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  • 1.
    Al-Saffar, Anas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Baghdad University/ College of Veterinary Medicine.
    Diaz, Hetzel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Gastrointestinal motility examined by wireless motility capsule (SmartPill®) and gut hormone profiles in inflammatory bowel diseases: Motility and hormones inIBDManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Inflammatory bowel disease (IBD) is associated with vague gastrointestinal (GI) discomfort even when inflammation is in clinical remission. In Crohn’s disease (CD) and ulcerative colitis (UC) motility disorders have been described throughout the GI tract. In clinics, considerable patient discomfort relates to symtoms of dysmotility (e.g., intestinal cramping, distension or diarrhea), which present in active and inactive disease. Treatment requires diagnostic methods to identify pathologies throughout the gut during meals while also evaluating gut peptide hormone changes.

    Methods: SmartPill® wireless motility capsule (WMC) technique to identify pH and motility derangements along the GI tract. pH, luminal pressure, transit time and prandial peptide hormone changes were compared between either 10 CD patients or 10 UC patients relative 20 age- and sex-matched healthy controls.

    Results: Motility index was significantly reduced in the stomach and contraction frequency and peak pressures were reduced in CD. Small bowel motility index was reduced in UC. In CD, meal responses of ghrelin, GIP, PYY and leptin, and to a lesser extent GLP-1, showed elevated plasma levels. In UC, ghrelin, GIP and GLP-1, but not PYY and leptin were elevated. Neither had a clear relationship to the motility discrepancies.

    Conclusion: Enhanced endocrine meal responses may be a cause or result of motility disturbances in IBD, but cannot be broken down by individual peptides. These observations potentially give pathophysiological explanations for GI disturbances in IBD, opening the possibility for pharmacological treatment.

  • 2.
    Al-Saffar, Anas K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Baghdad Univ, Coll Vet Medicine, Dept Surg & Obstet, Baghdad, Iraq..
    Halim, Md Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hall, G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Small intestinal lactulose and sucralose hyper-permeability in inflammatory bowel disease2018In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 12, p. S124-S124Article in journal (Other academic)
  • 3.
    Al-Saffar, Anas Kh.
    et al.
    Baghdad University/ College of Veterinary Medicine.
    Halim, Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Concurrent small and large intestinal permeability in inflammatory bowel disease: Hyper-permeability in IBDManuscript (preprint) (Other (popular science, discussion, etc.))
    Abstract [en]

    Hyper-permeability in inflammatory bowel disease (IBD) has mostly been explored in the colon, where symptomatic inflammation is prevalent. Relationships between small and large intestine barrier function were examined. Fasted (4h) IBD (19 ulcerative colitis, 11 Crohn's disease) and 25 healthy control subjects’ were investigated. Lactulose (10g), mannitol (5g), riboflavin (0.05g) and sucralose (5g) were ingested with 500 mL water. Urine lactulose and mannitol were measured by enzyme assays, riboflavin by intrinsic fluorescence and sucralose by HPLC. CRP was measured by nephelometry. In IBD, small intestine lactulose and sucralose % recoveries were 1.77 and 2.73 fold higher than controls; combined data revealed the two probes were correlated (R2=0.6). In IBD, large intestine sucralose % recovery was 2.6 fold higher than controls and correlated with small intestine sucralose % recovery (R2=0.6). Conclusions: Sucralose yields similar result as lactulose for small intestine permeability, while having higher S:N, implying sucralose is more sensitive. No evidence was found for riboflavin malabsorption in IBD. There is concurrent small and large intestine hyper-permeability in IBD. Small intestine hyper-permeability is presumably related to inflammation in the large intestine, but without obvious deficiency in transporter mediated micronutrient absorption (i.e., riboflavin) in the small intestine.

  • 4.
    Al-Saffar, Anas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Meijer, Carl Hampus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Gannavarapu, Venkata Ram
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hall, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Li, Yichen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Diaz Tartera, Hetzel O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Lördal, Mikael
    Department of Medicine, Division of Gastroenterology and Hepatology, Danderyds Sjukhus, Danderyd, Sweden.
    Ljung, Tryggve
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Abbvie, Solna, Sweden.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Parallel Changes in Harvey-Bradshaw Index, TNFα, and Intestinal Fatty Acid Binding Protein  in Response to Infliximab in Crohn’s Disease2017In: Gastroenterology Research and Practice, ISSN 1687-6121, E-ISSN 1687-630X, p. 1-8, article id 1745918Article in journal (Refereed)
    Abstract [en]

    Intestinal fatty acid binding protein (I-FABP) indicates barrier integrity. Aims: determine if I-FABP is elevated in active Crohn's disease (CD) and if I-FABP parallels anti-TNF alpha antibody (infliximab) induced lowering of TNF alpha and Harvey-Bradshaw Index (HBI) as potential indicator of mucosal healing. I-FABP distribution along human gut was determined. Serum from 10 CD patients collected during first three consecutive infliximab treatments with matched pretreatment and follow-up samples one week after each treatment and corresponding HBI data were analyzed. I-FABP reference interval was established from 31 healthy subjects with normal gut permeability. I-FABP and TNF alpha were measured by ELISA; CRP was measured by nephelometry. Healthy tissue was used for I-FABP immunohistochemistry. Pretreatment CD patient TNF alpha was 1.6-fold higher than in-house reference interval, while I-FABP was 2.5-fold higher, which lowered at follow-ups. Combining all 30 infusion/follow-up pairs also revealed changes in I-FABP. HBI followed this pattern; CRP declined gradually. I-FABP was expressed in epithelium of stomach, jejunum, ileum, and colon, with the highest expression in jejunum and ileum. I-FABP is elevated in active CD with a magnitude comparable to TNF alpha. Parallel infliximab effects on TNF alpha, HBI, and I-FABP were found. I-FABP may be useful as an intestine selective prognostic marker in CD.

  • 5.
    Diaz Tartera, Hetzel O.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Al-Saffar, Anas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Uppsala University.
    Halim, Mohammed Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Lindberg, G
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Gastroenterol & Hepatol Unit, Huddinge, Sweden.
    Sangfelt, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Validation of SmartPill® wireless motility capsule for gastrointestinaltransit time: Intra-subject variability, software accuracy and comparison with video capsule endoscopy2017In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 29, no 10, article id e13107Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: There is interest in ultimately combining endoscopy and motility assessments. Gastric emptying (GET), small bowel (SBTT), colon (CTT) and whole gut transit (WGTT) times are conveniently obtained by SmartPill® wireless motility capsule (WMC) that records luminal pH, temperature and pressure. Reproducibility within same subjects and accuracy of software derived times (MotiliGI® ) were investigated for diagnostic application. GET and SBTT were separately measured using video capsule endoscopy (VCE). The aim of this investigation was to assess same subject reproducibility of WMC, accuracy of software derived transit times and relate to Pillcam® SB (small bowel) VCE motility data.

    METHODS: Seventy three healthy adults ingested a 260 kcal mixed meal followed by WMC tests. Food intake was permitted after 6 hours. Regional transit data was obtained for GET, SBTT and CTT, the sum yielding WGTT. Nineteen subjects repeated WMC tests 2 or 4 weeks later; a separate 70 underwent VCE while fasted.

    KEY RESULTS: Visually derived data from WMC yielded GET 3.46±0.27, SBTT 5.15±0.21, CTT 20.76±1.19 and WGTT 29.53±1.28 hours (mean±SEM). Pearson's correlation coefficients (r) against software derived results were: GET 0.78 (P<.0001), SBTT 0.28 (P<.05), CTT 0.96 (P<.0001), WGTT 0.99 (P<.0001). VCE yielded lower GET (0.71±0.08 hours) and SBTT (4.15±0.13 hours).

    CONCLUSIONS AND INFERENCES: GET, SBTT, CTT and WGTT obtained by WMC are commensurate with literature values, including by other methods. Visually and software derived transit times have strongest correlations for CTT and WGTT. WMC yields longer GET and SBTT than VCE, perhaps due to meal related effects on motility.

  • 6. Falken, Y.
    et al.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Abraham-Nordling, M.
    Kressner, U.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Naslund, E.
    Intravenous ghrelin accelerates postoperative gastric emptying and time to first bowel movement in humans2013In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 25, no 6, p. 474-480Article in journal (Refereed)
    Abstract [en]

    Background Ghrelin has been shown to stimulate gastric emptying in healthy humans and patients with delayed gastric emptying. The aim of this study is to assess the effect of ghrelin on gastric emptying on day 2 after open colorectal surgery. Methods Twenty-four patients (mean age 69.2 +/- 1.4, BMI 25.8 +/- 0.8kgm2) were randomized to saline or ghrelin infusion (15pmolkg1min1) during 3h before and on day 2 after open colorectal surgery. Of these, 20 were assessed both before and after surgery. At start of infusion, a liquid meal (480kcal, 200mL) was administered together with 1.5g acetaminophen. Plasma was obtained at regular intervals together with visual analogue scales for hunger, satiety and nausea. Acetaminophen was analyzed as a marker of gastric emptying. Plasma glucose, insulin, acyl-ghrelin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinoptrophic peptide (GIP), pancreatic polypeptide and peptide YY (PYY) were analyzed. Key Results Gastric emptying was faster during ghrelin infusion compared to saline before and after surgery (P<0.02). In addition, plasma glucose was increased (P<0.05). With ghrelin infusion, plasma insulin was unchanged except for lower values postoperatively (P<0.05). Ghrelin did not alter plasma concentrations of gut peptides. After surgery, ghrelin shortened the time to first bowel movement compared to saline (2.1 +/- 0.3 vs 3.5 +/- 0.4days, P=0.02). Conclusions & Inferences A 3-h ghrelin infusion increased the gastric emptying rate and hastened the time to first bowel movement after surgery. Ghrelin/ghrelin receptor agonists have a therapeutic potential in postoperative ileus; Karolinska Clinical Trial Registry nr CT20110084.

  • 7. Farmer, Adam D
    et al.
    Ban, Vin F
    Coen, Steven J
    Sanger, Gareth J
    Barker, Gareth J
    Gresty, Michael A
    Giampietro, Vincent P
    Williams, Steven C
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Andrews, Paul L R
    Aziz, Qasim
    Visually induced nausea causes characteristic changes in cerebral, autonomic and endocrine function in humans2015In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 593, no 5, p. 1183-1196Article in journal (Refereed)
    Abstract [en]

    UNLABELLED: Nausea is a highly individual and variable experience. The reasons for this variability are incompletely understood although psychophysiological factors have been proposed. Herein we describe objective psychophysiological changes induced by the subjective sensation of motion sickness. In comparison to subjects who did not develop nausea, nausea-sensitive subjects demonstrated electrogastrographic and autonomic changes, which included an increase in sympathetic nervous system activity with a concomitant reduction in parasympathetic activity. Furthermore, differences were also evident in plasma ghrelin, and subcortical and cortical activity. These data have a number of important implications for future research examining the physiological mechanisms that underlie nausea: ○The physiological, hormonal and cortical patterns identified herein represent potential biomarkers of the physiological mechanisms of nausea. ○Reverse translation of the physiological factors identified may facilitate refinement of animal models used to investigate novel anti-emetic agents and emetic liability of candidate drugs, increasing their validity and translation of finding to humans.

    ABSTRACT: An integrated understanding of the physiological mechanisms involved in the genesis of nausea remains lacking. We aimed to describe the psychophysiological changes accompanying visually induced motion sickness, using a motion video, hypothesizing that differences would be evident between subjects who developed nausea in comparison to those who did not. A motion, or a control, stimulus was presented to 98 healthy subjects in a randomized crossover design. Validated questionnaires and a visual analogue scale (VAS) were used for the assessment of anxiety and nausea. Autonomic and electrogastrographic activity were measured at baseline and continuously thereafter. Plasma vasopressin and ghrelin were measured in response to the motion video. Subjects were stratified into quartiles based on VAS nausea scores, with the upper and lower quartiles considered to be nausea sensitive and resistant, respectively. Twenty-eight subjects were exposed to the motion video during functional neuroimaging. During the motion video, nausea-sensitive subjects had lower normogastria/tachygastria ratio and cardiac vagal tone but higher cardiac sympathetic index in comparison to the control video. Furthermore, nausea-sensitive subjects had decreased plasma ghrelin and demonstrated increased activity of the left anterior cingulate cortex. Nausea VAS scores correlated positively with plasma vasopressin and left inferior frontal and middle occipital gyri activity and correlated negatively with plasma ghrelin and brain activity in the right cerebellar tonsil, declive, culmen, lingual gyrus and cuneus. This study demonstrates that the subjective sensation of nausea is associated with objective changes in autonomic, endocrine and brain networks, and thus identifies potential objective biomarkers and targets for therapeutic interventions.

  • 8. Gibbons, C.
    et al.
    Caudwell, P.
    Finlayson, G.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Naslund, E.
    Blundell, J.
    Gastrointestinal Peptide Response To Fat And Carbohydrate: Implications For Satiety Control2013In: Annals of Nutrition and Metabolism, ISSN 0250-6807, E-ISSN 1421-9697, Vol. 63, no Suppl. 1, p. 458-458Article in journal (Other academic)
  • 9.
    Gibbons, Catherine
    et al.
    Univ Leeds, Sch Psychol, Appetite Control & Energy Balance Grp, Leeds LS2 9JZ, W Yorkshire, England.
    Blundell, John E
    Univ Leeds, Sch Psychol, Appetite Control & Energy Balance Grp, Leeds LS2 9JZ, W Yorkshire, England.
    Caudwell, Phillipa
    Univ Leeds, Sch Psychol, Appetite Control & Energy Balance Grp, Leeds LS2 9JZ, W Yorkshire, England.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Näslund, Erik
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, SE-18288 Stockholm, Sweden.
    Finlayson, Graham
    Univ Leeds, Sch Psychol, Appetite Control & Energy Balance Grp, Leeds LS2 9JZ, W Yorkshire, England.
    The Role of Episodic Postprandial Peptides in Exercise-Induced Compensatory Eating2017In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 11, p. 4051-4059Article in journal (Refereed)
    Abstract [en]

    Context: Prolonged physical activity gives rise to variable degrees of body weight and fat loss, and is associated with variability in appetite control. Whether these effects are modulated by postprandial, peptides is unclear. We examined the role of postprandial peptide response in compensatory eating during 12 weeks of aerobic exercise and in response to high-fat, low-carbohydrate (HFLC) and low-fat, high-carbohydrate (LFHC) meals.

    Methods: Of the 32 overweight/obese individuals, 16 completed 12 weeks of aerobic exercise and 16 nonexercising control subjects were matched for age and body mass index. Exercisers were classified as responders or nonresponders depending on net energy balance from observed compared with expected body composition changes from measured energy expenditure. Plasma samples were collected before and after meals to compare profiles of total and acylated ghrelin, insulin, cholecystokinin, glucagon-like peptide 1 (GLP-1), and total peptide YY (PYY) between HFLC and LFHC meals, pre- and postexercise, and between groups.

    Results: No differences between pre- and postintervention peptide release. Responders had greater suppression of acylated ghrelin (P < 0.05) than nonresponders, as well as higher postprandial levels of GLP-1 (P < 0.001) and total PYY (P < 0.001) compared with nonresponders and control subjects.

    Conclusion: No impact on postprandial peptide release was found after 12 weeks of aerobic exercise. Responders to exercise-induced weight loss showed greater suppression of acylated ghrelin and greater release of GLP-1 and total PYY at baseline. Therefore, episodic postprandial peptide profiles appear to form part of the pre-existing physiology of exercise responders and suggest differences in satiety potential may underlie exercise-induced compensatory eating.

  • 10. Gibbons, Catherine
    et al.
    Caudwell, Phillipa
    Finlayson, Graham
    Naslund, Erik
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellstrom, Per M.
    Blundell, John E.
    Susceptibility And Resistance To Exercise-induced Weight Loss Mediated By Physiological And Psychological Components Of Appetite2013In: Medicine & Science in Sports & Exercise, ISSN 0195-9131, E-ISSN 1530-0315, Vol. 45, no 5, p. 708-708Article in journal (Other academic)
  • 11. Gibbons, Catherine
    et al.
    Caudwell, Phillipa
    Finlayson, Graham
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Naslund, Erik
    Blundell, John E.
    Comparison of Postprandial Profiles of Ghrelin, Active GLP-1, and Total PYY to Meals Varying in Fat and Carbohydrate and Their Association With Hunger and the Phases of Satiety2013In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, no 5, p. E847-E855Article in journal (Refereed)
    Abstract [en]

    Context: The relationship between postprandial peptides at circulating physiological levels and short-term appetite control is not well understood. Objective: The purpose of this study was first to compare the postprandial profiles of ghrelin, glucagon-like peptide 1 (GLP-1), and peptide YY (PYY) after isoenergetic meals differing in fat and carbohydrate content and second to examine the relationships between ghrelin, GLP-1, and PYY with hunger, fullness, and energy intake. Design: Plasma was collected before and periodically after the meals for 180 minutes, after which time ad libitum food was provided. Simultaneous ratings of hunger and fullness were tracked for 180 minutes through phases identified as early (0-60 minutes) and late (60-180 minutes) satiety. Setting: This study was conducted at the Psychobiology and Energy Balance Research Unit, University of Leeds. Participants: The participants were 16 healthy overweight/obese adults. Main Outcome Measures: Changes in hunger and fullness and metabolic markers were indicators of the impact of the meals on satiety. Results: Ghrelin was influenced similarly by the 2 meals [F-(1,F- 12) = 0.658, P = .433] and was significantly associated with changes in hunger (P < .05), which in turn correlated with food intake (P < .05). GLP-1 and PYY increased more by the high-fat meal [F-(1,F- 15) = 5.099 and F-(1,F- 14) = 5.226, P < .05]. GLP-1 was negatively associated with hunger in the late satiety phase and with energy intake (P < .05), but the PYY profile was not associated with hunger or fullness, nor was PYY associated with food intake. Conclusions: The results demonstrate that under these conditions, these peptides respond differently to ingested nutrients. Ghrelin and GLP-1, but not PYY, were associated with short-term control of appetite over the measurement period.

  • 12. Gibbons, Catherine
    et al.
    Finlayson, Graham
    Caudwell, Phillipa
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Näslund, Erik
    Blundell, John E
    Postprandial profiles of CCK after high fat and high carbohydrate meals and the relationship to satiety in humans2016In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 77, p. 3-8Article in journal (Refereed)
    Abstract [en]

    CONTEXT: CCK is understood to play a major role in appetite regulation. Difficulties in measuring CCK have limited the potential to assess its profile in relation to food-induced satiety. Improvements in methodology and progress in theoretical understanding of satiety/satiation make it timely for this to be revisited.

    OBJECTIVE: First, examine how physiologically relevant postprandial CCK8/33(s) profiles are influenced by fat (HF) or carbohydrate (HCHO) meals. Second, to examine relationships between postprandial CCK and profiles of satiety (hunger/fullness) and satiation (meal size).

    PARTICIPANTS AND DESIGN: Sixteen overweight/obese adults (11 females/5 males) participated in a randomised-crossover study (46 years, 29.8kg/m(2)) in a university research centre. Plasma was collected preprandially and for 180min postprandially. Simultaneously, ratings of hunger/fullness were tracked for 180min before an ad libitum lunch was provided.

    RESULTS: CCK8/33(s) levels increased more rapidly and reached a higher peak following HF compared to HCHO breakfast (F(1,15)=14.737, p<0.01). Profiles of hunger/fullness did not differ between conditions (F(1,15)=0.505, p=0.488; F(1,15)=2.277, p=0.152). There was no difference in energy intake from the ad libitum meal (HF-3958 versus HCHO-3925kJ; t(14)=0.201, p=0.844). CCK8/33(s) profiles were not associated with subjective appetite during early and late phases of satiety; nor was there an association between CCK8/33(s) and meal size.

    CONCLUSIONS: These results demonstrate CCK levels were higher after HF meal compared to HCHO isocaloric meal. There was no association between CCK levels and intensity of satiety, or with meal size. Under these circumstances, CCK does not appear to play a unique independent role in satiety/satiation. CCK probably acts in conjunction with other peptides and the action of the stomach.

  • 13. Gromada, Jesper
    et al.
    Bark, Christina
    Smidt, Kamille
    Efanov, Alexander M
    Janson, Juliette
    Mandic, Slavena A
    Webb, Dominic-Luc
    Zhang, Wei
    Meister, Björn
    Jeromin, Andreas
    Berggren, Per-Olof
    Neuronal calcium sensor-1 potentiates glucose-dependent exocytosis in pancreatic beta cells through activation of phosphatidylinositol 4-kinase beta2005In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 102, no 29, p. 10303-8Article in journal (Refereed)
    Abstract [en]

    Cytosolic free Ca2+ plays an important role in the molecular mechanisms leading to regulated insulin secretion by the pancreatic beta cell. A number of Ca2+-binding proteins have been implicated in this process. Here, we define the role of the Ca2+-binding protein neuronal Ca2+ sensor-1 (NCS-1) in insulin secretion. In pancreatic beta cells, NCS-1 increases exocytosis by promoting the priming of secretory granules for release and increasing the number of granules residing in the readily releasable pool. The effect of NCS-1 on exocytosis is mediated through an increase in phosphatidylinositol (PI) 4-kinase beta activity and the generation of phosphoinositides, specifically PI 4-phosphate and PI 4,5-bisphosphate. In turn, PI 4,5-bisphosphate controls exocytosis through the Ca2+-dependent activator protein for secretion present in beta cells. Our results provide evidence for an essential role of phosphoinositide synthesis in the regulation of glucose-induced insulin secretion by the pancreatic beta cell. We also demonstrate that NCS-1 and its downstream target, PI 4-kinase beta, are critical players in this process by virtue of their capacity to regulate the release competence of the secretory granules.

  • 14.
    Halim, Abdul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Degerblad, Marie
    Karolinska Institutet.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Karlbom, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Juul Holst, Jens
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Glucagon-like peptide-1 inhibits prandial gastrointestinal motility through myenteric neuronal mechanisms in humans2018In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, no 2, p. 575-585Article in journal (Refereed)
    Abstract [en]

    Context: Glucagon-like peptide-1 (GLP-1) secretion from L-cells and postprandial inhibition of gastrointestinal motility.

    Objective: Investigate whether physiological plasma concentrations of GLP-1 can inhibit human postprandial gastrointestinal motility; determine target mechanism of GLP-1 and analogue ROSE-010 action.

    Design: Single-blind parallel study.

    Setting: University research laboratory.

    Participants: Healthy volunteers investigated with antroduodenojejunal manometry. Human gastric, intestinal and colonic muscle strips.

    Interventions: Motility indices (MI) obtained before and during infusion of saline or GLP-1 were compared. Plasma GLP-1 and glucagon-like peptide-2 (GLP-2) measured by radioimmunoassay. Gastrointestinal muscle strips, pre-contracted with bethanechol/electric field stimulation (EFS), investigated for GLP-1- or ROSE-010-induced relaxation. GLP-1, GLP-2 and their receptors localized by immunohistochemistry. Action mechanisms studied employing exendin(9-39)amide, Lω-nitro-monomethylarginine (L-NMMA), 2´,5´-dideoxyadenosine (DDA), tetrodotoxin (TTX).

    Main outcome measures: Hypothesize postprandial gastric relaxation induced by GLP-1, the mechanism of which intrinsic neuronally-mediated.

    Results: Food intake increased MI to 6.4±0.3 (antrum), 5.7±0.4 (duodenum) and 5.9±0.2 (jejunum). GLP-1 administered intravenously raised plasma GLP-1, but not GLP-2. GLP-1 0.7 pmol/kg·min significantly suppressed MI to 4.6±0.2, 4.7±0.4 and 5.0±0.2, respectively, while 1.2 pmol/kg·min suppressed corresponding MI to 5.4±0.2, 4.4±0.3 and 5.4±0.3 (p<0.0001-0.005). GLP-1 and ROSE-010 prevented bethanechol- or EFS-induced muscle contractions (p <0.005-0.05). Inhibitory responses to GLP-1 and ROSE-10 were blocked by exendin(9-39)amide, L-NMMA, DDA or TTX (all p <0.005-0.05). GLP-1 and GLP-2 were localized to epithelial cells; GLP-1 also in myenteric neurons. GLP-1R and GLP-2R were localized at myenteric neurons but not muscle, GLP-1R also in epithelial cells.

    Conclusions: GLP-1 inhibits postprandial motility through GLP-1R at myenteric neurons, involving nitrergic and cAMP-dependent mechanisms.

  • 15.
    Halim, M. Abdul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Gillberg, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Boghus, Sandy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Karlbom, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellstrom, Per. M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Nitric oxide regulation of migrating motor complex: randomized trial of N-G-monomethyl-L-arginine effects in relation to muscarinic and serotonergic receptor blockade2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, no 2, p. 105-118Article in journal (Refereed)
    Abstract [en]

    Aim: The migrating motor complex (MMC) propels contents through the gastrointestinal tract during fasting. Nitric oxide (NO) is an inhibitory neurotransmitter in the gastrointestinal tract. Little is known about how NO regulates the MMC. In this study, the aim was to examine nitrergic inhibition of the MMC in man using N-G-monomethyl-L-arginine (L-NMMA) in combination with muscarinic receptor antagonist atropine and 5-HT3 receptor antagonist ondansetron. Methods: Twenty-six healthy volunteers underwent antroduodenojejunal manometry for 8 h with saline or NO synthase (NOS) inhibitor L-NMMA randomly injected I.V. at 4 h with or without atropine or ondansetron. Plasma ghrelin, motilin and somatostatin were measured by ELISA. Intestinal muscle strip contractions were investigated for NO-dependent mechanisms using L-NMMA and tetrodotoxin. NOS expression was localized by immunohistochemistry. Results: L-NMMA elicited premature duodenojejunal phase III in all subjects but one, irrespective of atropine or ondansetron. L-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. L-NMMA did not change circulating ghrelin, motilin or somatostatin. Intestinal contractions were stimulated by L-NMMA, insensitive to tetrodotoxin. NOS immunoreactivity was detected in the myenteric plexus but not in smooth muscle cells. Conclusion: Nitric oxide suppresses phase III of MMC independent of muscarinic and 5-HT3 receptors as shown by nitrergic blockade, and acts through a neurocrine disinhibition step resulting in stimulated phase III of MMC independent of cholinergic or 5-HT3-ergic mechanisms. Furthermore, phase II of MMC is governed by inhibitory nitrergic and excitatory cholinergic, but not 5-HT3-ergic mechanisms.

  • 16.
    Halim, Md Abdul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Gillberg, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Boghus, Sandy
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Karlbom, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Dominic-Luc, Webb
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    M. Hellström, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Nitric oxide regulation of migrating motor complex: randomised trial of L-NMMA effects in relation to muscarinic and serotonergic receptor blockade2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, no 2, p. 105-118Article in journal (Refereed)
    Abstract [en]

    Aim

    The migrating motor complex (MMC) propels contents through the gastrointestinal tract during fasting. Nitric oxide (NO) is an inhibitory neurotransmitter in the gastrointestinal tract. Little is known about how NO regulates the MMC. In this study, the aim was to examine nitrergic inhibition of the MMC in man using NG-monomethyl-l-arginine (l-NMMA) in combination with muscarinic receptor antagonist atropine and 5-HT3 receptor antagonist ondansetron.

    Methods

    Twenty-six healthy volunteers underwent antroduodenojejunal manometry for 8 h with saline or NO synthase (NOS) inhibitor l-NMMA randomly injected I.V. at 4 h with or without atropine or ondansetron. Plasma ghrelin, motilin and somatostatin were measured by ELISA. Intestinal muscle strip contractions were investigated for NO-dependent mechanisms using l-NMMA and tetrodotoxin. NOS expression was localized by immunohistochemistry.

    Results

    l-NMMA elicited premature duodenojejunal phase III in all subjects but one, irrespective of atropine or ondansetron. l-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. l-NMMA did not change circulating ghrelin, motilin or somatostatin. Intestinal contractions were stimulated byl-NMMA, insensitive to tetrodotoxin. NOS immunoreactivity was detected in the myenteric plexus but not in smooth muscle cells.

    Conclusion

    Nitric oxide suppresses phase III of MMC independent of muscarinic and 5-HT3 receptors as shown by nitrergic blockade, and acts through a neurocrine disinhibition step resulting in stimulated phase III of MMC independent of cholinergic or 5-HT3-ergic mechanisms. Furthermore, phase II of MMC is governed by inhibitory nitrergic and excitatory cholinergic, but not 5-HT3-ergic mechanisms.

  • 17.
    Halim, Md. Abdul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University.
    Marie, Degerblad
    Karolinska Institutet.
    Magnus, Sundbom
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University.
    Karlbom, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Juul Holst, Jens
    Dominic-Luc, Webb
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University.
    Per, Hellström
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University.
    Glucagon-like peptide-1 inhibits prandial gastrointestinal motility through myenteric neuronal mechanisms in humansIn: Article in journal (Refereed)
    Abstract [en]

    Context

    Glucagon-like peptide-1 (GLP-1) secretion from L-cells and postprandial inhibition of gastrointestinal motility.

    Objective

    Investigate whether physiological plasma concentrations of GLP-1 can inhibit human postprandial gastrointestinal motility; determine target mechanism of GLP-1 and analogue ROSE-010 action.

    Design

    Single-blind parallel study.

    Setting

    University research laboratory.

    Participants

    Healthy volunteers investigated with antroduodenojejunal manometry. Human gastric, intestinal and colonic muscle strips.

    Interventions

    Motility indices (MI) obtained before and during infusion of saline or GLP-1 were compared. Plasma GLP-1 and glucagon-like peptide-2 (GLP-2) measured by radioimmunoassay. Gastrointestinal muscle strips, pre-contracted with bethanechol/electric field stimulation (EFS), investigated for GLP-1- or ROSE-010-induced relaxation. GLP-1, GLP-2 and their receptors localized by immunohistochemistry. Action mechanisms studied employing exendin(9-39)amide, Lω-nitro-monomethylarginine (L-NMMA), 2´,5´-dideoxyadenosine (DDA), tetrodotoxin (TTX).

    Main outcome measures

    Hypothesize postprandial gastric relaxation induced by GLP-1, the mechanism of which intrinsic neuronally-mediated.

    Results

    Food intake increased MI to 6.4±0.3 (antrum), 5.7±0.4 (duodenum) and 5.9±0.2 (jejunum). GLP-1 administered intravenously raised plasma GLP-1, but not GLP-2. GLP-1 0.7 pmol/kg·min significantly suppressed MI to 4.6±0.2, 4.7±0.4 and 5.0±0.2, respectively, while 1.2 pmol/kg·min suppressed corresponding MI to 5.4±0.2, 4.4±0.3 and 5.4±0.3 (p<0.0001-0.005). GLP-1 and ROSE-010 prevented bethanechol- or EFS-induced muscle contractions (p <0.005-0.05). Inhibitory responses to GLP-1 and ROSE-10 were blocked by exendin(9-39)amide, L-NMMA, DDA or TTX (all p <0.005-0.05). GLP-1 and GLP-2 were localized to epithelial cells; GLP-1 also in myenteric neurons. GLP-1R and GLP-2R were localized at myenteric neurons but not muscle, GLP-1R also in epithelial cells.

    Conclusions

    GLP-1 inhibits postprandial motility through GLP-1R at myenteric neurons, involving nitrergic and cAMP-dependent mechanisms.

  • 18.
    Hellström, Per M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Al-Saffar, Anas K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Tartera Diaz, Hetzel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Gannavarapu, Venkata Ram
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Intestinal fatty acid binding protein parallels temporal changes in Harvey-Bradshaw Index and TNF alpha in response to infliximab in Crohn’s disease2017In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 11, no suppl 1, p. S389-S389Article in journal (Refereed)
  • 19.
    Hellström, Per M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Uppsala University.
    Halim, Md Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Uppsala University.
    Tryggve, Ljung
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University.
    Holst, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Karolinska Institutet.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Uppsala University.
    Luminal Nitric Oxide and Plasma Nitrite/Nitrate As Predictors of Colectomy in Corticosteroid-Treated Acute Colitis2015In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 148, no 4, suppl. 1, article id Sul 231Article in journal (Refereed)
    Abstract [en]

    Background: Nitric oxide (NO) is known to be up-regulated by the induction of induciblenitric oxide synthase (iNOS) in inflammatory conditions. NO gas can be used as a markerof inflammatory activity in hollow organs. In parallel, plasma nitrite + nitrate (NOx) canreflect the ongoing inflammatory activity. We analyzed rectal NO before and after threedays, as well as plasma NOx in patients on glucocorticosteroid (GC) therapy in hospitalizedpatients. The aim of the study was to evaluate the relationship of rectal luminal NO andcirculating plasma NOx in acute fulminant colitis to the outcome as therapeutic responseor colectomy.

    Methods: 50 patients with median age 41 (range 20-78) years were hospitalizeddue to acute fulminant colitis and received treatment with high-dose GCs. Luminal nitricoxide was analyzed with chemiluminescence before therapy onset of therapy with GC andon day 3 of treatment. NOx was measured by nitrite/nitrate colorimetric assay. NO levelsand plasma NOx were compared to clinical disease activity index and C-reactive protein(CRP).

    Results: 32 responded to GC treatment and 18 did not, resulting in colectomy.The responders had higher luminal NO than non-responders (day 1: 12525±2600, day 3:15590±4157 ppb) vs non-responders (day 1: 2874±1283, day 3: 1137±297 ppb) (p<0.0114).Using an optimal cut-off NO level of 2250 ppb, sensitivity and specificity was 86% and81% for colectomy (p<0.0001). The area under the curve was 0.88 and likelihood ratio4.8. Similarly, plasma NOx was higher in responders vs non-responders (day 1: 6.2±0.3 vs3.9±0.4 umol/L) (p<0.0001). Using plasma NOx, we found a corresponding cut-off at 5umol/L with sensitivity 87% and specificity 87%. The area under the curve was 0.88 andlikelihood ratio 6.7. Luminal NO was also correlated to plasma NOx (r=0.33, p=0.0205).In the responder group, CRP levels decreased (day 1: 22.31±2.95, day 3: 15.69±3.57mg/L), whereas among non-responders CRP levels increased (day 1: 45.83±11.10, day 3:76.35±16.96 mg/L) (p<0.0167). Kaplan-Meier analysis showed that patients with baselineNO levels lower than 2250 ppb were at a significantly higher risk of colectomy within onemonth from onset of GCS treatment (p<0.0001). Twelve out of 18 (67%) in patients withday 1 NO <2250 ppb were colectomized, the corresponding number of patients with NO>2250 ppb was 3 out of 32 (9%). In a similar manner, using plasma NOx <5 uml/L foranalysis, we found 13 (72%) to be colectomized, and with >5 umol/L only two (6%).

    Conclusion: NO and its oxidation product NOx are markers of inflammatory activity in thegut. However, with more intense inflammation and mucosal damage, the less NO is produced.Luminal NO as well as plasma NOx can be used as a sensitive biomarker to predict colectomyin the outcome of acute fulminant colitis

  • 20.
    Hellström, Per M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hendolin, Panu
    Biohit Oyj, Clin Sci, Helsinki, Finland..
    Kaihovaara, Pertti
    Biohit Oyj, Clin Sci, Helsinki, Finland.;Univ Helsinki, Res Unit Acetaldehyde & Canc, Helsinki, Finland..
    Kronberg, Leif
    Abo Akad Univ, Johan Gadolin Proc Chem Ctr, Lab Organ Chem, Turku, Finland..
    Meierjohann, Axel
    Abo Akad Univ, Johan Gadolin Proc Chem Ctr, Lab Organ Chem, Turku, Finland..
    Millerhovf, Anders
    Univ Uppsala Hosp, Clin Trial Consultants, Uppsala, Sweden..
    Paloheimo, Lea
    Biohit Oyj, Clin Sci, Helsinki, Finland..
    Sundelin, Heidi
    Abo Akad Univ, Johan Gadolin Proc Chem Ctr, Lab Organ Chem, Turku, Finland..
    Syrjanen, Kari
    Biohit Oyj, Clin Sci, Helsinki, Finland..
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Salaspuro, Mikko
    Univ Helsinki, Res Unit Acetaldehyde & Canc, Helsinki, Finland..
    Slow-release L-cysteine capsule prevents gastric mucosa exposure to carcinogenic acetaldehyde: results of a randomised single-blinded, cross-over study of Helicobacter-associated atrophic gastritis2017In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 52, no 2, p. 230-237Article in journal (Refereed)
    Abstract [en]

    Introduction: Helicobacter-induced atrophic gastritis with a hypochlorhydric milieu is a risk factor for gastric cancer. Microbes colonising acid-free stomach oxidise ethanol to acetaldehyde, a recognised group 1 carcinogen. Objective: To assess gastric production of acetaldehyde and its inert condensation product, non-toxic 2-methyl-1,3-thiazolidine-4-carboxylic acid (MTCA), after alcohol intake under treatment with slow-release L-cysteine or placebo. Methods: Seven patients with biopsy-confirmed atrophic gastritis, low serum pepsinogen and high gastrin-17 were studied in a cross-over single-blinded design. On separate days, patients randomly received 200 mg slow-release L-cysteine or placebo with intragastric instillation of 15% (0.3 g/kg) ethanol. After intake, gastric concentrations of ethanol, acetaldehyde, L-cysteine and MTCA were analysed. Results: Administration of L-cysteine increased MTCA (p < .0004) and decreased gastric acetaldehyde concentrations by 68% (p < .0001). The peak L-cysteine level was 7552 +/- 2687 mu mol/L at 40 min and peak MTCA level 196 +/- 98 mu mol/L at 80 min after intake. Gastric L-cysteine and MTCA concentrations were maintained for 3 h. The AUC for MTCA was 11-fold higher than acetaldehyde, indicating gastric first-pass metabolism of ethanol. With placebo, acetaldehyde remained elevated also at low ethanol concentrations representing 'non-alcoholic' beverages and food items. Conclusions: After gastric ethanol instillation, slow-release L-cysteine eliminates acetaldehyde to form inactive MTCA, which remains in gastric juice for up to 3 h. High acetaldehyde levels indicate a marked gastric first-pass metabolism of ethanol resulting in gastric accumulation of carcinogenic acetaldehyde. Local exposure of the gastric mucosa to acetaldehyde can be mitigated by slow-release L-cysteine capsules.

  • 21.
    Hellström, Per M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Irritable Bowel syndrome: Principles and novel treatment options2011In: Drugs of the future, ISSN 0377-8282, E-ISSN 2013-0368, Vol. 36, no 9, p. 669-675Article, review/survey (Refereed)
    Abstract [en]

    There is growing interest in the area of irritable bowel syndrome (IBS) in developing tools to separate various subgroups of this disease in order to identify potentially different pathogenetic mechanisms. From such work, the ultimate goal is tailored treatment for the various subtypes of the disease. Among major achievements in this research, the finding of increased gut permeability is of great interest and suggests a luminal factor as a cause of disease, which would be able to maintain low-grade inflammation. There are various treatment options and significant activity in developing drugs that have the capability to inhibit gut motility and increase luminal secretion. The development of analogues to gut peptide hormones, such as glucagon-like peptide 1, is of primary interest, as these drugs rarely give rise to inconvenient adverse reactions at therapeutic doses. Some of these drugs even exert their action directly on the luminal membranes, such as linaclotide, which means that oral administration is favored to diminish the risk of systemic reactions. The concept of IBS is anticipated to evolve into different disease mechanisms that will serve as the basis for customized treatments.

  • 22. Hopkins, Mark
    et al.
    Gibbons, Catherine
    Caudwell, Phillipa
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Naslund, Erik
    Blundell, John E.
    Finlayson, Graham
    Fasting Leptin Is a Metabolic Determinant of Food Reward in Overweight and Obese Individuals during Chronic Aerobic Exercise Training2014In: International Journal of Endocrinology, ISSN 1687-8337, E-ISSN 1687-8345, p. 323728-Article in journal (Refereed)
    Abstract [en]

    Changes in food reward have been implicated in exercise-induced compensatory eating behaviour. However, the underlying mechanisms of food reward, and the physiological correlates of exercise-induced changes in food reward, are unknown. Methods. Forty-six overweight and obese individuals completed 12 weeks of aerobic exercise. Body composition, food intake, and fasting metabolic-related hormones were measured at baseline, week six, and postintervention. On separate days, the reward value of high-and-low-fat food (explicit liking and implicit wanting) was also assessed at baseline, week six, and postintervention. Results. Following the intervention, FM, FFM, and VO2peak improved significantly, while fasting leptin decreased. However, food intake or reward did not change significantly. Cross-sectional analyses indicated that FM (P = 0.022) and FFM (P = 0.046) were associated with explicit liking for high-fat food, but implicit wanting was associated with FM only (P = 0.005). Fasting leptin was associated with liking (P = 0.023) and wanting (P = 0.021) for high-fat food. Furthermore, a greater exercise-induced decline in fasting leptin was associated with increased liking (P = 0.018). Conclusion. These data indicate that food reward has a number of physiological correlates. In particular, fasting leptin appears to play an active role in mediating food reward during exercise-induced weight loss.

  • 23. Isaksson, Hanna
    et al.
    Tillander, Isabella
    Andersson, Roger
    Olsson, Johan
    Fredriksson, Helena
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Åman, Per
    Whole grain rye breakfast: Sustained satiety during three weeks of regular consumption2012In: Physiology and Behavior, ISSN 0031-9384, E-ISSN 1873-507X, Vol. 105, no 3, p. 877-884Article in journal (Refereed)
    Abstract [en]

    Whole grain rye products have previously been shown to increase feelings of satiety for up to 8h after intake under standardized conditions. This study was set out to investigate the sustainability of the satiating effect after regular consumption of breakfast meals with whole grain rye porridge or refined wheat bread. The study was randomized, cross-over and double-blind. Healthy subjects (n=24) were randomly assigned to daily consumption of iso-caloric standardized breakfast meals with whole grain rye porridge or refined wheat bread for two 3-wk phases, separated by a wash out of 3-4weeks. Each intervention phase had 3 scheduled visit days (days 1, 8 and 22) when appetite ratings (hunger, satiety and desire to eat) were registered for 24h at standardized conditions. Orocecal transit time (salicylazosulfapyridine/sulfapyridine method) and breath hydrogen as an indicator of colonic fermentation were measured at day 8 of each 3-wk phase in a subgroup (n=16). To investigate effects of breakfast on free-living food intake, 3-day weighed food diaries were self-registered during both intervention phases. Whole grain rye porridge breakfast resulted in higher ratings of satiety and lower hunger and desire to eat during 4h post consumption compared to refined wheat bread breakfast (p<0.001). This effect was sustained throughout the 3-wk study phases. Unlike previous studies, the effects did not persist into the afternoon (4-8h). The orocecal transit times after consumption of both breakfasts were similar and in the range of 5-6h. The rye porridge resulted in high levels of breath hydrogen 4-8h after intake, showing extensive colonic fermentation. This was however not related to any changes in appetite during this time-period. There were no significant differences in self-reported macronutrient- and energy intake between diets. This study shows that the satiating effect of rye persists after repeated daily consumption for up to three weeks.

  • 24. Juntti-Berggren, Lisa
    et al.
    Webb, Dominic-Luc
    Department of Molecular Medicine, The Rolf Luft Center for Diabetes Research, Karolinska Institutet, Stockholm.
    Arkhammar, Per O G
    Schultz, Vera
    Schweda, Elke K H
    Tornheim, Keith
    Berggren, Per-Olof
    Dihydroxyacetone-induced oscillations in cytoplasmic free Ca2+ and the ATP/ADP ratio in pancreatic beta-cells at substimulatory glucose.2003In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 278, no 42, p. 40710-40716Article in journal (Refereed)
    Abstract [en]

    Glucose stimulation of pancreatic beta-cells causes oscillatory influx of Ca2+, leading to pulsatile insulin secretion. We have proposed that this is due to oscillations of glycolysis and the ATP/ADP ratio, which modulate the activity of ATP-sensitive K+ channels. We show here that dihydroxyacetone, a secretagogue that feeds into glycolysis below the putative oscillator phosphofructokinase, could cause a single initial peak in cytoplasmic free Ca2+ ([Ca2+]i) but did not by itself cause repeated oscillations in [Ca2+]i in mouse pancreatic beta-cells. However, in the presence of a substimulatory concentration of glucose (4 mm), dihydroxyacetone induced [Ca2+]i oscillations. Furthermore, these oscillations correlated with oscillations in the ATP/ADP ratio, as seen previously with glucose stimulation. Insulin secretion in response to dihydroxyacetone was transient in the absence of glucose but was considerably enhanced and somewhat prolonged in the presence of a substimulatory concentration of glucose, in accordance with the enhanced [Ca2+]i response. These results are consistent with the hypothesized role of phosphofructokinase as the generator of the oscillations. Dihydroxyacetone may affect phosphofructokinase by raising the free concentration of fructose 1,6-bisphosphate to a critical level at which it activates the enzyme autocatalytically, thereby inducing the pulses of phosphofructokinase activity that cause the metabolic oscillations.

  • 25. Kass, G E
    et al.
    Chow, S C
    Gahm, A
    Webb, Dominic-Luc
    Rolf Luft Center for Diabetes Research, Department of Endocrinology, Karolinska Institutet, Stockholm, Sweden.
    Berggren, P O
    Llopis, J
    Orrenius, S
    Two separate plasma membrane Ca2+ carriers participate in receptor-mediated Ca2+ influx in rat hepatocytes.1994In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1223, no 2, p. 226-33Article in journal (Refereed)
    Abstract [en]

    The plasma membrane Ca2+ carrier system involved in receptor-mediated Ca2+ entry was studied. Using the Ca2+ readdition protocol, the rate of cytosolic free Ca2+ concentration ([Ca2+]i) increase in vasopressin-pretreated hepatocytes was significantly higher than in thapsigargin- or 2,5-di(tert-butyl)hydroquinone-pretreated cells. The addition of Mn2+ to unstimulated hepatocytes resulted in a biphasic quench of fura-2 fluorescence. After an initial phase that was fast in rate but of short duration, the rate of fura-2 quench by Mn2+ became much slower and lasted until all the cellular fura-2 was quenched. Pretreatment of the cells with vasopressin only accelerated the rate of the latter phase but not of the initial one. In agonist-stimulated cells, acidification of the extracellular medium or the presence of ruthenium red, econazole or SK&F 96365 decreased the rates of both [Ca2+]i increase and Mn2+ entry upon addition of the respective cation. By contrast, neomycin and N-tosyl-L-phenylalanine chloromethyl ketone markedly decreased the rate of [Ca2+]i increase upon Ca2+ readdition but had no effect on vasopressin-stimulated Mn2+ entry. None of the treatments affected the ability of vasopressin and thapsigargin to mobilize the internal Ca2+ store. It is concluded that in hepatocytes the two pathways of receptor-mediated Ca2+ entry control two distinct yet pharmacologically related cation carriers.

  • 26. Kass, G E
    et al.
    Webb, D L
    Karolinska inst, Stockholm, Sweden.
    Chow, S C
    Llopis, J
    Berggren, P O
    Receptor-mediated Mn2+ influx in rat hepatocytes: comparison of cells loaded with Fura-2 ester and cells microinjected with Fura-2 salt1994In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 302, p. 5-9Article in journal (Refereed)
    Abstract [en]

    In single Fura-2 ester-loaded hepatocytes, stimulation by vasopressin, but not emptying of the agonist-sensitive Ca2+ store by 2,5-di-(t-butyl)hydroquinone, resulted in an increase in the rate of Fura-2 fluorescence-quenching by Mn2+. Similarly, in cells microinjected with Fura-2 salt, vasopressin stimulated Mn2+ entry while 2,5-di-(t-butyl)hydroquinone or thapsigargin did not. The pattern of Fura-2 quenching by Mn2+ only correlated with the movement of Mn2+ across the plasma membrane.

  • 27.
    Lee, Isabella
    et al.
    Swedish Univ Agr Sci, Dept Food Sci, POB 7051, SE-75007 Uppsala, Sweden..
    Shi, Lin
    Swedish Univ Agr Sci, Dept Food Sci, POB 7051, SE-75007 Uppsala, Sweden.;Chalmers, Dept Biol & Biol Engn, Gothenburg, Sweden..
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Landberg, Rikard
    Swedish Univ Agr Sci, Dept Food Sci, POB 7051, SE-75007 Uppsala, Sweden.;Karolinska Inst, Unit Nutr Epidemiol, Inst Environm Med, POB 210, SE-17177 Stockholm, Sweden.;Chalmers, Dept Biol & Biol Engn Food & Nutr Sci, SE-41296 Gothenburg, Sweden.;Chalmers, Dept Biol & Biol Engn, Gothenburg, Sweden..
    Effects of whole-grain rye porridge with added inulin and wheat gluten on appetite, gut fermentation and postprandial glucose metabolism: a randomised, cross-over, breakfast study2016In: British Journal of Nutrition, ISSN 0007-1145, E-ISSN 1475-2662, Vol. 116, no 12, p. 2139-2149Article in journal (Refereed)
    Abstract [en]

    Whole-grain rye foods reduce appetite, insulin and sometimes glucose responses. Increased gut fermentation and plant protein may mediate the effect. The aims of the present study were to investigate whether the appetite-suppressing effects of whole-grain rye porridge could be enhanced by replacing part of the rye with fermented dietary fibre and plant protein, and to explore the role of gut fermentation on appetite and metabolic responses over 8 h. We conducted a randomised, cross-over study using two rye porridges (40 and 55 g), three 40-g rye porridges with addition of inulin: gluten (9:3; 6:6; 3:9 g) and a refined wheat bread control (55 g), served as part of complete breakfasts. A standardised lunch and an ad libitum dinner were served 4 and 8 h later, respectively. Appetite, breath hydrogen and methane, glucose, insulin and glucagon-like peptide-1 (GLP-1) responses were measured over 8 h. Twenty-one healthy men and women, aged 23-60 years, with BMI of 21-33 kg/m(2) participated in this study. Before lunch, the 55-g rye porridges lowered hunger by 20% and desire to eat by 22% and increased fullness by 29% compared with wheat bread (P < 0.05). Breath hydrogen increased proportionally to dietary fibre content (P < 0.05). Plasma glucose after lunch was 6% lower after the 55-g rye porridges compared with wheat bread (P< 0.05) and correlated to breath hydrogen (P < 0.001). No differences were observed in ad libitum food intake, insulin or GLP-1. We conclude that no further increase in satiety was observed when replacing part of the rye with inulin and gluten compared with plain rye porridges.

  • 28. Lehtihet, Mikael
    et al.
    Webb, Dominic-Luc
    Honkanen, Richard E
    Sjöholm, Ake
    Glutamate inhibits protein phosphatases and promotes insulin exocytosis in pancreatic beta-cells2005In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 328, no 2, p. 601-7Article in journal (Refereed)
    Abstract [en]

    In human type 2 diabetes mellitus, loss of glucose-sensitive insulin secretion from the pancreatic beta-cell is an early pathogenetic event, but the mechanisms involved in glucose sensing are poorly understood. A messenger role has been postulated for L-glutamate in linking glucose stimulation to sustained insulin exocytosis in the beta-cell, but the precise nature by which L-glutamate controls insulin secretion remains elusive. Effects of L-glutamate on the activities of ser/thr protein phosphatases (PPase) and Ca(2+)-regulated insulin exocytosis in INS-1E cells were investigated. Glucose increases L-glutamate contents and promotes insulin secretion from INS-1E cells. L-glutamate also dose-dependently inhibits PPase enzyme activities analogous to the specific PPase inhibitor, okadaic acid. L-glutamate and okadaic acid directly and non-additively promote insulin exocytosis from permeabilized INS-1E cells in a Ca(2+)-independent manner. Thus, an increase in phosphorylation state, through inhibition of protein dephosphorylation by glucose-derived L-glutamate, may be a novel regulatory mechanism linking glucose sensing to sustained insulin exocytosis.

  • 29. Lilja, L
    et al.
    Yang, S N
    Webb, Dominic-Luc
    Juntti-Berggren, L
    Berggren, P O
    Bark, C
    Cyclin-dependent kinase 5 promotes insulin exocytosis2001In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 276, no 36, p. 34199-34205Article in journal (Refereed)
    Abstract [en]

    Cyclin-dependent kinase 5 (Cdk5) is widely expressed although kinase activity has been described preferentially in neuronal systems. Cdk5 has an impact on actin polymerization during neuronal migration and neurite outgrowth and deregulation of the kinase has been implicated in the promotion of neurodegeneration. Recently it was shown that Cdk5 modulates dopamine signaling in neurons by regulating DARPP-32 function. In addition, Cdk5 phosphorylates munc-18 and synapsin I, two essential components of the exocytotic machinery. We have shown by reverse transcriptase-polymerase chain reaction, immunocytochemistry, and Western blotting that Cdk5 is present in the insulin-secreting pancreatic beta-cell. Subcellular fractionation of isolated beta-cells revealed a glucose-induced translocation of membrane-bound Cdk5 protein to lower density fractions. Inhibition of Cdk5 with roscovitine reduced insulin secretion with approximately 35% compared with control after glucose stimulation and with approximately 65% after depolarization with glucose and KCl. Capacitance measurements performed on single beta-cells that expressed a dominant-negative Cdk5 mutant showed impaired exocytosis. The effect on exocytosis by Cdk5 appeared to be independent of changes in free cytoplasmic Ca(2+) concentration. Taken together these results show that Cdk5 is present in beta-cells and acts as a positive regulator of insulin exocytosis.

  • 30. Resendez, Angel
    et al.
    Halim, Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Landhage, Caroline M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Singaram, Bakthan
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Rapid small intestinal permeability assay based on riboflavin and lactulose detected by bis-boronic acid appended benzyl viologens2015In: Clinica Chimica Acta, ISSN 0009-8981, E-ISSN 1873-3492, Vol. 439, p. 115-121Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Although organoboronic acids are efficient high-throughput sugar sensors, they have not been pursued for gut permeability studies. A modification of the lactulose/mannitol assay is described by which small intestinal permeability is assessed at the time of urine collection using a lactulose/riboflavin ratio.

    METHODS: Volunteers ingested 50mg riboflavin and either 5g mannitol or 10g lactulose. Urine was collected for 6hrs. Riboflavin was assayed by autofluorescence. Riboflavin was removed by C18 solid phase extraction. Lactulose and mannitol were then assayed using 1,1'-bis(2-boronobenzyl)-4,4'-bipyridinium (4,4'oBBV) coupled to the fluorophore HPTS.

    RESULTS: The temporal profile over 6hrs for riboflavin paralleled mannitol. Riboflavin recovery in urine was 11.1±1.9 % (mean±SEM, n=7), similar to mannitol. There was selective binding of 4,4'oBBV to lactulose, likely involving cooperativity between the fructose and galactose moieties. Lower limits of detection and quantification were 90 and 364μM. The lactulose assay was insensitive to other permeability probes (e.g., sucrose, sucralose) while tolerating glucose or lactose. This assay can be adapted to automated systems. Stability of 4,4'oBBV exceeds 4years.

    CONCLUSIONS: Riboflavin measured by autofluorescence combined with lactulose measured with 4,4'oBBV represents a useful new chemistry for rapid measurement of intestinal permeability with excellent stability, cost and throughput benefits.

  • 31. Resendez, Angel
    et al.
    Halim, Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Singh, Jasmeet
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Singaram, Bakthan
    Boronic acid recognition of non-interacting carbohydrates for biomedical applications: increasing fluorescence signals of minimally interacting aldoses and sucralose.2017In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 15, no 45, p. 9727-9733Article in journal (Refereed)
    Abstract [en]

    To address carbohydrates that are commonly used in biomedical applications with low binding affinities for boronic acid based detection systems, two chemical modification methods were utilized to increase sensitivity. Modified carbohydrates were analyzed using a two component fluorescent probe based on boronic acid-appended viologen-HPTS (4,4'-o-BBV). Carbohydrates normally giving poor signals (fucose, l-rhamnose, xylose) were subjected to sodium borohydride (NaBH4) reduction in ambient conditions for 1 h yielding the corresponding sugar alcohols from fucose, l-rhamnose and xylose in essentially quantitative yields. Compared to original aldoses, apparent binding affinities were increased 4-25-fold. The chlorinated sweetener and colon permeability marker sucralose (Splenda), otherwise undetectable by boronic acids, was dechlorinated to a detectable derivative by reactive oxygen and hydroxide intermediates by the Fenton reaction or by H2O2 and UV light. This method is specific to sucralose as other common sugars, such as sucrose, do not contain any carbon-chlorine bonds. Significant fluorescence response was obtained for chemically modified sucralose with the 4,4'-o-BBV-HPTS probe system. This proof of principle can be applied to biomedical applications, such as gut permeability, malabsorption, etc.

  • 32.
    Resendez, Angel
    et al.
    Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA.
    Panescu, Priera
    Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA.
    Zuniga, Ruth
    Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA.
    Banda, Isaac
    Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA.
    Joseph, Jorly
    Mahatma Gandhi Univ, IIRBS, Kottayam 686560, Kerala, India.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA.
    Singaram, Bakthan
    Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA.
    Multiwell Assay for the Analysis of Sugar Gut Permeability Markers: Discrimination of Sugar Alcohols with a Fluorescent Probe Array Based on Boronic Acid Appended Viologens2016In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 88, no 10, p. 5444-5452Article in journal (Refereed)
    Abstract [en]

    With the aim of discerning between different sugar and sugar alcohols of biomedical relevance, such as gut permeability, arrays of 2-component probes were assembled with up to six boronic acid-appended viologens (BBVs): 4,4'-o-BBV, 3,3'-o-BBV, 3,4'-o-BBV, 4,4'-o,m-BBV, 4,7'-o-PBBV, and pBoB, each coupled to the fluorophore 8-hydroxypyrene, 1,3,6-trisulfonic acid trisodium salt (HPTS). These probes were screened for their ability to discriminate between lactulose, l-rhamnose, 3-O-methyl-d-glucose, and xylose. Binding studies of sugar alcohols mannitol, sorbitol, erythritol, adonitol, arabitol, galactitol, and xylitol revealed that diols containing threo-1,2-diol units have higher affinity for BBVs relative diols containing erythro-1,2 units. Those containing both threo-1,2- and 1,3-syn diol motifs showed high affinity for boronic acid binding. Fluorescence from the arrays were examined by principle component analysis (PCA) and linear discriminant analysis (LDA). Arrays with only three BBVs sufficed to discriminate between sugars (e.g., lactulose) and sugar alcohols (e.g., mannitol), establishing a differential probe. Compared with 4,4'-o-BBV, 2-fold reductions in lower limits of detection (LOD) and quantification (LOQ) were achieved for lactulose with 4,7-o-PBBV (LOD 41 μM, LOQ 72 μM). Using a combination of 4,4'-o-BBV, 4,7-o-PBBV, and pBoB, LDA statistically segregated lactulose/mannitol (L/M) ratios from 0.1 to 0.5, consistent with values encountered in small intestinal permeability tests. Another triad containing 3,3'-o-BBV, 4,4'-o-BBV, and 4,7-o-PBBV also discerned similar L/M ratios. This proof-of-concept demonstrates the potential for BBV arrays as an attractive alternate to HPLC to analyze mixtures of sugars and sugar alcohols in biomedical applications and sheds light on structural motifs that make this possible.

  • 33. Richard, Ann-Marie T
    et al.
    Webb, Dominic-Luc
    Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Goodman, Jessie M
    Schultz, Vera
    Flanagan, John N
    Getty-Kaushik, Lisa
    Deeney, Jude T
    Yaney, Gordon C
    Dunaway, George A
    Berggren, Per-Olof
    Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Tornheim, Keith
    Tissue-dependent loss of phosphofructokinase-M in mice with interrupted activity of the distal promoter: impairment in insulin secretion2007In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 293, no 3, p. E794-801Article in journal (Refereed)
    Abstract [en]

    Phosphofructokinase is a key enzyme of glycolysis that exists as homo- and heterotetramers of three subunit isoforms: muscle, liver, and C type. Mice with a disrupting tag inserted near the distal promoter of the phosphofructokinase-M gene showed tissue-dependent differences in loss of that isoform: 99% in brain and 95-98% in islets, but only 50-75% in skeletal muscle and little if any loss in heart. This correlated with the continued presence of proximal transcripts specifically in muscle tissues. These data strongly support the proposed two-promoter system of the gene, with ubiquitous use of the distal promoter and additional use of the proximal promoter selectively in muscle. Interestingly, the mice were glucose intolerant and had somewhat elevated fasting and fed blood glucose levels; however, they did not have an abnormal insulin tolerance test, consistent with the less pronounced loss of phosphofructokinase-M in muscle. Isolated perifused islets showed about 50% decreased glucose-stimulated insulin secretion and reduced amplitude and regularity of secretory oscillations. Oscillations in cytoplasmic free Ca(2+) and the rise in the ATP/ADP ratio appeared normal. Secretory oscillations still occurred in the presence of diazoxide and high KCl, indicating an oscillation mechanism not requiring dynamic Ca(2+) changes. The results suggest the importance of phosphofructokinase-M for insulin secretion, although glucokinase is the overall rate-limiting glucose sensor. Whether the Ca(2+) oscillations and residual insulin oscillations in this mouse model are due to the residual 2-5% phosphofructokinase-M or to other phosphofructokinase isoforms present in islets or involve another metabolic oscillator remains to be determined.

  • 34.
    Saudi, Wan Salman Wan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Halim, Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Gillberg, A. L.
    Feldreich, T. Rudholm
    Sundbom, M.
    Karlbom, U.
    Naslund, E.
    Sommansson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Neuropeptide S reduce small intestinal motility in rats and humans2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, no S696, p. 94-94, article id P61Article in journal (Other academic)
  • 35.
    Saudi, Wan Salman Wan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Halim, Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Neuropeptide S Reduces Gut Motility in Rats and Humans2015In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 29, no S1Article in journal (Other academic)
  • 36.
    Sima, Eduardo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Non-Responders After Gastric Bypass: Hormone Response And Glucose Homeostasis During An Oral Glucose Tolerance Test2017In: IFSO 2017 22nd World Congress, Springer, 2017, Vol. 27, p. 208-208Conference paper (Other academic)
  • 37.
    Sima, Eduardo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Non-Responders after Gastric Bypass Surgery for Morbid Obesity: Peptide Hormones and Glucose Homeostasis2017Conference paper (Other academic)
  • 38.
    Sima, Eduardo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Non-responders After Gastric Bypass Surgery for Morbid Obesity: Peptide Hormones and Glucose Homeostasis2019In: Obesity Surgery, ISSN 0960-8923, E-ISSN 1708-0428, Vol. 29, no 12, p. 4008-4017Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: About 20% of patients operated with Roux-en-Y gastric bypass (RYGBP) experience poor long-term weight result. This study compared levels of leptin and gut hormones in long-term weight responders with non-responders after RYGBP. In a subgroup analysis, hormone levels were assessed in T2DM (type 2 diabetes mellitus) and normoglycemic participants.

    METHODS: Insulin, glucose, leptin, acyl-ghrelin, total PYY, active GLP-1, and GIP were measured during an oral glucose tolerance test (OGTT) in post-RYGBP subjects: 22 non-responders (BMI 40.6 ± 6.0 kg/m2 after an excess BMI loss [EBMIL] of 26.0 ± 15.9%) and 18 responders (BMI 29.5 ± 3.5 kg/m2 after an EBMIL of 74.9 ± 18.2%). Subjects were matched for preoperative age, BMI, and years of follow-up. Measures of glucose homeostasis were calculated, and body composition was measured.

    RESULTS: Fat mass-adjusted fasting leptin correlated negatively with %EBMIL (r = - 0.57, p < 0.01). Non-responders presented higher levels of leptin during the OGTT. Leptin decreased and ghrelin returned to baseline levels earlier in non-responders. Despite having higher insulin resistance than responders, non-responders demonstrated similar OGTT responses of GLP-1, GIP, and PYY. T2DM participants demonstrated lower GLP-1 levels than normoglycemic participants of similar weight.

    CONCLUSION: Fasting leptin is associated with weight result after RYGBP, and hormonal responses to a glucose oral load might work towards promoting obesity in long-term non-responders after RYGBP. Poor long-term weight result and glycemic status after RYGBP are each associated with differences in peptide hormone levels.

  • 39.
    Wan Saudi, Wan Salman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Halim, Mohammed Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Gillberg, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Rudholm-Feldreich, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Rosenqvist, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Karlbom, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Näslund, Erik
    Webb, Dominic-Luc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Hellström, Per M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Neuropeptide S inhibits gastrointestinal motility and increases mucosal permeability through nitric oxide2015In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 309, no 8, p. G625-G634Article in journal (Refereed)
    Abstract [en]

    Neuropeptide S (NPS) receptor (NPSR1) polymorphisms are associated with enteral dysmotility and inflammatory bowel disease (IBD). This study investigated the role of NPS in conjunction with nitrergic mechanisms in the regulation of intestinal motility and mucosal permeability. In rats, small intestinal myoelectric activity and luminal pressure changes in small intestine and colon, along with duodenal permeability were studied. In human intestine, NPS and NPSR1 were localized by immunostaining. Pre- and postprandial plasma NPS was measured by ELISA in healthy and active IBD humans. Effects and mechanisms of NPS were studied in human intestinal muscle strips. In rats, NPS 100-4000 pmol/kg·min had effects on the small intestine and colon. Low doses of NPS increased myoelectric spiking (p<0.05). Higher doses reduced spiking and prolonged the cycle length of the migrating myoelectric complex, reduced intraluminal pressures (p<0.05-0.01) and increased permeability (p<0.01) through NO-dependent mechanisms. In human intestine, NPS localized at myenteric nerve cell bodies and fibers. NPSR1 was confined to nerve cell bodies. Circulating NPS in humans was tenfold below the ~0.3 nmol/l dissociation constant (Kd) of NPSR1, with no difference between healthy and IBD subjects. In human intestinal muscle strips pre-contracted by bethanechol, NPS 1-1000 nmol/l induced NO-dependent muscle relaxation (p<0.05) that was sensitive also to tetrodotoxin (p<0.01). In conclusion, NPS inhibits motility and increases permeability in neurocrine fashion acting through NO in the myenteric plexus in rats and humans. Aberrant signaling and up-regulation of NPSR1 could potentially exacerbate dysmotility and hyperpermeability by local mechanisms in gastrointestinal functional and inflammatory reactions.

  • 40.
    Webb, Dominic-Luc
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Abrahamsson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Bariatric surgery - time to replace with GLP-1?2017In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 52, no 6-7, p. 635-640Article, review/survey (Refereed)
    Abstract [en]

    Obesity with a body mass index (BMI) over 30kg/m(2) represents a significant risk for increased morbidity and mortality, with reduced life expectancy of about 10 years. Until now, surgical treatment has been the only effective longterm intervention. The currently standardized method of bariatric surgery, gastric bypass, means that many gastrointestinal peptide hormones are activated, yielding net reductions in appetite and food intake. Among the most important gut peptide hormones in this perspective is glucagon-like peptide-1 (GLP-1), which rises sharply after gastric bypass. Consistent with outcomes of this surgery, GLP-1 suppresses appetite and reduces food intake. This implies that GLP-1 has the potential to achieve a similar therapeutic outcome as gastric bypass. GLP-1 analogs, which are used for the treatment of type 2 diabetes mellitus, also lead to significant weight loss. Altered hormonal profiles after gastric bypass therefore indicate a logical connection between gut peptide hormone levels, weight loss and glucose homeostasis. Furthermore, combinations of GLP-1 with other gut hormones such as peptide YY (PYY) and cholecystokinin (CCK) may be able to reinforce GLP-1 driven reduction in appetite and food intake. Pharmacological intenvention in obesity by use of GLP-1 analogs (exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, taspoglutide) and inhibitors of dipeptidyl peptidase-IV (DPP-IV) degradation that inactivate GLP-1 (sitagliptin, vildagliptin), leading to reduced appetite and weight with positive effects on metabolic control, are realistically achievable. This may be regarded as a low-risk therapeutic alternative to surgery for reducing obesity-related risk factors in the obese with lower BMIs.

  • 41.
    Webb, Dominic-Luc
    et al.
    Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.
    Islam, M. Shahidul
    Swedish Medical Research Council.
    Efanov, Alexandre M.
    Brown, Graham
    Köhler, Martin
    Larsson, Olof
    Berggren, Per-Olof
    Insulin exocytosis and glucose-mediated increase in cytoplasmic free Ca2+ concentration in the pancreatic beta-cell are independent of cyclic ADP-ribose1996In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 271, no 32, p. 19074-19079Article in journal (Refereed)
    Abstract [en]

    Stimulation of pancreatic beta-cells by glucose gives rise to an increase in the cytoplasmic free calcium concentration ([Ca2+]i) and exocytosis of insulin. Cyclic adenosine 5'-diphosphate ribose (cADPR), a metabolite of beta-NAD+, has been reported to increase [Ca2+]i in pancreatic beta-cells by releasing Ca2+ from inositol 1,4,5-trisphosphate-insensitive intracellular stores. In the present study, we have examined the role of cADPR in glucose-mediated increases in [Ca2+]i and insulin exocytosis. Dispersed ob/ob mouse beta-cell aggregates were either pressure microinjected with fura-2 salt or loaded with fura-2 acetoxymethyl ester, and [Ca2+]i was monitored by microfluorimetry. Microinjection of beta-NAD+ into fura-2-loaded beta-cells did not increase [Ca2+]i nor did it alter the cells' subsequent [Ca2+]i response to glucose. Cells microinjected with the cADPR antagonist 8NH2-cADPR increased [Ca2+]i in response to glucose equally well as those injected with cADPR. Finally, the ability of cADPR to promote exocytosis of insulin in electropermeabilized beta-cells was investigated. cADPR on its own did not increase insulin secretion nor did it potentiate Ca2+-induced insulin secretion. We conclude that cADPR neither plays a significant role in glucose-mediated increases in [Ca2+]i nor interacts directly with the molecular mechanisms regulating exocytosis of insulin in normal pancreatic beta-cells.

  • 42.
    Webb, Dominic-Luc
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Rudholm-Feldreich, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Gillberg, Linda
    Halim, Abdul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Theodorsson, Elvar
    Sanger, Gareth J.
    Campbell, Colin A.
    Boyce, Malcolm
    Näslund, Erik
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    The type 2 CCK/gastrin receptor antagonist YF476 acutely prevents NSAID-induced gastric ulceration while increasing iNOS expression2013In: Naunyn-Schmiedeberg's Archives of Pharmacology, ISSN 0028-1298, E-ISSN 1432-1912, Vol. 386, no 1, p. 41-49Article in journal (Refereed)
    Abstract [en]

    YF476 differs from the proton pump inhibitor (PPI) esomeprazole in mode of action by antagonizing the type 2 receptor of cholecystokinin/gastrin (CCK-2R). YF476 protection against diclofenac-induced gastric ulcers was compared to esomeprazole and correlated with plasma levels of hormones related to gastric pH (gastrin, ghrelin, and somatostatin), gastric gene expression of these hormones, their receptors, and inducible nitric oxide synthase (iNOS). YF476 or esomeprazole pretreatments were followed by diclofenac. Four hours later, gastric tissue was excised and analyzed for ulcer index. An intragastrically implanted Bravo capsule measured pH for 5 days during YF476 plus pentagastrin treatment. Changes in gene expression were assayed for gastrin, ghrelin, and somatostatin; their receptors; and iNOS. YF476 acutely (within 4 h) protected against diclofenac-induced gastric ulcers equivalent to esomeprazole. Gastric pH recorded during 5 days in the presence of pentagastrin was 1.83 (+/- 0.06). YF476 raised pH to 3.67 (+/- 0.09) and plasma ghrelin, gastrin, and somatostatin increased. YF476 increased gene expression of somatostatin receptor and gastrin, while ghrelin receptor decreased; transcripts coding ghrelin, somatostatin, and CCK-2R remained unchanged. In the presence of diclofenac, esomeprazole increased expression of all these transcripts and that of iNOS, while YF476 yielded only decreased CCK-2R and increased iNOS transcripts. YF476 is a potential new preventative treatment for patients at risk of nonsteroidal antiinflammatory drug (NSAID)-induced ulceration. Gastric gene expressions of ghrelin, gastrin, and somatostatin and their receptors differ between esomeprazole and YF476. Despite these differences and different modes of action to raise gastric pH, both drugs acutely increase iNOS, suggesting iNOS expression parallels pH.

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