not C or P, infusion (P=0.004). A significant interaction effect was noted between the infusion groups and CCK levels (P=0.002). A significant linear increase was noted in CCK levels during F but not during C or P infusion (P=0.02). A significant inverse correlation was found between CCK levels and LES pressure (ρ=-0.43; P=0.04). Esophageal acid exposure was significantly increased in the F infusion group (median; interquartile range: 1.10%; 0.25-4.7%) compared to both the C (0.03%; 0.00-0.39%) and P infusion (0.03%; 0.00-0.39%) groups (P=0.04). Intraduodenal F infusion was associated with an increase in CCK levels, while P and C were not. LES pressure decreased significantly after fat infusion and reflux events were more frequent. Fat-induced CCK release is another mechanism that contributes to GER.

Relationship between altered small intestinal motility and absorption after abdominal aortic aneurysm repair

Small intestinal (SI) motor patterns are often disrupted after major non-gastrointestinal (non-GI) surgery, but the impact on luminal flow and nutrient absorption is unclear. This study examines interactions between SI motility, flow and absorption in the first 3 days after surgical repair of abdominal aortic aneurysm (AAA). Concurrent assessments of SI motility (manometry), flow (impedancometry) and lipid (¹³C-triolein) and glucose [plasma 3-O-methyl-glucose (3-OMG)] absorption were performed in 13 patients (12 male; 77 ± 2 years) on days 1 and 3 post surgery during 3-h intra-duodenal nutrient infusion (Ensure® with 200 μl ¹³C-triolein, 3 g 3-OMG). Data, presented as mean ± standard error of mean (SEM), are compared with 10 healthy volunteers (9 male; 57 ± 4 years). On day 1 post surgery, there were more motility bursts, fewer impedance events and reduced absorption of ¹³C-triolein [cumulative percent dose recovery (cPDR) 22.9 ± 2.4% versus 31.2 ± 4.2%; P < 0.001] and 3-OMG, compared with health. By day 3, total number of bursts and flow events were similar between groups, with fewer retrograde and more antegrade flow episodes. ¹³C-triolein absorption remained low in patients on day 3 (26.7 ± 2.2%, P < 0.05), correlating positively with total number of flow events (r = 0.49; P < 0.01), but negatively with prolonged events (r = -0.37; P = 0.03). In patients, 3-OMG absorption increased from day 1 to 3 to a level comparable to health. Whilst disruption in SI motility and flow (impedance) events was associated with reduced absorption of both lipid and carbohydrate, lipid malabsorption was more prolonged. This may reflect inadequate mixing of chyme from altered motility, so varying the nutrient composition of enteral feed may improve absorption in these patients.

Effects of Intraduodenal Nutrient Infusion on CCK Levels, LES Pressure, and Gastroesophageal Reflux (GER)

Purpose: Background: Fats are associated with increased GER and CCK (cholecystokinin) is thought to play a role. The contribution of other nutrients to GER is not well described. Aims: Evaluate the effects of intraduodenal nutrient infusion on serum CCK levels, lower esophageal sphincter (LES) pressure, and GER. Methods: 24 healthy asymptomatic Caucasian volunteers were studied. A water-perfused, 6 cm Dent sleeve catheter (Dentsleeve International Ltd) was positioned across the LES fluoroscopically; an infusion port was located in the 2nd portion of the duodenum. An impedance-pH catheter (Sandhill Scientific) was attached to the catheter with the pH probe 5 cm above the upper border of the LES. After a 1-hour accommodation period baseline CCK levels were measured. Volunteers were randomized to receive one of 3 separate 60 kcal nutrient infusions over 30 minutes (2 cc/min): fat (F; Microlipid, Novartis Medical Nutrition); carbohydrate (C; Polycose, Ross Nutrition); or protein (P; Beneprotein, Novartis Medical Nutrition). All substances were dispersed in normal saline. Blood samples were drawn 5, 10, 15, and 25 minutes after nutrient infusion. LES resting pressure was measured at baseline and 60 minutes after nutrient infusion. Reflux events were categorized as either acid or non-acid in nature using a pH cut-off of 4.0. Results: No statistically significant difference was found among the 3 groups with regards to demographics, number of reflux events, number of acid events or percent of time with acid. A trend was noted for increased reflux and acid exposure events in the fat group. CCK levels were significantly higher in the fat group compared to the other 2 groups at 10, 15, and 25 minutes after nutrient infusion. The mean post-infusion LES pressure was significantly lower than mean baseline LES pressure in the F group (P= 0.02). Conclusion: Intraduodenal fat infusion led to a statistically significant increase in CCK levels in normal volunteers, while protein and carbohydrate did not. Reflux events were more frequent in volunteers infused with fat compared to protein or carbohydrate, although this did not reach statistical significance. LES pressure decreased significantly after fat infusion. Further studies are needed to better define the relationship between fat infusion, CCK release, LES pressure, and GER.Table

Pressure-geometry relationship in the antroduodenal region in humans.

Understanding of the control mechanisms underlying gastric motor function is still limited. The aim of the present study was to evaluate antral pressure-geometry relationships during gastric emptying slowed by intraduodenal nutrient infusion and enhanced by erythromycin. In seven healthy subjects, antral contractile activity was assessed by combined dynamic magnetic resonance imaging and antroduodenal high-resolution manometry. After intragastric administration of a 20% glucose solution (750 ml), gastric motility and emptying were recorded during intraduodenal nutrient infusion alone and, subsequently, combined with intravenous erythromycin. Before erythromycin, contraction waves were antegrade (propagation speed: 2.7 +/- 1.7 mm/s; lumen occlusion: 47 +/- 14%). Eighty-two percent (51/62) of contraction waves were detected manometrically. Fifty-four percent of contractile events (254/473) were associated with a detectable pressure event. Pressure and the degree of lumen occlusion were only weakly correlated (r(2) = 0.02; P = 0.026). After erythromycin, episodes of strong antroduodenal contractions were observed. In conclusion, antral contractions alone do not reliably predict gastric emptying. Erythromycin induces strong antroduodenal contractions not necessarily associated with fast emptying. Finally, manometry reliably detects ~80% of contraction waves, but conclusions from manometry regarding actual contractile activity must be made with care.

Relative contributions of "pressure pump" and "peristaltic pump" to gastric emptying.

The relative contributions to gastric emptying from common cavity antroduodenal pressure difference ("pressure pump") vs. propagating high-pressure waves in the distal antrum ("peristaltic pump") were analyzed in humans by high-resolution manometry concurrently with time-resolved three-dimensional magnetic resonance imaging during intraduodenal nutrient infusion at 2 kcal/min. Gastric volume, space-time pressure, and contraction wave histories in the antropyloroduodenal region were measured in seven healthy subjects. The subjects fell into two distinct groups with an order of magnitude difference in levels of antral pressure activity. However, there was no significant difference in average rate of gastric emptying between the two groups. Antral pressure history was separated into "propagating high-pressure events" (HPE), "nonpropagating HPEs," and "quiescent periods." Quiescent periods dominated, and average pressure during quiescent periods remained unchanged with decreasing gastric volume, suggesting that common cavity pressure levels were maintained by increasing wall muscle tone with decreasing volume. When propagating HPEs moved to within 2-3 cm of the pylorus, pyloric resistance was found statistically to increase with decreasing distance between peristaltic waves and the pylorus. We conclude that transpyloric flow tends to be blocked when antral contraction waves are within a "zone of influence" proximal to the pylorus, suggesting physiological coordination between pyloric and antral contractile activity. We further conclude that gastric emptying of nutrient liquids is primarily through the "pressure pump" mechanism controlled by pyloric opening during periods of relative quiescence in antral contractile wave activity.

Effects of small-intestinal fat and carbohydrate infusions on appetite and food intake in obese and nonobese men

To determine whether the satiating effects of nutrients in the small intestine are lower in obese than in nonobese people, 9 healthy, obese men [age: 18-33 y; body mass index (BMI; in kg/m2) 30.4-40.8] and 11 healthy, nonobese men (age: 18-33 y; BMI: 19.1-26.4) received an intraduodenal infusion of saline (control), lipid ( 11.97 kJ/min, or 2.86 kcal/min), or glucose (11.97 kJ/min) for 120 min on separate days. Fullness, hunger, and nausea were assessed by visual analogue scales. After the infusions, a meal was offered and food intake was quantified. There was no difference in appetite ratings between the obese and nonobese subjects during the infusions, in the amount or macronutrient composition of food eaten after the infusions, or in the time taken to eat the meals. Both the lipid and glucose infusions were associated with greater fullness than the control infusion. The energy content of the food eaten was less after the lipid infusion than after either the control or glucose infusion (P < 0.01): lipid infusion suppressed energy intake by 22% compared with the control infusion and by 15% compared with the glucose infusion. Suppression of energy intake after intraduodenal nutrient infusions was due to slower eating (P < 0.01). Intraduodenal infusions of fat suppressed appetite and food intake more than did equienergetic infusions of carbohydrate in both obese and nonobese young men, and the responses to intraduodenal fat and glucose were not affected by obesity. The latter observation suggests that established obesity is not associated with reduced small-intestinal responses to dietary fat or carbohydrate.

Effects of intraduodenal glucose infusion on gastric myoelectrical activity and antropyloroduodenal motility.

Intraduodenal nutrient infusions cause an inhibition of antral motility and an increase in pyloric motility. The involvement of gastric myoelectrical activity in this intestinogastric feedback was studied. Electrogastrography and antropyloroduodenal manometry were performed in 10 healthy volunteers. The effects of 20-mininfusions of 25% glucose (4 kcal/min) and saline were compared. Intraduodenal glucose infusions caused a decrease in the power of the dominant frequency in the electrogastrogram (P = 0.028), but the frequency itself remained unchanged. The total number of dysrhythmias increased (P = 0.035). An inhibition of antral motor activity (P = 0.001), an increase in the number of isolated pyloric pressure waves (P = 0.027), and an increase in basal pyloric tone (P = 0.001) were simultaneously recorded. The change in power during glucose infusion correlated positively with the change in the antral motility index (rs = 0.50, P = 0.001). It is concluded that inhibition of gastric myoelectrical activity is one of the mechanisms underlying an inhibition of motor activity in the gastric antrum.

Effects of small intestinal nutrient infusion on appetite and pyloric motility are modified by age.

The mechanisms responsible for the reduction in appetite and slowing of gastric emptying in older persons are unknown. The aims of this study were to evaluate the effects of aging on small intestinal regulation of appetite and pyloric motility. Eight healthy older (age 65-75 yr) and seven healthy young (age 20-34 yr) male subjects received isocaloric (2.9 kcal/min) intraduodenal infusions of lipid and glucose for 120 min, each on separate days. During the intraduodenal infusions, perceptions of hunger, desire to eat, and fullness were assessed by visual analog scales. Pyloric motility (isolated pyloric pressure waves and tonic pyloric pressure) was measured by manometry during the intraduodenal lipid infusion. On each day, after completion of the intraduodenal nutrient infusion the subject was offered a buffet meal and food intake was quantified. Before intraduodenal nutrient infusions, sensations of hunger (P < 0.01) and desire to eat (P < 0.05) were less in the older compared with the young subjects. In the young, intraduodenal lipid suppressed hunger to a greater extent than intraduodenal glucose (P < 0.05). In older persons, neither intraduodenal nutrient infusion suppressed hunger. Intraduodenal lipid and glucose increased fullness in both age groups (P < 0.05 for both), with no significant difference between the two nutrients. There was no significant difference in food intake from the buffet meal between the elderly and young subjects. Intraduodenal lipid infusion stimulated phasic pyloric pressure waves in both age groups (P < 0.01 for both), and this response was greater (P < 0.05) in older persons. There was an increase (P < 0.01) in tonic pyloric pressure during intraduodenal lipid infusion that was not significantly different between the two age groups. We conclude that the effect of small intestinal lipid infusion on hunger is attenuated, and the stimulation of phasic pyloric pressure waves increased in healthy older persons compared with healthy young males. Increased feedback from small intestinal nutrients does not appear to be responsible for the physiological anorexia of aging.

Effects of intraduodenal nutrient infusion on insulin response to subsequent intravenous glucose in rats

To elucidate the so-called incretin effect, the effects of intraduodenal bolus injection of glucose, 0.9% NaCl (saline), amino acids, and triglyceride on insulin response to subsequent intravenous injection of glucose (0.5 g/kg in 10% solution) was investigated in rats. Portal and femoral venous insulin and glucose concentration were simultaneously measured. Significantly higher portal insulin and lower femoral glucose values were observed in intraduodenal glucose or saline injection rats compared with controls (nothing was infused into the duodenum). Peripheral removal of insulin in these rats was not decreased. In the rats with intraduodenal injection of amino acids or triglyceride, slightly higher portal insulin and lower femoral glucose values were observed, but they were not significantly different from controls. These results indicate that incretin effect is provoked by intraduodenal infusion of glucose and saline, and may have some important physiologic role on glucose metabolism in rats in vivo.