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Sima, E., Webb, D.-L., Hellström, P. M. & Sundbom, M. (2019). Non-responders After Gastric Bypass Surgery for Morbid Obesity: Peptide Hormones and Glucose Homeostasis. Obesity Surgery, 29(12), 4008-4017
Open this publication in new window or tab >>Non-responders After Gastric Bypass Surgery for Morbid Obesity: Peptide Hormones and Glucose Homeostasis
2019 (English)In: Obesity Surgery, ISSN 0960-8923, E-ISSN 1708-0428, Vol. 29, no 12, p. 4008-4017Article in journal (Refereed) Published
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.

Keywords
Gastric bypass, Incretins, Leptin, Long-term results, Weight loss
National Category
Gastroenterology and Hepatology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-400343 (URN)10.1007/s11695-019-04089-8 (DOI)000504613300014 ()31338735 (PubMedID)
Funder
The Swedish Medical Association
Available from: 2019-12-19 Created: 2019-12-19 Last updated: 2020-01-09Bibliographically approved
Halim, A., Degerblad, M., Sundbom, M., Karlbom, U., Juul Holst, J., Webb, D.-L. & Hellström, P. M. (2018). Glucagon-like peptide-1 inhibits prandial gastrointestinal motility through myenteric neuronal mechanisms in humans. Journal of Clinical Endocrinology and Metabolism, 103(2), 575-585
Open this publication in new window or tab >>Glucagon-like peptide-1 inhibits prandial gastrointestinal motility through myenteric neuronal mechanisms in humans
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2018 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, no 2, p. 575-585Article in journal (Refereed) Published
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.

National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:uu:diva-334892 (URN)10.1210/jc.2017-02006 (DOI)000424937300025 ()29177486 (PubMedID)
Funder
Swedish Research Council, 7916The Karolinska Institutet's Research FoundationSwedish Society of MedicineSven Jerring Foundation
Available from: 2017-11-28 Created: 2017-11-28 Last updated: 2018-04-16Bibliographically approved
Al-Saffar, A. K., Halim, M. A., Hall, G., Hellström, P. M. & Webb, D.-L. (2018). Small intestinal lactulose and sucralose hyper-permeability in inflammatory bowel disease. Journal of Crohn's & Colitis, 12, S124-S124
Open this publication in new window or tab >>Small intestinal lactulose and sucralose hyper-permeability in inflammatory bowel disease
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2018 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 12, p. S124-S124Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2018
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:uu:diva-357062 (URN)000427318900189 ()
Available from: 2018-08-13 Created: 2018-08-13 Last updated: 2018-08-13Bibliographically approved
Webb, D.-L., Abrahamsson, N., Sundbom, M. & Hellström, P. M. (2017). Bariatric surgery - time to replace with GLP-1?. Scandinavian Journal of Gastroenterology, 52(6-7), 635-640
Open this publication in new window or tab >>Bariatric surgery - time to replace with GLP-1?
2017 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 52, no 6-7, p. 635-640Article, review/survey (Refereed) Published
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.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2017
Keywords
Gastric bypass, gastric emptying, glucagon-like peptides, glucose homeostasis, weight loss
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-328850 (URN)10.1080/00365521.2017.1293154 (DOI)000399808100004 ()28276830 (PubMedID)
Available from: 2017-09-01 Created: 2017-09-01 Last updated: 2017-09-01Bibliographically approved
Resendez, A., Halim, A., Singh, J., Webb, D.-L. & Singaram, B. (2017). Boronic acid recognition of non-interacting carbohydrates for biomedical applications: increasing fluorescence signals of minimally interacting aldoses and sucralose.. Organic and biomolecular chemistry, 15(45), 9727-9733
Open this publication in new window or tab >>Boronic acid recognition of non-interacting carbohydrates for biomedical applications: increasing fluorescence signals of minimally interacting aldoses and sucralose.
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2017 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 15, no 45, p. 9727-9733Article in journal (Refereed) Published
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.

Keywords
boron, permeability, sugar, biomarker
National Category
Medical and Health Sciences
Research subject
Molecular Medicine
Identifiers
urn:nbn:se:uu:diva-334434 (URN)10.1039/c7ob01893b (DOI)000415990300025 ()29130464 (PubMedID)
Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2018-02-23Bibliographically approved
Hellström, P. M., Al-Saffar, A. K., Tartera Diaz, H., Gannavarapu, V. R. & Webb, D.-L. (2017). Intestinal fatty acid binding protein parallels temporal changes in Harvey-Bradshaw Index and TNF alpha in response to infliximab in Crohn’s disease. Journal of Crohn's & Colitis, 11(suppl 1), S389-S389
Open this publication in new window or tab >>Intestinal fatty acid binding protein parallels temporal changes in Harvey-Bradshaw Index and TNF alpha in response to infliximab in Crohn’s disease
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2017 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 11, no suppl 1, p. S389-S389Article in journal (Refereed) Published
Keywords
i-FABP, gut permeability
National Category
Gastroenterology and Hepatology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-334297 (URN)10.1093/ecco-jcc/jjx002.730 (DOI)000398606901140 ()
Available from: 2017-11-22 Created: 2017-11-22 Last updated: 2019-02-21Bibliographically approved
Sima, E., Hellström, P. M., Webb, D.-L. & Sundbom, M. (2017). Non-Responders After Gastric Bypass: Hormone Response And Glucose Homeostasis During An Oral Glucose Tolerance Test. In: IFSO 2017 22nd World Congress: . Paper presented at IFSO 2017 22nd World Congress (International federation for the surgery of obesity and metabolic disorders), 29 August - 2 September 2017, London, UK (pp. 208-208). Springer, 27
Open this publication in new window or tab >>Non-Responders After Gastric Bypass: Hormone Response And Glucose Homeostasis During An Oral Glucose Tolerance Test
2017 (English)In: IFSO 2017 22nd World Congress, Springer, 2017, Vol. 27, p. 208-208Conference paper, Oral presentation with published abstract (Other academic)
Place, publisher, year, edition, pages
Springer, 2017
Series
Obesity Surgery, ISSN 0960-8923, E-ISSN 1708-0428
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-347528 (URN)
Conference
IFSO 2017 22nd World Congress (International federation for the surgery of obesity and metabolic disorders), 29 August - 2 September 2017, London, UK
Available from: 2018-04-04 Created: 2018-04-04 Last updated: 2018-04-04Bibliographically approved
Sima, E., Webb, D.-L., Hellström, P. M. & Sundbom, M. (2017). Non-Responders after Gastric Bypass Surgery for Morbid Obesity: Peptide Hormones and Glucose Homeostasis. In: : . Paper presented at ARCE 2017 the 9th Congress of The Romanian Association of Endoscopic Surgery (RAES) organized in conjunction with the 9th National Symposium of Bariatric and Metabolic Surgery (SBMS), 23 - 25 NOVEMBER 2017, Bucharest, Romania.
Open this publication in new window or tab >>Non-Responders after Gastric Bypass Surgery for Morbid Obesity: Peptide Hormones and Glucose Homeostasis
2017 (English)Conference paper, Oral presentation only (Other academic)
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-347527 (URN)
Conference
ARCE 2017 the 9th Congress of The Romanian Association of Endoscopic Surgery (RAES) organized in conjunction with the 9th National Symposium of Bariatric and Metabolic Surgery (SBMS), 23 - 25 NOVEMBER 2017, Bucharest, Romania
Available from: 2018-04-04 Created: 2018-04-04 Last updated: 2018-04-04Bibliographically approved
Al-Saffar, A., Meijer, C. H., Gannavarapu, V. R., Hall, G., Li, Y., Diaz Tartera, H. O., . . . Webb, D.-L. (2017). Parallel Changes in Harvey-Bradshaw Index, TNFα, and Intestinal Fatty Acid Binding Protein  in Response to Infliximab in Crohn’s Disease. Gastroenterology Research and Practice, 1-8, Article ID 1745918.
Open this publication in new window or tab >>Parallel Changes in Harvey-Bradshaw Index, TNFα, and Intestinal Fatty Acid Binding Protein  in Response to Infliximab in Crohn’s Disease
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2017 (English)In: Gastroenterology Research and Practice, ISSN 1687-6121, E-ISSN 1687-630X, p. 1-8, article id 1745918Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Egypt: Hindawi Publishing Corporation, 2017
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:uu:diva-334232 (URN)10.1155/2017/1745918 (DOI)000413557400001 ()
Funder
Swedish Research Council, 7916The Karolinska Institutet's Research FoundationThe Swedish Medical Association, SLS-411921; SLS-503131
Note

Title in WoS: Parallel Changes in Harvey-Bradshaw Index, TNF alpha, and Intestinal Fatty Acid Binding Protein in Response to Infliximab in Crohn's Disease

Available from: 2017-11-21 Created: 2017-11-21 Last updated: 2019-04-29Bibliographically approved
Hellström, P. M., Hendolin, P., Kaihovaara, P., Kronberg, L., Meierjohann, A., Millerhovf, A., . . . Salaspuro, M. (2017). 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 gastritis. Scandinavian Journal of Gastroenterology, 52(2), 230-237
Open this publication in new window or tab >>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 gastritis
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2017 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 52, no 2, p. 230-237Article in journal (Refereed) Published
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.

Keywords
Alcohol, carcinogenesis, ethanol, prophylaxis, stomach
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:uu:diva-316135 (URN)10.1080/00365521.2016.1249403 (DOI)000392488000020 ()27806647 (PubMedID)
Available from: 2017-03-03 Created: 2017-03-03 Last updated: 2017-11-29Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-6979-9194

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