Amylin,Food Intake,and Obesity

Amylin, also known as islet amyloid polypeptide, identified in 1987, is a naturally occurring hormone, released by the β cells of the pancreas and consists of 37 amino acids. Amylin seems to decrease food intake through both central and peripheral mechanisms and indirectly by slowing gastric emptying. The mean basal amylin concentration is higher in obese than in lean human subjects. The amylin response to oral glucose is also greater in obese subjects, whether or not they have impaired glucose tolerance. The elevated amylin levels in obesity may lead to down-regulation of amylin receptors and lessen the impact of postprandial amylin secretion on satiety and gastric emptying. Amylin administration may overcome resistance at target tissues, delay gastric emptying, and have potential for inducing weight loss in obese individuals.     

Gastric emptying of liquids in patients with peptic ulcer disease

This study was designed to determine the rates of gastric emptying of water, saline and a 20% glucose solution in patients with gastric and duodenal ulcers. In all subjects, gastric emptying was fastest after administration of the saline, slower with water and the slowest with glucose. Significant statistical differences (p less than 0.05) in emptying rates between normal subjects and the group with duodenal ulcer were seen when water and saline but not glucose were used. We conclude that inhibitory effects of the osmotic receptors are not changed in gastric and duodenal ulcer patients. However, the emptying rates were higher when osmotic stimulus was withheld.     

Intestinal transit of a glucose bolus and incretin kinetics: a mathematical model with application to the oral glucose tolerance test

The rate of appearance (R(a)) of exogenous glucose in plasma after glucose ingestion is presently measured by tracer techniques that cannot be used in standard clinical testing such as the oral glucose tolerance test (OGTT). We propose a mathematical model that represents in a simple way the gastric emptying, the transport of glucose along the intestinal tract, and its absorption from gut lumen into portal blood. The model gives the R(a) time course in terms of parameters with a physiological counterpart and provides an expression for the release of incretin hormones as related to glucose transit into gut lumen. Glucose absorption was represented by assuming two components related to a proximal and a distal transporter. Model performance was evaluated by numerical simulations. The model was then validated by fitting OGTT glucose and GLP-1 data in healthy controls and type 2 diabetic patients, and useful information was obtained for the rate of gastric emptying, the rate of glucose absorption, the R(a) profile, the insulin sensitivity, and the glucose effectiveness. Model-derived estimates of insulin sensitivity were well correlated (r = 0.929 in controls and 0.886 in diabetic patients) to data obtained from the euglycemic hyperinsulinemic clamp. Although the proposed OGTT analysis requires the measurement of an additional hormone concentration (GLP-1), it appears to be a reasonable choice since it avoids complex and expensive techniques, such as isotopes for glucose R(a) measurement and direct assessment of gastric emptying and intestinal transit, and gives additional correlated information, thus largely compensating for the extra expense.     

Cholecystokinin pathways modulate sensations induced by gastric distension in humans

Ingested fat releases CCK, causes gastric relaxation, delays gastric emptying, and limits meal size; however, the mechanistic link among these actions has not been established. Fatty acid release of CCK is chain-length sensitive; dodecanoic acid (C12) induces greater CCK release than decanoic acid (C10). The effect of C12 or C10 on tolerance to subsequent intragastric infusion of liquid was determined in healthy subjects, with and without the CCK(1) receptor antagonist dexloxiglumide. Gastric wall relaxation after either fatty acid was assessed by graded volume distension and by barostat; gastric emptying was measured by gastric aspiration and by a [(13)C]octanoic acid breath technique. C12 released more CCK (mean plasma CCK after vehicle, 4.7 +/- 0.8 pM; C10, 4.8 +/- 0.3 pM; C12, 8 +/- 1.2 pM; P < 0.05 C12 vs. C10 or vehicle) and reduced the volume of water (and of 5 and 25% glucose solutions) delivered at maximum tolerance compared with C10 or vehicle (volume of water tolerated after vehicle, 1,535 +/- 164 ml; C10, 1,335 +/- 160 ml; C12, 842 +/- 103 ml; P < 0.05 C12 vs. C10 or vehicle); this effect was abolished by dexloxiglumide. Intragastric volumes were always similar at the limit of tolerance, and, whereas gastric relaxation occurred to similar degrees after the fatty acids, its duration was longer after C12, which also induced a longer delay in half-gastric emptying [t(1/2)(min) after vehicle, 53 +/- 2; C10, 67 +/- 3; C12, 88 +/- 7; P < 0.05 C12 vs. C10 or vehicle]. In conclusion, ingestion of a CCK-releasing fatty acid reduces the tolerated volume of liquid delivered into the stomach, primarily via a CCK(1) receptor-mediated delay in gastric emptying.     

Role of endogenous amylin in glucagon secretion and gastric emptying in rats demonstrated with the selective antagonist, AC187

Amylin is a 37-amino acid polypeptide co-secreted with insulin from the pancreatic beta-cells. It complements insulin's stimulation of the rate of glucose disappearance (Rd) by slowing the rate of glucose appearance (Ra) through several mechanisms, including an inhibition of mealtime glucagon secretion and a slowing of gastric emptying. To determine if endogenous amylin tonically inhibits these processes, we studied the effects of the amylin receptor blocker AC187 upon glucagon secretion during euglycemic, hyperinsulinemic clamps in Sprague-Dawley (HSD) rats, upon gastric emptying in HSD rats, and upon gastric emptying and plasma glucose profile in hyperamylinemic, and genetically obese, Lister Albany/NIH rats during a glucose challenge. Amylin blockade increased glucagon concentration, accelerated gastric emptying of liquids, and resulted in an exaggerated post-challenge glycemia. These data collectively indicate a physiologic role for amylin in glucose homeostasis via mechanisms that include regulation of glucagon secretion and gastric emptying.     

GIP and insulin release in relation to gastric emptying of a mixed meal in man

To clarify the role of GIP (gastric inhibitory polypeptide) as an incretin, we related temporally the gastric emptying of fat, protein and glucose to plasma levels of glucose, GIP and insulin in man. Five healthy volunteers with a multiple lumen duodenal tube ingested a mixed meal with phase-specific markers for the aqueous phase, liquid fat and the solid protein phase. Duodenal passage was determined by intraduodenal infusion of a second set of phase-specific non-absorbable markers. Plasma insulin rose rapidly from a basal value of 59 pM to 300 pM at 60 min, and then declined to reach basal levels after 180 min. By contrast, plasma GIP rose more slowly than insulin, from a basal value of 9.4 pM, and remained elevated, in the range of 14-18 pM, throughout the 240 min observation period. The time course of plasma insulin concentration paralleled gastric emptying of the aqueous phase, containing most of the meal's glucose (r = 0.952, P less than 0.001). The time course of plasma GIP concentrations paralleled the gastric emptying of fat and protein (r = 0.763-0.834; P less than 0.01-0.05). Plasma insulin concentrations showed no correlation to the rate of emptying of fat and protein (r = 0.142-0.420; n.s.) and to plasma levels of GIP (r = 0.365; n.s.). The threshold for plasma glucose at which GIP would exert an incretin effect only reached at one time point, 30 min after ingestion of the meal. Our findings of simultaneously tracked gastric emptying of meal nutrients, hormone release and plasma glucose levels do not support an important physiological role for GIP as an insulinotropic hormone after ingestion of mixed meals in man.     

Post-exercise gastric emptying of carbohydrate solutions determined using the 13C acetate breath test

In an attempt to measure gastric emptying of carbohydrate solutions after exercise, we used the ¹³C acetate breath test to differentiate the gastric emptying of three approximately isoenergetic carbohydrate solutions (i.e. glucose, glucose polymer and sucrose) from each other and from water. On four separate occasions, six post-absorptive subjects walked on an inclined treadmill at 70% maximum oxygen uptake for 1 h and were then given 330 ml of one of the solutions in which 150 mg of sodium 1-[¹³C] acetate had been dissolved. Breath samples were collected at regular (2–30 min) intervals over the next 3.5 h for analysis of expired ¹³CO₂ by isotope ratio mass spectrometry. When water was given, all subjects reached peak breath enrichment after 30 min, and had a mean (SE) gastric emptying time of 33.2 (1.6) min. Peak breath enrichment occurred later for sucrose and glucose polymer at 54.3 (3.1) min and 59.0 (2.1) min respectively (P < 0.01), and for glucose this was even later, at 62.3 (1.0) min (P < 0.05). Calculated gastric emptying times for sucrose and glucose polymer were almost identical [66.5 (2.5) and 69.8 (2.9) min respectively], whereas that for glucose was significantly slower [76.8 (3.2) min; P < 0.02], probably reflecting the effects of increased osmolality. The gastric emptying of all carbohydrates were significantly longer than for water (P < 0.01). These results show that in the post-exercise state the ¹³C acetate breath test can be used to differentiate the gastric emptying rates of water and carbohydrate solutions of different properties.     

Novel actions of proadrenomedullin N-terminal 20 peptide (PAMP).

Poadrenomedullin N-terminal 20 peptide (PAMP) is a hypotensive peptide derived from the precursor of adrenomedullin. We identified novel actions of proadrenomedullin N-terminal 20 peptide (PAMP) on blood glucose, food intake and gastric emptying after exogenous administration. PAMP elevated blood glucose levels after central injection in fasted mice. PAMP had affinity for bombesin (BN) receptor and the hyperglycemic effect of PAMP was blocked by a BN antagonist, indicating that the elevation of blood glucose after central administration of PAMP was mediated by BN receptor. Centrally administered PAMP inhibited food intake and gastric emptying in fasted conscious mice. However, studies using a BN antagonist and BN receptor knockout mice suggested that the inhibitory effects of PAMP on feeding and gastric emptying were mediated not via BN receptor but via another receptor specific for PAMP. In the present review, we summarize these effects of PAMP and report other novel actions of PAMP on body temperature and oxygen consumption. In addition, the mechanism underlying the cardiovascular functions of PAMP is discussed.     

Effect of solid meal on gastric emptying of,and glycemic and cardiovascular responses to,liquid glucose in older subjects

Gastric emptying is a determinant of the postprandial glycemic and cardiovascular responses to oral carbohydrate. We evaluated the effects of a solid meal on gastric emptying and the glycemic and cardiovascular responses to oral glucose in healthy older subjects. Ten subjects aged 72.1 +/- 1.9 yr were studied. Each subject had measurements of gastric emptying, blood glucose, serum insulin, blood pressure, and heart rate after ingestion of a 50-g glucose drink (300 ml) with (mixed meal) or without (liquid only) a solid meal (300 g ground beef). Gastric emptying of liquid was initially slightly more rapid (P < 0.05) after the mixed meal compared with liquid only at 5 min (92.0 +/- 1.5 vs. 96.0 +/- 1.3%) and much slower (P < 0.05) after 120 min. The time to peak blood glucose was less (39.0 +/- 4.0 vs. 67.5 +/- 10.3 min; P < 0.01) and blood glucose subsequently lower (P < 0.01) after the mixed meal. The increase in serum insulin was greater (P < 0.001) after the mixed meal. Blood pressure fell (P < 0.05) in the first 30 min, with no difference between the two meals. Increase in heart rate after both meals (P < 0.005), was greater (P < 0.05) after the mixed meal. The presence of a noncarbohydrate solid meal had discrepant effects on early and subsequent emptying of a nutrient liquid, which affects postprandial glycemia and increased heart rate.     

Pathophysiology of post-gastrectomy hypoglycaemia

The blood glucose and plasma insulin response to oral glucose and slow intravenous infusion of glucose was determined in seven patients who had undergone partial gastrectomy or gastroenterostomy. Similar studies were conducted in normal subjects; in these experiments oral glucose administration was replaced by infusion of glucose direct into the jejunum in order to simulate the rapid gastric emptying which occurs after gastric surgery.Peak insulin levels were much higher after oral or intrajejunal glucose, though peak blood glucose levels were higher after intravenous glucose. Despite the high insulin levels occurring with oral administration the late fall in blood glucose below fasting levels was not significantly greater after oral or intrajejunal glucose than after intravenous administration of the sugar. This does not support the concept that hyperinsulinaemia alone is responsible for reactive hypoglycaemia.     

The effect of macronutrients on gastric volume responses and gastric emptying in humans: A magnetic resonance imaging study

The effects of macronutrients on gastric volume changes, emptying, and gastrointestinal symptoms are incompletely understood. Three liquid meals of 500 ml (fat emulsion, 375 kcal; protein solution, 375 kcal; glucose solution, 400 kcal) were infused into the stomach of 12 healthy volunteers on three occasions. Studies were performed in seated body position using an open-configuration magnetic resonance imaging (MRI) system. MRI imaging sequences, assessing stomach and meal volumes, were performed prior to and at times t = 0, 3, 6, 9, 12, 15, 25, 35, 45, 60, 75, and 90 min after meal administration. Areas under the curve for the early emptying phase (0-15 and 0-45 min) were calculated, and characteristics of the volume curves were analyzed by a gastric emptying model. Gastrointestinal symptoms were assessed by a self-report scale. Initial (t = 0 min) and early postprandial gastric volumes were highest for glucose because of lower initial emptying. However, in the early emptying phase the characteristics of the volume curves for stomach and meal were uniform for all macronutrients. Perceptions of fullness and satiety were linearly associated with postprandial gastric volumes, but not with macronutrient composition. Isovolumic macronutrient meals modulate gastric volume response by initial meal emptying patterns. Macronutrient specific accommodation responses, as shown in barostat studies, are not reflected as gastric volume responses under noninvasive conditions.     

Hydroxycitric acid delays intestinal glucose absorption in rats

In this study, we investigated in rats if hydroxycitric acid (HCA) reduces the postprandial glucose response by affecting gastric emptying or intestinal glucose absorption. We compared the effect of regulator HCA (310 mg/kg) and vehicle (control) on the glucose response after an intragastric or intraduodenal glucose load to investigate the role of altered gastric emptying. Steele's one-compartment model was used to investigate the effect of HCA on systemic glucose appearance after an intraduodenal glucose load, using [U-(13)C]-labeled glucose and d-[6,6-(2)H(2)]-labeled glucose. Because an effect on postabsorptive glucose clearance could not be excluded, the effect of HCA on the appearance of enterally administered glucose in small intestinal tissue, liver, and portal and systemic circulation was determined by [U-(14)C]glucose infusion. Data show that HCA treatment delays the intestinal absorption of enterally administered glucose at the level of the small intestinal mucosa in rats. HCA strongly attenuated postprandial blood glucose levels after both intragastric (P < 0.01) and intraduodenal (P < 0.001) glucose administration, excluding a major effect of HCA on gastric emptying. HCA delayed the systemic appearance of exogenous glucose but did not affect the total fraction of glucose absorbed over the study period of 150 min. HCA treatment decreased concentrations of [U-(14)C]glucose in small intestinal tissue at 15 min after [U-(14)C]glucose administration (P < 0.05), in accordance with the concept that HCA delays the enteral absorption of glucose. These data support a possible role for HCA as food supplement in lowering postprandial glucose profiles.     

Substrate specificity of human ABCC4 (MRP4)-mediated cotransport of bile acids and reduced glutathione

Obese CCK-1 receptor-lacking Otsuka Long Evans Tokushima fatty (OLETF) rats are hyperphagic relative to control, nonmutant Long Evans Tokushima Otsuka (LETO) rats. This study sought to assess whether the overeating observed in OLETF rats is associated with changes in gastric emptying rates or detection of gastric volume. We performed experiments in both 12- and 29-wk-old OLETF and LETO rats to address possible alterations in gastric functions during the development of increased body weight and blood glucose abnormalities in OLETF rats. Gastric emptying of a 5-g solid chow test meal was not significantly different between strains at either 1, 2, or 4 h postmeal. When rats with ad libitum access to chow were tested, there were no significant differences in gastric emptying between strains at any time period despite OLETF rats consuming significantly more chow than LETO rats. Similar to solid food, 5-min gastric emptying of a 5-ml isosmotic and hyperosmotic saline or glucose load was not significantly different between strains. When the stomach was distended with a 15-ml semisolid chow load, there was no significance difference in emptying at either 1 or 2 h. No significant differences in gastric emptying were detected between 12- and 29-wk-old rats under any conditions. Both young and old OLETF rats, however, reduced sham intake significantly less compared with LETO rats during a brief period of gastric distension by 5- or 10-ml balloon inflation. Finally, OLETF rats showed decreased Fos expression in the nucleus of the solitary tract relative to LETO rats after an 8-ml gastric distension. These findings demonstrate that OLETF rats do not express deficits in controlling gastric emptying rates; however, they exhibit decreased behavioral and vagal responsiveness to gastric distension that may contribute to the increased meal size in these animals.     

The stomach, cholecystokinin, and satiety

The stomach of the rhesus monkey empties liquids in a fashion that varies with the character of the solutions. Physiological saline empties exponentially. Glucose solutions empty biphasically--rapidly for the first minutes, then slowly and proportionately to glucose concentration to deliver glucose calories through the pylorus at a regulated rate (0.4 kcal/min). This prolonged and regulated second phase of gastric emptying depends on intestinal inhibition of the stomach. Cholecystokinin (CCK), a hormone released by food in the intestine, is an inhibitor of gastric emptying. In vitro receptor autoradiography demonstrates CCK receptors to be clustered on the circular muscle of the pylorus. Exogenous CCK, in doses that inhibit gastric emptying, will reduce food intake only if combined with an infusion of saline in the stomach. These observations indicate how gastric distension can be a means for provoking satiety. The variably sustained distension produced by the stomach's slow, calorically regulated emptying could prolong intermeal intervals and thus permit high-calorie meals to inhibit further caloric intake over time. CCK, by directly inhibiting gastric emptying during a meal, could promote gastric distension and so restrict the duration and size of individual meals.     

Stimulatory effect of endogenous orexin A on gastric emptying and acid secretion independent of gastrin

Orexin A (OXA) increases food intake and inhibits fasting small bowel motility in rats. The aim of this study was to examine the effect of exogenous OXA and endogenous OXA on gastric emptying, acid secretion, glucose metabolism and distribution of orexin immunoreactivity in the stomach. Rats equipped with a gastric fistula were subjected to intravenous (IV) infusion of OXA or the selective orexin-1 receptor (OX1R) antagonist SB-334867-A during saline or pentagastrin infusion. Gastric emptying was studied with a liquid non-nutrient or nutrient, using 51Cr as radioactive marker. Gastric retention was measured after a 20-min infusion of OXA or SB-334867-A. Plasma concentrations of OXA, insulin, glucagon, glucose and gastrin were studied. Immunohistochemistry against OXA, OX1R and gastrin in gastric tissue was performed. OXA alone had no effect on either acid secretion or gastric emptying. SB-334867-A inhibited both basal and pentagastrin-induced gastric acid secretion and increased gastric retention of the liquid nutrient, but not PEG 4000. Plasma gastrin levels were unchanged by IV OXA or SB-334867-A. Plasma OXA levels decreased after intake of the nutrient meal and infusion of the OX1R antagonist. Only weak effects were seen on plasma glucose and insulin by OXA. Immunoreactivity to OXA and OX1R were found in the mucosa, myenteric cells bodies and varicose nerve fibers in ganglia and circular muscle of the stomach. In conclusion, endogenous OXA influences gastric emptying of a nutrient liquid and gastric acid secretion independent of gastrin. This indicates a role for endogenous OXA, not only in metabolic homeostasis, but also in the pre-absorptive processing of nutrients in the gut.     

Expression of 5-HT3 receptors by extrinsic duodenal afferents contribute to intestinal inhibition of gastric emptying

Intestinal perfusion with carbohydrates inhibits gastric emptying via vagal and spinal capsaicin-sensitive afferent pathways. The aim of the present study was to determine the role of 1) 5-hydroxytryptamine (5-HT)(3) receptors (5-HT(3)R) in mediating glucose-induced inhibition of gastric emptying and 2) 5-HT(3)R expression in vagal and spinal afferents in innervating the duodenum. In awake rats fitted with gastric and duodenal cannulas, perfusion of the duodenum with glucose (50 and 100 mg) inhibited gastric emptying. Intestinal perfusion of mannitol inhibited gastric emptying only at the highest concentration (990 mosm/kgH(2)O). Pretreatment with the 5-HT(3)R antagonist tropisetron abolished both glucose- and mannitol-induced inhibition of gastric emptying. Retrograde labeling of visceral afferents by injection of dextran-conjugated Texas Red into the duodenal wall was used to identify extrinsic primary afferents. Immunoreactivity for 5-HT(3)R, visualized with an antibody directed to the COOH terminus of the rat 5-HT(3)R, was found in >80% of duodenal vagal and spinal afferents. These results show that duodenal extrinsic afferents express 5-HT(3)R and that the receptor mediates specific glucose-induced inhibition of gastric emptying. These findings support the hypothesis that enterochromaffin cells in the intestinal mucosa release 5-HT in response to glucose, which activates 5-HT(3)R on afferent nerve terminals to evoke reflex changes in gastric motility. The primary glucose sensors of the intestine may be mucosal enterochromaffin cells.     

Effects of glucose ingestion on postprandial lipemia and triglyceride clearance in humans

To determine whether the metabolism of diet-derived triglycerides (TG) is acutely regulated by the consumption of insulinogenic carbohydrates, we measured the effects of glucose ingestion on oral and intravenous fat tolerance, and on serum triglyceride concentrations obtained during duodenal fat perfusion. Postprandial lipemia was diminished by the ingestion of 50 g (148 +/- 121 mg.dl-1 x 7 h-1 vs 192 +/- 124 mg.dl-1 x 7 h-1, P less than 0.05) and 100 g (104 +/- 106 mg.dl-1 x 7 h-1 vs 171 +/- 104 mg.dl-1 x 7 h-1, P less than 0.05) glucose. Peak postprandial TG concentrations occurred later after meals containing glucose and fat than after meals containing fat alone. This effect could be reproduced when an iso-osmotic quantity of urea was substituted for glucose in the test meal. Starch ingestion had no discernible effect on postprandial lipemia. Intravenous fat tolerance was similar before (4.9 +/- 1.2%.min-1) and 2 h (4.4 +/- 1.3%.min-1) and 4 h (4.8 +/- 1.5%.min-1) after 50 g glucose ingestion. During duodenal fat perfusion, glucose ingestion caused a progressive decrease in plasma triglyceride concentrations. These data suggest that glucose ingestion diminishes postprandial lipemia in a dose-dependent manner, but that this effect is not due to increased clearance of triglyceride from the circulation. The hypotriglyceridemic effects of glucose appear to reflect delayed gastric emptying and decreased hepatic secretion of triglyceride.     

Faster gastric emptying for glucose-polymer and fructose solutions than for glucose in humans

This study examined the rates of gastric emptying for water and 13 different carbohydrate-containing solutions in seven subjects, using conventional gastric intubation techniques. The rates of gastric emptying for water and a 10% glucose-polymer solution were also measured during 90 min of treadmill running at 75% of each subject's maximum oxygen consumption (VO2max). At rest, 15% glucose-polymer (P) and fructose (F) solutions emptied more rapidly from the stomach and provided a faster rate of carbohydrate delivery than did a 15% glucose (G) solution (p less than 0.05). The G solutions showed a constant energy delivery rate of 3.3 kcal.min-1; energy delivery from P and F solutions rose with increasing solution concentrations. The osmolality of the gastric aspirate predicted the rate of gastric emptying for all solutions (p less than 0.05) but overestimated rates of emptying for 10% and 15% P solutions and underestimated emptying rates for 10% and 15% F solutions. Exercise at 75% VO2max decreased the rate of gastric emptying of water but not of 10% P solutions. Thus the different rates of gastric emptying for different carbohydrate-containing solutions were not entirely explained by differences in osmolality. Furthermore, exercise may have different effects on the gastric emptying rates of water and carbohydrate solutions.