Per Grybäck

Gastrointestinal hormones and gastric emptying 20 years after jejunoileal bypass for massive obesity

OBJECTIVE: Some studies have shown a more rapid gastric emptying in obese subjects. Six to twelve months after jejunoileal bypass (JIB) neurotensin (NT) and enteroglucagon have been shown to be elevated after food intake. These hormones, together with peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) have been implicated in the reduction of upper gastrointestinal motility seen after infusion of nutrients into the ileum. AIM: To study if the postprandial gut hormone pattern and gastric emptying is altered 20u2005y after JIB. SUBJECTS: Seven subjects operated with JIB a mean (s.d.) 20±3u2005y ago, with a BMI of 44±4u2005kg/m2; at the time of surgery and 31±4 at present. For comparison seven sex-matched non-operated obese controls (BMI 43±3) were studied. METHODS: Serial blood samples were obtained every 10u2005min after intake of a 280u2005kcal meal. Radioimmunoassays for motilin, cholecystokinin (CCK), NT, PYY and GLP-1 were performed. Gastric emptying of a solid meal was studied using a radioactively labelled omelette (of 310u2005kcal) for 120u2005min). RESULTS: After JIB postprandial motilin, CCK, NT, PYY and GLP-1 were elevated compared to non-operated obese subjects. Similarly, basal levels of CCK, motilin, GLP-1 and PYY were elevated in the operated group. No difference was observed in the rate of gastric emptying between the two groups. CONCLUSION: Both fasting and postprandial gut hormone levels are elevated 20u2005y after JIB. The impact of long-term rapid stimulation of the ileum and subsequent raised gut hormone levels on gastric emptying is not clear.

Differential effect of PYY1-36 and PYY3-36 on gastric emptying in man

Peptide tyrosine-tyrosine (PYY) is a prandially controlled hormone in endocrine ileal and colonic mucosa cells. In plasma, PYY appears as full-length PYY1-36 and truncated PYY3-36. Both have different pharmacological profile, and PYY3-36 seems to inhibit food intake. We aimed at investigating the effect of intravenously administered PYY1-36 and PYY3-36 on gastric emptying and short-term metabolic control. Eight healthy adults were studied in single-blinded, randomized design. At separate occasions, intravenous infusion of saline, PYY1-36 or PYY3-36 (0.8 pmol kg(-1) min(-1)) and a radio-labelled omelette were given. Gastric emptying (scintigraphy), appetite ratings (VAS), and plasma concentrations of insulin, glucose, GLP-1 and PYY were measured. PYY3-36 and PYY1-36 both inhibited gastric emptying, PYY3-36 most effectively. Half-emptying time was prolonged from 63.1+/-5.2 (saline) to 87.0+/-11.5 min (PYY3-36), whereas retention at 120 min was 2.5+/-1.4% for saline, 10.7+/-4.4 for PYY1-36 and 15.8+/-4.4 for PYY3-36. Neither form influenced glucose or GLP-1 concentrations, but both decreased the postprandial rise in insulin. PYY3-36 induced nausea (VAS increase 47.5+/-22.6 mm) and decreased prospective consumption (VAS change 39.5+/-7.7 mm). In conclusion, PYY3-36s reducing effect upon food intake might be mediated by a decreased gastric emptying rate.

Actions of prolonged ghrelin infusion on gastrointestinal transit and glucose homeostasis in humans

Backgroundu2002 Ghrelin is produced by enteroendocrine cells in the gastric mucosa and stimulates gastric emptying in healthy volunteers and patients with gastroparesis in short‐term studies. The aim of this study was to evaluate effects of intravenous ghrelin on gastrointestinal motility and glucose homeostasis during a 6‐h infusion in humans.

Involvement of endogenous glucagon-like peptide-1 in regulation of gastric motility and pancreatic endocrine secretion

Abstract Objective. To study the role of endogenous glucagon-like peptide-1 (GLP-1) on gastric emptying rates of a solid meal as well as postprandial hormone secretion and glucose disposal. Material and methods. In nine healthy subjects, gastric emptying of a 310-kcal radio-labelled solid meal and plasma concentrations of insulin, glucagon and glucose were measured during infusion of saline or the GLP-1 receptor antagonist exendin(9-39)amide (Ex(9-39)) at 300 pmol·kg−1·min−1. Results. Ex(9-39) infusion had no effect on the total gastric emptying curve, but changed the intra-gastric distribution of the meal. During infusion of Ex(9-39), more content stayed in the upper stomach (79.1 ± 2.5% of total during Ex(9-39) compared to 66.6 ± 5.7% during saline at 5 min). During Ex(9-39) infusion, higher concentrations of plasma glucagon were measured both before (after 40 min of Ex(9-39) infusion the glucagon level was 15.1 ± 0.7 pmol·L−1 compared to 5.4 ± 1.4 during saline) and after the meal, and postprandial GLP-1 levels increased. Basal insulin and glucose levels were not affected by Ex(9-39), but the postprandial rise of insulin and glucose enhanced during Ex(9-39). Conclusions. Endogenous GLP-1 is involved in the regulation of gastric motility in relation to meal intake and also in the regulation of postprandial insulin and glucose levels. Furthermore, endogenous GLP-1 seems to tonically restrain glucagon secretion.

Volumetric FDG-PET predicts overall and progression- free survival after 14 days of targeted therapy in metastatic renal cell carcinoma

BackgroundTo determine whether changes in the metabolism of metastatic renal cell carcinoma (mRCC) assessed by F18-FDG-PET after 14 and 28xa0days of treatment with tyrosine kinase inhibitors can predict overall and progression- free patient survival.MethodsThirty-nine consecutive patients with mRCC were included prospectively and underwent PET examinations prior to and after 14 and 28xa0days of standard treatment with sunitinib (nu2009=u200918), sorafenib (nu2009=u200919) or pazopanib (nu2009=u20092). The PET response was analyzed in terms of SUVmax, SULpeak, and total lesion glycolysis and a positive response (defined as a 30% reduction) compared to overall and progression- free survival.ResultsThirty-five patients with at least one metabolically active metastatic lesion prior to treatment underwent additional FDG-PET examinations after 14 (nu2009=u200932) and/or 28xa0days (nu2009=u200930) of treatment. Changes in either SULpeak or total lesion glycolysis were correlated to both progression-free and overall survival (for TLG2.5 responders, HRu2009=u20090.38 (95% CI: 0.18-0.83) and 0.22 (95% CI: 0.09-0.53), and for TLG50 responders, HRu2009=u20090.25 (0.10-0.62) and 0.25 (95% CI: 0.11-0.57) and for SULpeak responders, HRu2009=u20090.39 (95% CI: 0.17-0.91) and 0.38 (95% CI: 0.15-0.93), respectively). In contrast SUVmax response did not predict progression- free or overall survival (HRu2009=u20090.43 (95% CI: 0.18-1.01) and 0.50 (95% CI: 0.21-1.19), respectively).ConclusionsAssessment of early changes in SULpeak and total lesion glycolysis undergoing treatment with tyrosine kinase inhibitors by FDG-PET can possibly predict progression- free and overall survival in patients with mRCC.

GLP-1 Inhibits Gastric Emptying of Water but Does Not Influence Plasma Vasopressin, Sodium, or Osmolality

Background: Glucagon-like peptide-1 (GLP-1) has been shown to inhibit gastric emptying of a caloric load but the effect on a non-caloric load is unknown. Methods: Seven healthy men were studied after an over-night fast. Thirty min before the intake of 330 ml radioactively labeled water either GLP-1 (0.75 pmol/kg/min) or saline was administered intravenously and continued for 75 min. Scintigraphic gastric emptying was performed for 45 min and plasma samples were obtained for analysis of vasopressin, sodium, osmolality, GLP-1, insulin, and glucose. In addition, electric field stimulation of human gastric muscle strips was done. Results: The median (range) percent water retained in the stomach, 45 min after intake of water, was 96% (68%-98%) and 12% (2%-42%) (P = 0.02) during infusion of GLP-1 and saline, respectively. Additionally, GLP-1 did not affect basal tone or contractile response of gastric muscle strips to electric field stimulation or acetylcholine (ACh). There was no change in plasma concentrations of vasopressin, sodium, or plasma osmolality during GLP-1 compared to saline infusion. Conclusion: GLP-1 has a profound inhibitory effect on the gastric emptying of water in man, but no short-term effect on water homeostasis. No effect was seen on contractility of gastric muscle strips suggesting an indirect action on gastric emptying.BACKGROUNDnGlucagon-like peptide-1 (GLP-1) has been shown to inhibit gastric emptying of a caloric load but the effect on a non-caloric load is unknown.nnnMETHODSnSeven healthy men were studied after an over-night fast. Thirty min before the intake of 330 ml radioactively labeled water either GLP-1 (0.75 pmol/kg/min) or saline was administered intravenously and continued for 75 min. Scintigraphic gastric emptying was performed for 45 min and plasma samples were obtained for analysis of vasopressin, sodium, osmolality, GLP-1, insulin, and glucose. In addition, electric field stimulation of human gastric muscle strips was done.nnnRESULTSnThe median (range) percent water retained in the stomach, 45 min after intake of water, was 96% (68%-98%) and 12% (2%-42%) (P = 0.02) during infusion of GLP-1 and saline, respectively. Additionally, GLP-1 did not affect basal tone or contractile response of gastric muscle strips to electric field stimulation or acetylcholine (ACh). There was no change in plasma concentrations of vasopressin, sodium, or plasma osmolality during GLP-1 compared to saline infusion.nnnCONCLUSIONnGLP-1 has a profound inhibitory effect on the gastric emptying of water in man, but no short-term effect on water homeostasis. No effect was seen on contractility of gastric muscle strips suggesting an indirect action on gastric emptying.

Characterization of [11C]PXT012253 as a PET Radioligand for mGlu4 Allosteric Modulators in Nonhuman Primates

PurposeModulation of presynaptic metabotropic glutamate receptor 4 (mGlu4) by an allosteric ligand has been proposed as a promising therapeutic target in Parkinson’s disease and levodopa-induced dyskinesia. A positron emission tomography (PET) ligand for an allosteric site of mGlu4 may provide evidence that a clinical drug candidate reaches and binds the target. A carbon-11-labeled PET radioligand binding an allosteric site of mGlu4, [11C]PXT012253, has been recently developed. Here, we describe the detailed characterization of this novel radiolabeled mGlu4 ligand in nonhuman primates.Procedures[11C]PXT012253 binding in the brain of cynomolgus monkeys, under the baseline and blocking conditions with the structurally different mGlu4 allosteric ligand PXT002331, currently in clinical trials for Parkinson’s disease, was quantified with compartment and graphical modeling approaches using a radiometabolite-corrected plasma input function. Whole-body biodistribution of [11C]PXT012253 was then assessed using PET/x-ray computed tomography to estimate the human effective doses of [11C]PXT012253 for further clinical studies.Results[11C]PXT012253 displayed binding in mGlu4-expressing regions in the brain of cynomolgus monkeys. Brain regional time-activity curves of [11C]PXT012253 were well described in the two-tissue compartment model (2TC). Total distribution volume was stably estimated using Logan plot and multilinear analysis (MA1) although 2TC showed unstable values in some cases. Competition with PXT002331 showed high specific binding in the total distribution volume. Whole-body PET showed high accumulation of [11C]PXT012253 in the liver, kidney, heart, and brain in the initial phase. The radioligand was excreted through both the gastrointestinal and the urinary tracts. Effective dose of [11C]PXT012253 was estimated to be 0.0042xa0mSv/MBq.Conclusions[11C]PXT012253 was shown to be a promising PET radioligand for mGlu4 allosteric modulators in the monkey brain. MA1 would be the choice of quantitative method. Further development of [11C]PXT012253 in human subjects is warranted.

Reduced acquisition times in whole body bone scintigraphy using a noise-reducing Pixon®-algorithm—a qualitative evaluation study

BackgroundReducing scan-time while maintaining sufficient image quality is a common issue in nuclear medicine diagnostics. This matter can be addressed by different post-processing methods such as Pixon® image processing. The aim of the present study was to evaluate if a commercially available noise-reducing Pixon-algorithm applied on whole body bone scintigraphy acquired with half the standard scan-time could provide the same clinical information as full scan-time non-processed images.MethodsTwenty patients were administered with 500xa0MBq 99mTc-diphosphonate and scanned on a Siemens Symbia T16 system. Each patient was first imaged using a standard clinical protocol and subsequently imaged using a protocol with half the standard scan-time. Half-time images were processed using a commercially available software package, Enhanced Planar Processing, from Siemens. All images were anonymized and visually evaluated with regard to clinically relevant lesion detectability by three experienced nuclear medicine physicians. The result of this evaluation was grouped into four BMI intervals to investigate the performance of the algorithm with regard to different patient size. Also, a comparison study was performed where the physicians compared the standard image and the processed half-time image corresponding to the same patient with regard to lesion detectability, image noise, and artifacts.ResultsThe results showed that 93xa0% of the processed half-time images and 98xa0% of the standard images were rated as sufficient or good with regard to lesion detectability. The processed half-time images were predominately considered sufficient (65xa0%), whereas the majority of the standard images were graded as good (83xa0%). The performance of the algorithm was unaffected by patient size as the average grading of all half-time processed images was constant independent of patient BMI. The comparison study showed that the standard images were rated superior with regard to lesion detectability, image noise, and artifacts, in 32, 65, and 23xa0% of the evaluations, respectively.ConclusionsThe results indicate that the Pixon Enhanced Planar Processing does not fully compensate for the loss of counts associated with reducing the scan-time in half for whole body bone scintigraphies. The findings showed that implementing the Pixon-algorithm on images acquired with half the acquisition time in overall provide sufficient clinical information regardless of patient size. The half-time processed images were predominantly graded lower in comparison to images acquired with full time protocols, and a less aggressive reduction in scan-time is therefore recommended.

Clinical activity of sorafenib in a previously treated advanced urothelial cancer patient.

A male patient, with advanced urothelial carcinoma, who had previously received cisplatin, was treated with sorafenib off-licence for 10.7 months. Evaluation of tumour response with computed tomography scans indicated a reduction in tumour size and necrosis of the metastases within 2 months. Progression-free survival was 10.5 months. Side effects were manageable and not beyond the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 grade 2. Molecular profiling of two of the proposed targets of sorafenib, platelet-derived growth factor receptor &bgr; and vascular endothelial growth factor receptor 2, of the patient’s tumour lesion showed high and intermediate expression levels in the tumour as compared with the surrounding non-neoplastic tissue. In contrast to previous reports, we report a clinically meaningful effect of sorafenib in a patient with advanced urothelial carcinoma. Hence, it appears that a fraction of patients with this disease are sensitive to this compound. To identify subpopulations of responders, we propose that clinical trials evaluating sorafenib and other targeted drugs should be biomarker-driven and designed with endpoints that consider the mode of action of the specific compound.