Claus Hovendal

The effect of exogenous GLP-1 on food intake is lost in male truncally vagotomized subjects with pyloroplasty

Rapid degradation of glucagon-like peptide-1 (GLP-1) by dipeptidyl peptidase-4 suggests that endogenous GLP-1 may act locally before being degraded. Signaling via the vagus nerve was investigated in 20 truncally vagotomized subjects with pyloroplasty and 10 matched healthy controls. Subjects received GLP-1 (7-36 amide) or saline infusions during and after a standardized liquid mixed meal and a subsequent ad libitum meal. Despite no effect on appetite sensations, GLP-1 significantly reduced ad libitum food intake in the control group but had no effect in the vagotomized group. Gastric emptying was accelerated in vagotomized subjects and was decreased by GLP-1 in controls but not in vagotomized subjects. Postprandial glucose levels were reduced by the same percentage by GLP-1 in both groups. Peak postprandial GLP-1 levels were approximately fivefold higher in the vagotomized subjects. Insulin secretion was unaffected by exogenous GLP-1 in vagotomized subjects but was suppressed in controls. GLP-1 significantly reduced glucagon secretion in both groups, but levels were approximately twofold higher and were nonsuppressible in the early phase of the meal in vagotomized subjects. Our results demonstrate that vagotomy with pyloroplasty impairs the effects of exogenous GLP-1 on food intake, gastric emptying, and insulin and glucagon secretion, suggesting that intact vagal innervation may be important for GLP-1s actions.

Effect of dopamine on pentagastrin-stimulated gastric antral motility in dogs with gastric fistula.

The purpose of the present study was to evaluate the effect of dopamine on gastric antral motility in conscious dogs with gastric fistula by using miniature strain-gauge transducers. Infusion of pentagastrin changed the contractile activity to a digestive state. Dopamine, an endogenous catecholamine, was used alone and in conjunction with selective blockade or adrenergic and dopaminergic receptors. The stimulated antral motility was inhibited by dopamine. The effect was significantly blocked by the peripherally acting dopaminergic blocker domperidone and by cis-flupenthixol, which blocks both peripheral and central dopaminergic receptors. The effect of dopamine was not significantly altered by the beta 1-adrenoceptor blocker practolol, the alpha-adrenoceptor blocker phentolamine, or the alpha + beta-adrenoceptor blocker labetalol. Consequently, this study indicates that dopamine acts on gastric antral motility through dopaminergic receptors. beta-Adrenergic receptors, which are active in the impairment of gastric acid secretion, seem not to be involved in the motility response.

Characterisation of oral and i.v. glucose handling in truncally vagotomised subjects with pyloroplasty

Objective Glucagon-like peptide 1 (GLP1) is rapidly inactivated by dipeptidyl peptidase 4 (DPP4), but may interact with vagal neurons at its site of secretion. We investigated the role of vagal innervation for handling of oral and i.v. glucose. Design and methods Truncally vagotomised subjects (n=16) and matched controls (n=10) underwent 50 g-oral glucose tolerance test (OGTT)±vildagliptin, a DPP4 inhibitor (DPP4i) and isoglycaemic i.v. glucose infusion (IIGI), copying the OGTT without DPP4i. Results Isoglycaemia was obtained with 25±2 g glucose in vagotomised subjects and 18±2 g in controls (P<0.03); thus, gastrointestinal-mediated glucose disposal (GIGD) – a measure of glucose handling (100%×(glucoseOGTT−glucoseIIGI/glucoseOGTT)) – was reduced in the vagotomised compared with the control group. Peak intact GLP1 concentrations were higher in the vagotomised group. Gastric emptying was faster in vagotomised subjects after OGTT and was unaffected by DPP4i. The early glucose-dependent insulinotropic polypeptide response was higher in vagotomised subjects. Despite this, the incretin effect was equal in both groups. DPP4i enhanced insulin secretion in controls, but had no effect in the vagotomised subjects. Controls suppressed glucagon concentrations similarly, irrespective of the route of glucose administration, whereas vagotomised subjects showed suppression only during IIGI and exhibited hyperglucagonaemia following OGTT. DPP4i further suppressed glucagon secretion in controls and tended to normalise glucagon responses in vagotomised subjects. Conclusions GIGD is diminished, but the incretin effect is unaffected in vagotomised subjects despite higher GLP1 levels. This, together with the small effect of DPP4i, is compatible with the notion that part of the physiological effects of GLP1 involves vagal transmission.

TNM staging and assessment of resectability of pancreatic cancer by laparoscopic ultrasonography.

AbstractBackground: Laparoscopic ultrasonography (LUS) is an imaging modality that combines laparoscopy and ultrasonography. The purpose of this prospective blinded study was to evaluate the TNM stage and assessment of resectability by LUS in patients with pancreatic cancer. Methods: Of the 71 consecutive patients admitted to our department, 36 were excluded from the study, mainly due to evident signs of metastatic disease or another condition that would preclude surgery. Thus, a total of 35 patients were enrolled in the study. All patients underwent abdominal CT scan, ultrasonography, endoscopic ultrasonography (EUS), diagnostic laparoscopy, and LUS. Histopathologic examination was considered to be the final evaluation for LUS in all but three patients, where EUS was used as the reference. Results: The accuracy of LUS in T staging was 29/33 (80%); in N staging it was 22/34 (76%); in M staging, it was 23/34 (68%); and in overall TNM staging, it was 23/34 (68%). In assessment of nonresectability, distant metastases, and lymph node metastases, the sensitivity was 0.86, 0.43 and 0.67, respectively, for LUS alone. Combining the information gleaned from laparoscopy and LUS, the accuracy in finding nonresectable tumors was 89%. Conclusions: Diagnostic laparoscopy with LUS is highly accurate in TNM staging and assessment of resectability of pancreatic cancer and should be considered an important modality in the assessment algorithm.

Combined Endoscopic Ultrasonography and Laparoscopic Ultrasonography in the Pretherapeutic Assessment of Resectability in Patients with Upper Gastrointestinal Malignancies

BACKGROUND Even though endoscopic ultrasonography (EUS) has improved the pretherapeutic staging and assessment of resectability in patients with upper gastrointestinal (GI) tract malignancies, a considerable number of patients still have to undergo unnecessary explorative laparotomy to obtain the final assessment of resectability. The aim of the present study was to evaluate laparoscopic ultrasonography (LUS) and the combination of EUS and LUS in the pretherapeutic study of these patients with special reference to resectability. METHODS Each of 44 patients with esophageal, gastric, or pancreatic cancer was assigned to a treatment-related resectability group based on five different imaging modalities: computer tomography (CT) + ultrasonography (US), EUS, laparoscopy, LUS, and EUS + LUS. The findings with these imaging modalities were compared with intraoperative findings. RESULTS Overall group assignment accuracy showed significantly better results for EUS, LUS, and EUS + LUS than for CT + US and laparoscopy. EUS + LUS identified all non-resectable patients, whereas the sensitivity of CT + US, laparoscopy, and EUS were 14%, 36%, and 79%, respectively. Median time consumption for each EUS, laparoscopy, or LUS procedure was less than 25 min, and no complications were seen during or after the EUS, laparoscopy, or LUS procedures. CONCLUSION Preliminary experience with the combination of EUS and LUS for pretherapeutic assessment of upper GI tract malignancies showed that this combination was superior to CT + US, laparoscopy, and EUS. EUS + LUS correctly identified all non-resectable patients, but two overstaged patients also indicated the need for larger prospective studies to identify the indications and the limitations of this new approach.

Impact of endoscopic ultrasonography (EUS) on surgical decision-making in upper gastrointestinal tract cancer : An international multicenter study

BackgroundEndoscopic ultrasonography (EUS) is an integrated part of the pretherapeutic evaluation program for patients with upper gastrointestinal (GI) tract cancer. Whether the clinical impact of EUS differs between surgeons from different countries is unknown. The same applies to the potential clinical influence of EUS misinterpretations. The aim of this study was to evaluate the interobserver agreement on predefined treatment strategies between surgeons from four different countries, with and without EUS, and to evaluate the clinical consequences of EUS misinterpretations.MethodsOne hundred patients with upper GI tract cancer were randomly selected from all upper GI tract cancer patients treated at Odense University Hospital between 1997 and 2000. Based on patient records and EUS database results, a case story was created with and without the EUS result for each patient. Four surgeons were asked to select the relevant treatment strategy in each case, at first without knowledge of the EUS and thereafter with the EUS result available. Interobserver agreement and impact of EUS misinterpretations were evaluated using the actual final treatment of each patient as reference.ResultsThree of four or all four surgeons agreed on the same treatment strategy for nearly 60% of the patients with and without the EUS results. Treatment decisions were changed in 34% based on the EUS results, and the majority of these changes were toward nonsurgical and palliative treatments (85%). Interobserver agreement was relatively low, but overall EUS increased kappa values from 0.16 (“poor”) to 0.33 (“fair”), thus indicating increased overall agreement after the EUS results were available. EUS conclusion regarding stage or resectability was wrong in 17% of the cases, but only one serious event would have been the clinical result of EUS misinterpretations.ConclusionDespite being used in different ways by different surgeons, EUS did change patient management in one third of the cases. The impact of EUS misinterpretations seemed very low, and this study confirmed one of the strongest clinical possibilities of EUS, i.e., the ability to detect nonresectable cases. EUS is an important imaging modality for oncosurgeons from different countries.

Endoscopic ultrasound, endoscopic sonoelastography, and strain ratio evaluation of lymph nodes with histology as gold standard

BACKGROUND AND STUDY AIMS Accurate lymph node staging is essential for the selection of an optimal treatment in patients with upper gastrointestinal cancer. Endoscopic ultrasound (EUS) and fine-needle aspiration (FNA) are considered to be the most accurate method for locoregional staging. Endoscopic sonoelastography (ESE) assesses the elasticity of lymph nodes and has been used to differentiate lymph nodes with promising results. The aim of this study was to evaluate the use of EUS, EUS - FNA, ESE, and ESE-strain ratio using histology as the gold standard. PATIENTS AND METHODS Patients with upper gastrointestinal cancer who were referred for EUS examination were enrolled if surgical treatment was planned and the patient had a lymph node that was accessible for EUS - FNA and EUS-guided fine-needle marking (FNM). The lymph node was classified using EUS, ESE, and ESE-strain ratio. Finally, EUS - FNA and EUS - FNM were performed. The marked lymph node was isolated during surgery for histological examination. RESULTS The marked lymph node was isolated for separate histological examination in 56 patients, of whom 22 (39 %) had malignant lymph nodes and 34 (61 %) had benign lymph nodes. There were no complications of EUS - FNM. The sensitivity of EUS for differentiation between malignant and benign lymph nodes was 86 % compared with 55 % - 59 % for the different ESE modalities. The specificity of EUS was 71 % compared with 82 % - 85 % using ESE modalities. CONCLUSION The use of the EUS - FNM technique enabled the identification of a specific lymph node and thereby the use of histology as gold standard. ESE and ESE-strain ratio were no better than standard EUS in differentiating between malignant and benign lymph nodes in patients with resectable upper gastrointestinal cancer.

Increases in plasma motilin follow each episode of gallbladder emptying during the interdigestive period, and changes in serum bile acid concentration correlate to plasma motilin

BACKGROUND The relationship between each single period of gallbladder emptying during the migrating motor complex (MMC) cycle and changes in concentration of plasma motilin and serum bile acids is unknown. METHODS The variations in the concentration of plasma motilin and serum bile acids in relation to interdigestive gallbladder motility and the MMCs was studied in nine healthy male volunteers. A method combining biliary scintigraphy (99mTc-labelled dimethyl-iminodiacetic acid) and continuous pressure recording from the antroduodenal region was used. RESULTS During 9 MMC cycles a total of 15 episodes of gallbladder emptying were observed with a median (range) duration of 25 min (15-45 min). Each episode of gallbladder emptying was followed by a steep increase in plasma motilin, reaching a median value of 30 pmol/l (13-43 pmol/l), corresponding to an increase of 18 pmol/l (4-33 pmol/l). The increase in plasma motilin started at the beginning of gallbladder emptying, but the peak value was not reached until a median of 20 min (10-45 min) later. Low plasma motilin concentrations were found between the emptying periods in cases with two or more emptying during the MMC cycle. The serum concentration of bile acids also showed a cyclic variation in relation to gallbladder motility. During periods of gallbladder emptying serum bile acid concentration had a median value of 1.78 mumol/l, as compared with a median value of 1.17 mumol/l during periods of gallbladder filling. This difference did not reach significance, however. In the pooled data from all subjects, a significant correlation (p < 0.01) between the serum concentration of bile acids and plasma concentration of motilin was found. CONCLUSION Gallbladder emptying was followed by a steep increase in plasma motilin concentration, and in cases of two or more emptying periods during the MMC cycle the concentration decreased in between. The shape of the serum bile acid profile is dependent on the intestinal transport and absorption of bile acids, and the significance of the cyclic variation in serum concentration of bile acids in relation to plasma motilin, gallbladder motility, and MMC needs further investigation.

Effect of Dopamine on Pentagastrin-Stimulated Gastric Acid Secretion and Mucosal Blood Flow in Dogs with Gastric Fistula

The purpose of this study was to elucidate the effect of intravenously administered dopamine on dopamine receptors and adrenergic receptors in terms of its effect on gastric acid secretion, the kinetic mechanism, blood flow, and antral motility. Dopamine was used alone and in conjunction with selective blockade of alpha-, beta-, and dopaminergic receptors. A significant inhibition of gastric acid secretion was found with the highest dose of dopamine used (40 micrograms/kg/min). The kinetic study showed characteristics of a non-competitive type. The anti-secretory effect dopamine was significantly blocked by non-selective beta-blockade or by selective beta-blockade but not by alpha- or dopaminergic receptor blockade. This suggests that the inhibitory effect of dopamine on gastric secretion is mediated by beta-receptors. There was no significant effect on gastric mucosal blood flow, but the ratio between blood flow and acid secretion was significantly elevated during dopamine infusion, indicating that the acid inhibition was not secondary to changes in blood flow. It is concluded that the dopamine inhibition of acid secretion is mediated by beta 1-receptors, unlike the effect on antral gastric motility, which is mediated by dopamine receptors.

Effect of Isoprenaline on Pentagastrin-Stimulated Gastric Acid Secretion in Dogs with Gastric Fistula

The purpose of this study was to elucidate the effect of a beta 1-adrenoceptor agonist on gastric acid secretion in conscious dogs with gastric fistula. Isoprenaline, a beta 1- and beta 2-agonist was used alone and in conjunction with selective blockade of beta 2- and beta 1-receptors. Isoprenaline dose-dependently inhibited the secretory volume and the acidity. The antisecretory effect of isoprenaline was significantly blocked by the beta 1-adrenoceptor blocker practolol and by the beta 1 + beta 2-adrenoceptor blocker propranolol but not by H 35/25, a beta 2-adrenoceptor blocker. This indicates that isoprenaline acts on the acid secretion exclusively through beta 1-receptors. Dose-response experiments with five logarithmically increased doses of pentagastrin and one dose of isoprenaline showed unchanged calculated maximum response and an increase in half-maximum acid response. It is concluded that the inhibitory effect of isoprenaline on gastric acid secretion is of competitive or uncompetitive type.