Effect of hyperglycemia on triggering of transient lower esophageal sphincter relaxations

Acute changes in blood glucose concentration have major effects on gastrointestinal motor function. Patients with diabetes mellitus have an increased prevalence of gastroesophageal reflux. Transient lower esophageal sphincter (LES) relaxation (TLESR) is the most common sphincter mechanism underlying reflux. The aim of this study was to investigate the effect of acute hyperglycemia on triggering TLESRs evoked by gastric distension in healthy volunteers. TLESRs were stimulated by pressure-controlled and volume-controlled (500 ml) gastric distension using an electronic barostat and performed on separate days. On each day, esophageal manometry was performed in the sitting position during gastric distension for 1 h under euglycemia (5 mM), and either marked hyperglycemia (15 mM) or physiological hyperglycemia (8 mM) in randomized order was maintained by a glucose clamp. Marked hyperglycemia doubled the rate of TLESRs in response to both pressure-controlled [5 (3-10.5, median or interquartile range) to 10 (9.5-14.5) per hour, P < 0.02] and volume-controlled [4 (2.5-7.5) to 10.5 (7-12.5) per hour, P < 0.02] gastric distension but had no effect on basal LES pressure. Physiological hyperglycemia had no effect on the triggering of TLESRs or basal LES pressure. In healthy human subjects, marked hyperglycemia increases the rate of TLESRs. Increase in the rate of TLESRs is independent of proximal gastric wall tension. Mechanisms underlying the effect remain to be determined. Hyperglycemia may be an important factor contributing to the increased esophageal acid exposure in patients with diabetes mellitus.     

Distension of the esophagogastric junction augments triggering of transient lower esophageal sphincter relaxation

Patients with gastroesophageal reflux disease show an increase in esophagogastric junction (EGJ) distensibility and in frequency of transient lower esophageal sphincter relaxations (TLESR) induced by gastric distension. The objective was to study the effect of localized EGJ distension on triggering of TLESR in healthy volunteers. An esophageal manometric catheter incorporating an 8-cm internal balloon adjacent to a sleeve sensor was developed to enable continuous recording of EGJ pressure during distension of the EGJ. Inflation of the balloon doubled the cross-section of the trans-sphincteric portion of the catheter from 5 mm OD (round) to 5 × 11 mm (oval). Ten healthy subjects were included. After catheter placement and a 30-min adaptation period, the EGJ was randomly distended or not, followed by a 45-min baseline recording. Subjects consumed a refluxogenic meal, and recordings were made for 3 h postprandially. A repeat study was performed on another day with EGJ distension status reversed. Additionally, in one subject MRI was performed to establish the exact position of the balloon in the inflated state. The number of TLESR increased during periods of EGJ distension with the effect being greater after a meal [baseline: 2.0(0.0-4.0) vs. 4.0(1.0-11.0), P=0.04; postprandial: 15.5(10.0-33.0) vs. 22.0(17.0-58.0), P=0.007 for undistended and distended, respectively]. EGJ distension augments meal-induced triggering of TLESR in healthy volunteers. Our data suggest the existence of a population of vagal afferents located at sites in/around the EGJ that may influence triggering of TLESR.     

Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes

We examined the contributions of insulin secretion, glucagon suppression, splanchnic and peripheral glucose metabolism, and delayed gastric emptying to the attenuation of postprandial hyperglycemia during intravenous exenatide administration. Twelve subjects with type 2 diabetes (3 F/9 M, 44 +/- 2 yr, BMI 34 +/- 4 kg/m2, Hb A(1c) 7.5 +/- 1.5%) participated in three meal-tolerance tests performed with double tracer technique (iv [3-3H]glucose and oral [1-14C]glucose): 1) iv saline (CON), 2) iv exenatide (EXE), and 3) iv exenatide plus glucagon (E+G). Acetaminophen was given with the mixed meal (75 g glucose, 25 g fat, 20 g protein) to monitor gastric emptying. Plasma glucose, insulin, glucagon, acetaminophen concentrations and glucose specific activities were measured for 6 h post meal. Post-meal hyperglycemia was markedly reduced (P < 0.01) in EXE (138 +/- 16 mg/dl) and in E+G (165 +/- 12) compared with CON (206 +/- 15). Baseline plasma glucagon ( approximately 90 pg/ml) decreased by approximately 20% to 73 +/- 4 pg/ml in EXE (P < 0.01) and was not different from CON in E+G (81 +/- 2). EGP was suppressed by exenatide [231 +/- 9 to 108 +/- 8 mg/min (54%) vs. 254 +/- 29 to189 +/- 27 mg/min (26%, P < 0.001, EXE vs. CON] and partially reversed by glucagon replacement [247 +/- 15 to 173 +/- 18 mg/min (31%)]. Oral glucose appearance was 39 +/- 4 g in CON vs. 23 +/- 6 g in EXE (P < 0.001) and 15 +/- 5 g in E+G, (P < 0.01 vs. CON). The glucose retained within the splanchnic bed increased from approximately 36g in CON to approximately 52g in EXE and to approximately 60g in E+G (P < 0.001 vs. CON). Acetaminophen((AUC)) was reduced by approximately 80% in EXE vs. CON (P < 0.01). We conclude that exenatide infusion attenuates postprandial hyperglycemia by decreasing EGP (by approximately 50%) and by slowing gastric emptying.     

Differential relaxation and contractile responses of the human upper esophageal sphincter mediated by interplay of mucosal and deep mechanoreceptor activation

BACKGROUND AND AIMS: the neural mechanisms of distension-induced esophagoupper esophageal sphincter (UES) reflexes have not been explored in humans. We investigated the modulation of these reflexes by mucosal anesthesia, acid exposure, and GABA(B) receptor activation. In 55 healthy human subjects, UES responses to rapid esophageal air insufflation and slow balloon distension were examined before and after pretreatment with 15 ml of topical esophageal lidocaine, esophageal HCl infusion, and baclofen 40 mg given orally. In response to rapid esophageal distension, UES can variably relax or contract. Following a mucosal blockade by topical lidocaine, the likelihood of a UES relaxation response was reduced by 11% (P < 0.01) and the likelihood of a UES contractile response was increased by 14% (P < 0.001) without alteration in the overall UES response rate. The UES contractile response to rapid esophageal air insufflation was also increased by 8% (P < 0.05) following sensitization by prior mucosal acid exposure. The UES contractile response, elicited by balloon distension, was regionally dependent (P < 0.05) (more frequent and of higher amplitude with proximal esophageal distension), and the response was attenuated by topical lidocaine (P < 0.05). Baclofen (40 mg po) had no effect on these UES reflexes. Abrupt gaseous esophageal distension activates simultaneously both excitatory and inhibitory pathways to the UES. Partial blockade of the mucosal mechanosensitive receptors permits an enhanced UES contractile response mediated by deeper esophageal mechanoreceptors. Activation of acid-sensitive esophageal mucosal chemoreceptors upregulates the UES contractile response, suggestive of a protective mechanism.     

Capsaicin-sensitive vagal fibres and 5-HT3-, gastrin releasing peptide- and cholecystokinin A-receptors are involved in distension-induced inhibition of gastric emptying in the rat.

The present study was undertaken to investigate how the activation of gastric mechanoreceptors by distension of the stomach in conscious gastric fistula rats influences gastric emptying; and the roles of capsaicin sensitive vagal afferent fibres and the 5-HT3, GRP and CCK-A receptors involved in mediating these responses. To activate mechanoreceptors by non-nutrient dependent pathways, methylcellulose in saline was used to distend the stomach (5 cm H2O) and the subsequent emptying of saline was examined immediately, and at 3, 5 and 10 min following distension. Prior distension delayed the subsequent emptying of saline instilled into the stomach compared with non-distended controls (2.28+/-0.09 ml/5 min; P < 0.001). Topical application of capsaicin, completely abolished the distension-induced inhibition of gastric emptying when compared with vehicle treated rats (2.82+/-0.09 vs. 2.38+/-0.04 ml/5 min; P < 0.001). Peripheral administration of a GRP antagonist (2258 U89UJ, 1 mg/kg), and a 5-HT3 antagonist (BRL4369UA, 50 microg/kg) significantly reversed (2.56+/-0.14 ml/5 min; P < 0.05 and 2.61+/-0.07 ml/5 min; P < 0.01; respectively) the delay in gastric emptying induced by distension. When the rats were treated with the CCK-A antagonist, gastric emptying of saline following distension was also significantly facilitated (2.56+/-0.07 ml/5 min; P < 0.001). In contrast, the CCK-B/gastrin receptor antagonist had no significant effect on the distension induced delay in gastric emptying (1.95+/-0.12 ml/5 min). The present results suggest that gastric distension in conscious gastric fistula rats delays gastric emptying by activating capsaicin-sensitive extrinsic afferent nerve fibres. Moreover, the results also indicate that distension-induced mechanisms involve GRP, 5-HT3 and CCK-A receptors, but not CCK-B receptors.     

Effects of variations in intragastric volume on blood pressure and splanchnic blood flow during intraduodenal glucose infusion in healthy older subjects

The postprandial reduction in blood pressure (BP) is triggered by the interaction of nutrients with the small intestine and associated with an increase in splanchnic blood flow. Gastric distension may attenuate the postprandial fall in BP. The aim of this study was to determine the effects of differences in intragastric volume, including distension at a low (100 ml) volume, on BP and superior mesenteric artery (SMA) blood flow responses to intraduodenal glucose in healthy older subjects. BP and heart rate (HR; automated device), SMA blood flow (Doppler ultrasound), mesenteric vascular resistance (MVR), and plasma norepinephrine of nine male subjects (65-75 yr old) were measured after an overnight fast on 4 separate days in random order. On each day, subjects were intubated with a nasoduodenal catheter, incorporating a duodenal infusion port, and orally with a second catheter, incorporating a barostat bag, positioned in the fundus. Each subject received a 60-min (t = 0-60 min) intraduodenal glucose infusion (3 kcal/min) and gastric distension at a volume of 1) 0 ml (V0), 2) 100 ml (V100), 3) 300 ml (V300), or 4) 500 ml (V500). Systolic BP fell (P < 0.05) during V0, but not during V100, V300, or V500. In contrast, HR (P < 0.01) and SMA blood flow (P < 0.001) increased and MVR decreased (P < 0.05) comparably on all 4 days. Plasma norepinephrine rose (P < 0.01) in response to intraduodenal glucose, with no difference between the four treatments. There was a relationship between the areas under the curve for the change in systolic BP from baseline with intragastric volume (r = 0.60, P < 0.001). In conclusion, low-volume (≤100 ml) gastric distension has the capacity to abolish the fall in BP induced by intraduodenal glucose in healthy older subjects without affecting SMA blood flow or MVR. These observations support the concept that nonnutrient gastric distension prior to a meal has potential therapeutic applications in the management of postprandial hypotension.     

Baclofen blocks LES relaxation and crural diaphragm inhibition by esophageal and gastric distension in cats

Esophageal distension and transient lower esophageal sphincter (LES) relaxation (TLESR) are accompanied by simultaneous relaxation of the LES and inhibition of crural diaphragm. Recent studies indicate that baclofen decreases the frequency of TLESR; however, its effect on the crural diaphragm is not known. We evaluated the effects of baclofen on LES relaxation and crural diaphragm inhibition induced by gastric distension and esophageal distension in cats. Five adult cats underwent surgical implantation of wire electrodes into the crural and costal diaphragm for measurement of their EMG activity, respectively. One week after the surgery, animals were lightly sedated and recordings were performed using a manometry catheter equipped with a 2.5-cm balloon. The effects of baclofen (10 micromol/kg iv) on the graded esophageal distension and gastric distension-induced LES and crural diaphragm responses were studied. Distension of the esophagus and stomach induces relaxation of the LES and inhibition of the crural diaphragm, simultaneously. Baclofen blocks both the esophageal and the gastric distension-induced relaxation of the LES and inhibition of the crural diaphragm. The magnitude of response to baclofen was significantly larger for the crural diaphragm inhibition than for the LES relaxation. Baclofen, a GABA(B) receptor agonist, blocks the reflex inhibitory pathway to the LES and crural diaphragm. The reflex inhibitory pathway to the crural diaphragm is more sensitive to blockade by baclofen than the reflex LES inhibitory pathway.     

Mechanisms of reflexes induced by esophageal distension

We investigated the mechanisms of esophageal distension-induced reflexes in decerebrate cats. Slow air esophageal distension activated esophago-upper esophageal sphincter (UES) contractile reflex (EUCR) and secondary peristalsis (2P). Rapid air distension activated esophago-UES relaxation reflex (EURR), esophago-glottal closure reflex (EGCR), esophago-hyoid distraction reflex (EHDR), and esophago-esophagus contraction reflex (EECR). Longitudinal esophageal stretch did not activate these reflexes. Magnitude and timing of EUCR were related to 2P but not injected air volume. Cervical esophagus transection did not affect the threshold of any reflex. Bolus diversion prevented swallow-related esophageal peristalsis. Lidocaine or capsaicin esophageal perfusion, esophageal mucosal layer removal, or intravenous baclofen blocked or inhibited EURR, EGCR, EHDR, and EECR but not EUCR or 2P. Thoracic vagotomy blocked all reflexes. These six reflexes can be activated by esophageal distension, and they occur in two sets depending on inflation rate rather than volume. EUCR was independent of 2P, but 2P activated EUCR; therefore, EUCR may help prevent reflux during peristalsis. All esophageal peristalsis may be secondary to esophageal stimulation in the cat. EURR, EHDR, EGCR, and EECR may contribute to belching and are probably mediated by capsaicin-sensitive, rapidly adapting mucosal mechanoreceptors. GABA-B receptors also inhibit these reflexes. EUCR and 2P are probably mediated by slowly adapting muscular mechanoreceptors. All six reflexes are mediated by vagal afferent fibers.     

Effect of meal and propranolol on whole body and splanchnic oxygen consumption in patients with cirrhosis

Our aim was to measure whole body energy expenditure after a mixed liquid meal, with and without simultaneous propranolol infusion, in patients with cirrhosis. We also wanted to investigate the effect of propranolol on substrate fluxes and oxygen uptake in the tissues drained by the hepatic vein and azygos vein in the postprandial period in these patients. Whole-body oxygen uptake, hepatic blood flow, hepatic venous pressure gradient and net-hepatic fluxes of oxygen, lactate, glucose, glycerol, and free fatty acids (FFA) were measured in 12 patients with alcoholic cirrhosis before and for 2 h after ingestion of a mixed liquid meal (700 kcal). Half of the patients (n = 6) were randomized to a treatment group receiving intravenous infusion of propranolol in combination with the meal. The meal-induced energy expenditure was significantly lower in patients given propranolol [15.0 +/- 18.9 vs. 67.0 +/- 26.1 kJ/120 min (means +/- SD), P < 0.01]. Meal-induced whole body oxygen uptake was lower in patients receiving propranolol (19.2 +/- 38 vs. 135.7 +/- 61 mmol/120 min, P < 0.01), and the meal-induced increase in splanchnic oxygen uptake was nonexistent when propranolol was administered in combination (-13.2 +/- 34.8 vs. 110.4 +/- 34.8 mmol/120 min, P = 0.04). Postprandially, the propranolol group had a tendency toward a reduced splanchnic glucose output, and the FFA uptake was significantly reduced. Propranolol reduces meal-induced whole body oxygen uptake and energy expenditure as well as splanchnic oxygen uptake. The splanchnic reduction in oxygen consumption can explain almost the entire reduction in whole body oxygen consumption.     

Glucose production during exercise in humans: a-hv balance and isotopic-tracer measurements compared.

The present study compared the arteriohepatic venous (a-hv) balance technique and the tracer-dilution method for estimation of hepatic glucose production during both moderate and heavy exercise in humans. Eight healthy young men (aged 25 yr; range, 23-30 yr) performed semisupine cycling for 40 min at 50.4 +/- 1.5(SE)% maximal O(2) consumption, followed by 30 min at 69.0 +/- 2.2% maximal O(2) consumption. The splanchnic blood flow was estimated by continuous infusion of indocyanine green, and net splanchnic glucose output was calculated as the product of splanchnic blood flow and a-hv blood glucose concentration differences. Glucose appearance rate was determined by a primed, continuous infusion of [3-(3)H]glucose and was calculated by using formulas for a modified single compartment in non-steady state. Glucose production was similar whether determined by the a-hv balance technique or by the tracer-dilution method, both at rest and during moderate and intense exercise (P > 0. 05). It is concluded that, during exercise in humans, determination of hepatic glucose production can be performed equally well with the two techniques.     

Infusion of a novel peptide, calcitonin gene-related peptide (CGRP) in man. Pharmacokinetics and effects on gastric acid secretion and on gastrointestinal hormones

Calcitonin gene-related peptide (CGRP) is a recently discovered widespread regulatory peptide which is encoded in the same gene as calcitonin. We assessed the effect of systemic infusion of synthetic rat CGRP at low dose (range 0.32-2.56 pmol/kg per min) on submaximal pentagastrin-stimulated gastric secretion and on gastrointestinal hormones. To assess its pharmacokinetic parameters in man the MCR and plasma half-life were estimated by the continuous infusion method. Gastric acid output and pepsin secretion were significantly reduced by CGRP (-29% of basal, P less than 0.01 and -40% of basal, P less than 0.005, respectively). There was a significant fall in basal levels of gastrin (-39%, P less than 0.001); gastric inhibitory peptide (-44.7%, P less than 0.001); enteroglucagon (-25%, P less than 0.001) and neurotensin (-33%, P less than 0.05). There was no significant change in plasma levels of insulin, motilin, pancreatic polypeptide or glucose. Suppression of gastric secretion and the fall in gastrointestinal hormones was prolonged and basal levels were not re-established after stopping the CGRP infusion. The disappearance curve of immunoreactive CGRP from the plasma was bi-exponential. The plasma half-life of immunoreactive CGRP was calculated as 6.9 +/- 0.9 min for the fast decay and 26.4 +/- 4.7 min for the slow decay. The calculated MCR was 11.3 +/- 1.2 ml/kg per min. Except for flushing of the face no untoward effects were observed. The results of this study suggest the possibility that CGRP could play a role in the regulation of gastric secretion and gastrointestinal hormone release.     

Effect of oral glutamine on whole body carbohydrate storage during recovery from exhaustive exercise.

The purpose of this study was to determine the efficacy of glutamine in promoting whole body carbohydrate storage and muscle glycogen resynthesis during recovery from exhaustive exercise. Postabsorptive subjects completed a glycogen-depleting exercise protocol, then consumed 330 ml of one of three drinks, 18.5% (wt/vol) glucose polymer solution, 8 g glutamine in 330 ml glucose polymer solution, or 8 g glutamine in 330 ml placebo, and also received a primed constant infusion of [1-13C]glucose for 2 h. Plasma glutamine concentration was increased after consumption of the glutamine drinks (0.7-1.1 mM, P < 0.05). In the second hour of recovery, whole body nonoxidative glucose disposal was increased by 25% after consumption of glutamine in addition to the glucose polymer (4.48 +/- 0.61 vs. 3.59 +/- 0.18 mmol/kg, P < 0.05). Oral glutamine alone promoted storage of muscle glycogen to an extent similar to oral glucose polymer. Ingestion of glutamine and glucose polymer together promoted the storage of carbohydrate outside of skeletal muscle, the most feasible site being the liver.     

Effects of drink volume and glucose load on gastric emptying and postprandial blood pressure in healthy older subjects

Postprandial hypotension (PPH) occurs frequently in the elderly; the magnitude of the fall in blood pressure (BP) is related to the rate of glucose entry into the duodenum during intraduodenal glucose infusion and spontaneous gastric emptying (GE). It is unclear if glucose concentration affects the hypotensive response. Gastric distension may attenuate PPH; therefore, meal volume could influence the BP response. We aimed to determine the effects of 1) drink volume, 2) glucose concentration, and 3) glucose content on the BP and heart rate (HR) responses to oral glucose. Ten subjects (73.9 +/- 1.2 yr) had measurements of BP, GE, and blood glucose on 4 days after 1) 25 g glucose in 200 ml (12.5%), 2) 75 g glucose in 200 ml (37.5%), 3) 25 g glucose in 600 ml (4%), and 4) 75 g glucose in 600 ml (12.5%). GE, BP, HR, and blood glucose were measured for 180 min. After all drinks, duodenal glucose loads were similar in the first 60 min. Regardless of concentration, 600-ml (but not 200-ml) drinks initially increased BP, and in the first 30 min, systolic BP correlated (P < 0.01) with volume in both the proximal and total stomach. At the same concentration (12.5%), systolic BP fell more (P = 0.02) at the smaller volume; at the same volumes, there were no effects of concentration on BP. There was no difference in the glycemic response to drinks of identical glucose content. We conclude that 1) ingestion of glucose at a higher volume attenuates and 2) under constant duodenal load, glucose concentration (4-37%) does not affect the fall in BP.     

Effect of sparteine sulfate on insulin secretion in normal men

This study aimed at evaluating the influence of sparteine sulfate either upon basal plasma glucose and insulin or glucose-induced insulin secretion in normal man. Thirteen overnight fasted volunteers took part in this study; five of them were submitted to sparteine sulfate bolus (15 mg in 10 ml of saline solution) followed by a slow infusion (90 mg/100 ml X 60 min) and eight subjects underwent two different glucose pulses (20 gr. i.v.) in absence or in presence of sparteine, infused as described above. In basal conditions, along with sparteine infusion, plasma glucose showed a progressive and significant decrease (P less than 0.0001) and plasma insulin was significantly higher from min 10 to 120' (P less than 0.0005-0.001). Even during the glucose-induced insulin secretion, in the presence of sparteine infusion, plasma glucose levels were significantly lower while plasma insulin levels were significantly higher when compared to those observed after glucose alone. The acute insulin response (AIR) was 42 +/- 10 microU/ml after glucose alone vs 67 +/- 9 microU/ml after glucose plus sparteine (P less than 0.05). Total insulinemic areas were significantly different being 1410 +/- 190 vs 2250 +/- 310 microU/ml/min (P less than 0.001) during glucose and glucose plus sparteine infusion, respectively. This study thereby, demonstrates that in normal man sparteine sulfate, administrated by intravenous infusion, is able to increase either basal or glucose-induced insulin secretion.     

Effect of antibodies to the neuropeptide GRP on distention-induced gastric acid secretion in the rat

The present study examined and compared the effects of muscarinic blockade, beta-adrenergic blockade and immunoneutralization of the neuropeptide gastrin-releasing peptide (GRP) on distention-induced gastric acid secretion and gastrin release. In response to distention of rat stomachs with 0.9% NaCl, acid output rose from 3.5 +/- 0.5 mumol H+/30 min to 15.4 +/- 2.5 mumol H+/30 min (P less than 0.01). Intravenous administration of 4 mg/kg propranolol did not affect the acid secretory response to distention, however both 2 mg/kg atropine and 6 mg/kg pirenzepine significantly decreased gastric acid secretion by 44.8 +/- 7.8% and 40.9 +/- 5.7% (P less than 0.05), respectively. When specific antibodies to GRP were infused intravenously, the acid secretory response to distention was nearly abolished, decreasing to 5.1 +/- 0.8 mumol H+/30 min (P less than 0.01). In contrast to the effects on acid secretion, GRP antiserum did not significantly alter the gastrin release observed following distention. Results of these studies indicate that, under the conditions of these experiments, the acid secretory response to gastric distention may be independent of its effect on gastrin release. Although distention-induced gastric acid secretion may be partially governed by muscarinic pathways, the acid secretory response to distention in the rat appears to involve GRP-containing neurons.     

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.     

Free fatty acid-induced peripheral insulin resistance augments splanchnic glucose uptake in healthy humans

To investigate the effect of elevated plasma free fatty acid (FFA) concentrations on splanchnic glucose uptake (SGU), we measured SGU in nine healthy subjects (age, 44 +/- 4 yr; body mass index, 27.4 +/- 1.2 kg/m(2); fasting plasma glucose, 5.2 +/- 0.1 mmol/l) during an Intralipid-heparin (LIP) infusion and during a saline (Sal) infusion. SGU was estimated by the oral glucose load (OGL)-insulin clamp method: subjects received a 7-h euglycemic insulin (100 mU x m(-2) x min(-1)) clamp, and a 75-g OGL was ingested 3 h after the insulin clamp was started. After glucose ingestion, the steady-state glucose infusion rate (GIR) during the insulin clamp was decreased to maintain euglycemia. SGU was calculated by subtracting the integrated decrease in GIR during the period after glucose ingestion from the ingested glucose load. [3-(3)H]glucose was infused during the initial 3 h of the insulin clamp to determine rates of endogenous glucose production (EGP) and glucose disappearance (R(d)). During the 3-h euglycemic insulin clamp before glucose ingestion, R(d) was decreased (8.8 +/- 0.5 vs. 7.6 +/- 0.5 mg x kg(-1) x min(-1), P < 0.01), and suppression of EGP was impaired (0.2 +/- 0.04 vs. 0.07 +/- 0.03 mg x kg(-1) x min(-1), P < 0.01). During the 4-h period after glucose ingestion, SGU was significantly increased during the LIP vs. Sal infusion study (30 +/- 2 vs. 20 +/- 2%, P < 0.005). In conclusion, an elevation in plasma FFA concentration impairs whole body glucose R(d) and insulin-mediated suppression of EGP in healthy subjects but augments SGU.     

Impaired basal glucose effectiveness but unaltered fasting glucose release and gluconeogenesis during short-term hypercortisolemia in healthy subjects

Excess cortisol has been demonstrated to impair hepatic and extrahepatic insulin action. To determine whether glucose effectiveness and, in terms of endogenous glucose release (EGR), gluconeogenesis, also are altered by hypercortisolemia, eight healthy subjects were studied after overnight infusion with hydrocortisone or saline. Glucose effectiveness was assessed by a combined somatostatin and insulin infusion protocol to maintain insulin concentration at basal level in the presence of prandial glucose infusions. Despite elevated insulin concentrations (P < 0.05), hypercortisolemia resulted in higher glucose (P < 0.05) and free fatty acid concentrations (P < 0.05). Furthermore, basal insulin concentrations were higher during hydrocortisone than during saline infusion (P < 0.01), indicating the presence of steroid-induced insulin resistance. Postabsorptive glucose production (P = 0.64) and the fractional contribution of gluconeogenesis to EGR (P = 0.33) did not differ on the two study days. During the prandial glucose infusion, the integrated glycemic response above baseline was higher in the presence of hydrocortisone than during saline infusion (P < 0.05), implying a decrease in net glucose effectiveness (4.42 +/- 0.52 vs. 6.65 +/- 0.83 ml.kg-1.min-1; P < 0.05). To determine whether this defect is attributable to an impaired ability of glucose to suppress glucose production, to stimulate its own uptake, or both, glucose turnover and "hot" (labeled) indexes of glucose effectiveness (GE) were calculated. Hepatic GE was lower during cortisol than during saline infusion (2.39 +/- 0.24 vs. 3.82 +/- 0.51 ml.kg-1.min-1; P < 0.05), indicating a defect in the ability of glucose to restrain its own production. In addition, in the presence of excess cortisol, glucose disappearance was inappropriate for the prevailing glucose concentration, implying a decrease in glucose clearance (P < 0.05). The decrease in glucose clearance was confirmed by the higher increment in [3-3H]glucose during hydrocortisone than during saline infusion (P < 0.05), despite the administration of identical tracer infusion rates. In conclusion, short-term hypercortisolemia in healthy individuals with normal beta-cell function decreases insulin action but does not alter rates of EGR and gluconeogenesis. In addition, cortisol impairs the ability of glucose to suppress its own production, which due to accumulation of glucose in the glucose space results in impaired peripheral glucose clearance. These results suggest that cortisol excess impairs glucose tolerance by decreasing both insulin action and glucose effectiveness.     

Dopamine-1 receptor stimulation attenuates the vasoconstrictive response to gut ischemia.

The effects of fenoldopam, a dopamine-1 (DA-1) receptor agonist, were studied in two groups of anesthetized dogs before and after induction of splanchnic ischemia by way of hemorrhage. During the first portion of the experiment, both groups received fenoldopam (1.5 microg x kg(-1) x min(-1)) for 45 min followed by a 45-min washout. During the second portion, hemorrhage (10 ml/kg) was induced, followed by no intervention in group I (controls) and restarting of the fenoldopam infusion in group II. Prehemorrhage, fenoldopam increased composite portal blood flow by 33% (P < 0.01). After hemorrhage-induced splanchnic ischemia, fenoldopam restored portal vein blood flow to near baseline, maintained the splanchnic fraction of cardiac output, and attenuated the rise in gut mucosal PCO(2). DA-1 receptor stimulation increased portal blood flow and redistributed blood flow away from the serosal layer in favor of the mucosa during basal conditions and after hemorrhage, suggesting a more concentrated distribution of splanchnic DA-1 receptors within the mucosal layer vasculature. Fenoldopam maintained splanchnic blood flow during hypoperfusion and attenuated the splanchnic vasoconstrictive response to hemorrhage.     

Regional disposal of intravenously infused glucose during prolonged hyperglycemia-hyperinsulinemia

We measured splanchnic and leg glucose uptake during prolonged (i.e., 15 hours), moderate hyperglycemia-hyperinsulinemia (clamp). Plasma free fatty acid (FFA) concentration was maintained at basal concentration during the clamp via infusion of exogenous lipids and heparin in healthy volunteers to create a metabolic profile similar to glucose intolerance (i.e., hyperglycemia-hyperinsulinemia with elevated FFA concentration). During the clamp, glucose was infused at an average rate of 49 +/- 4 micromol/kg/min, which resulted in a plasma glucose concentration of 8.8 +/- 0.5 mmol/L compared with a concentration of 4.4 +/- 0.2 mmol/L in the basal state (P < 0.05). Insulin concentration increased from 5.5 +/- 1.1 microU/mL (basal) to 31.3 +/- 12.7 microU/mL (clamp; P < 0.05), whereas plasma FFA concentration was similar in the two conditions (3.9 +/- 0.5 mmol/L and 4.1 +/- 0.5 mmol/L, basal and clamp, respectively). Glucose balance across the splanchnic region switched from net release (-5.8 +/- 0.7 micromol/kg/min) in the basal state to net uptake in the clamp (19.8 +/- 3.7 micromol/kg/min; P < 0.05) and accounted for approximately 40% of the infused glucose. Glucose uptake across the leg was 0.7 +/- 0.2 micromol/kg/min (basal) and 5.5 +/- 2.2 micromol/kg/min (clamp; P < 0.05). In summary, tissues in the splanchnic region (i.e., liver) are important for disposal of intravenously infused glucose during prolonged, moderate hyperglycemia-hyperinsulinemia. Accelerated hepatic glucose uptake may disrupt normal liver metabolism, with potentially dangerous consequences for the patient. Measures to control systemic glucose concentration may be necessary to prevent excessive glucose disposal in the liver.