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Holst JJ, Madsbad S, Bojsen-Møller KN, Dirksen C, Svane M. New Lessons from the gut: Studies of the role of gut peptides in weight loss and diabetes resolution after gastric bypass and sleeve gastrectomy. Peptides 2024; 176:171199. [PMID: 38552903 DOI: 10.1016/j.peptides.2024.171199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 03/18/2024] [Accepted: 03/22/2024] [Indexed: 04/05/2024]
Abstract
It has been known since 2005 that the secretion of several gut hormones changes radically after gastric bypass operations and, although more moderately, after sleeve gastrectomy but not after gastric banding. It has therefore been speculated that increased secretion of particularly GLP-1 and Peptide YY (PYY), which both inhibit appetite and food intake, may be involved in the weight loss effects of surgery and for improvements in glucose tolerance. Experiments involving inhibition of hormone secretion with somatostatin, blockade of their actions with antagonists, or blockade of hormone formation/activation support this notion. However, differences between results of bypass and sleeve operations indicate that distinct mechanisms may also be involved. Although the reductions in ghrelin secretion after sleeve gastrectomy would seem to provide an obvious explanation, experiments with restoration of ghrelin levels pointed towards effects on insulin secretion and glucose tolerance rather than on food intake. It seems clear that changes in GLP-1 secretion are important for insulin secretion after bypass and appear to be responsible for postbariatric hypoglycemia in glucose-tolerant individuals; however, with time the improvements in insulin sensitivity, which in turn are secondary to the weight loss, may be more important. Changes in bile acid metabolism do not seem to be of particular importance in humans.
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Affiliation(s)
- Jens Juul Holst
- The NovoNordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Denmark.
| | - Sten Madsbad
- Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Denmark
| | | | - Carsten Dirksen
- Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Denmark
| | - Maria Svane
- Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Denmark
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Hope DCD, Vincent ML, Tan TMM. Striking the Balance: GLP-1/Glucagon Co-Agonism as a Treatment Strategy for Obesity. Front Endocrinol (Lausanne) 2021; 12:735019. [PMID: 34566894 PMCID: PMC8457634 DOI: 10.3389/fendo.2021.735019] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 08/18/2021] [Indexed: 12/24/2022] Open
Abstract
Obesity and Type 2 diabetes represent global health challenges, and there is an unmet need for long-lasting and effective pharmacotherapies. Although long-acting glucagon-like peptide-1 (GLP-1) analogues are now in routine use for diabetes and are now being utilised for obesity per se, the need for ever better treatments has driven the development of co-agonists, with the theoretical advantages of improved efficacy by targeting multiple pathways and reduced adverse effects. In this review, we highlight the past and present progress in our understanding and development of treatments based on GLP-1/glucagon co-agonism. We also reflect on the divergent effects of varying the GLP-1:glucagon activity and ratio in the context of pre-clinical and human clinical trial findings. In particular, the multiple metabolic actions of glucagon highlight the importance of understanding the contributions of individual hormone action to inform the safe, effective and tailored use of GLP-1/glucagon co-agonists to target weight loss and metabolic disease in the future.
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Affiliation(s)
| | | | - Tricia M. M. Tan
- Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
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Schalla MA, Taché Y, Stengel A. Neuroendocrine Peptides of the Gut and Their Role in the Regulation of Food Intake. Compr Physiol 2021; 11:1679-1730. [PMID: 33792904 DOI: 10.1002/cphy.c200007] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The regulation of food intake encompasses complex interplays between the gut and the brain. Among them, the gastrointestinal tract releases different peptides that communicate the metabolic state to specific nuclei in the hindbrain and the hypothalamus. The present overview gives emphasis on seven peptides that are produced by and secreted from specialized enteroendocrine cells along the gastrointestinal tract in relation with the nutritional status. These established modulators of feeding are ghrelin and nesfatin-1 secreted from gastric X/A-like cells, cholecystokinin (CCK) secreted from duodenal I-cells, glucagon-like peptide 1 (GLP-1), oxyntomodulin, and peptide YY (PYY) secreted from intestinal L-cells and uroguanylin (UGN) released from enterochromaffin (EC) cells. © 2021 American Physiological Society. Compr Physiol 11:1679-1730, 2021.
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Affiliation(s)
- Martha A Schalla
- Charité Center for Internal Medicine and Dermatology, Department for Psychosomatic Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
| | - Yvette Taché
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, CURE: Digestive Diseases Research Center, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.,VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Andreas Stengel
- Charité Center for Internal Medicine and Dermatology, Department for Psychosomatic Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.,Department of Psychosomatic Medicine and Psychotherapy, Medical University Hospital Tübingen, Tübingen, Germany
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Holst JJ, Madsbad S, Bojsen-Møller KN, Svane MS, Jørgensen NB, Dirksen C, Martinussen C. Mechanisms in bariatric surgery: Gut hormones, diabetes resolution, and weight loss. Surg Obes Relat Dis 2018; 14:708-714. [PMID: 29776493 PMCID: PMC5974695 DOI: 10.1016/j.soard.2018.03.003] [Citation(s) in RCA: 141] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Accepted: 03/04/2018] [Indexed: 12/11/2022]
Abstract
Gastric bypass surgery leads to profound changes in the secretion of gut hormones with effects on metabolism, appetite, and food intake. Here, we discuss their contributions to the improvement in glucose tolerance and the weight loss that results from the operations. We find that the improved glucose tolerance is due the following events: a negative energy balance and resulting weight loss, which improve first hepatic and later peripheral insulin sensitivity, in combination with increased postprandial insulin secretion elicited particularly by exaggerated glucagon-like peptide-1 responses. The weight loss is due to loss of appetite resulting in reduced energy intake, and we find it probable that this process is driven by exaggerated secretion of appetite-regulating gut hormones including, but probably not limited to, glucagon-like peptide-1 and peptide-YY. The increased secretion is due to an accelerated exposure to and absorption of nutrients in the small intestine. This places the weight loss and the gut hormones in key positions with respect to the metabolic improvements after bypass surgery.
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Affiliation(s)
- Jens Juul Holst
- NNF Center for Basic Metabolic Research and Dept. Biomedical Sciences, the Panum Institute, University of Copenhagen, Copenhagen, Denmark.
| | - Sten Madsbad
- NNF Center for Basic Metabolic Research and Dept. Biomedical Sciences, the Panum Institute, University of Copenhagen, Copenhagen, Denmark; Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Kirstine N Bojsen-Møller
- NNF Center for Basic Metabolic Research and Dept. Biomedical Sciences, the Panum Institute, University of Copenhagen, Copenhagen, Denmark; Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Maria Saur Svane
- NNF Center for Basic Metabolic Research and Dept. Biomedical Sciences, the Panum Institute, University of Copenhagen, Copenhagen, Denmark; Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Nils Bruun Jørgensen
- NNF Center for Basic Metabolic Research and Dept. Biomedical Sciences, the Panum Institute, University of Copenhagen, Copenhagen, Denmark; Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Carsten Dirksen
- NNF Center for Basic Metabolic Research and Dept. Biomedical Sciences, the Panum Institute, University of Copenhagen, Copenhagen, Denmark; Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Christoffer Martinussen
- NNF Center for Basic Metabolic Research and Dept. Biomedical Sciences, the Panum Institute, University of Copenhagen, Copenhagen, Denmark; Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
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Anandhakrishnan A, Korbonits M. Glucagon-like peptide 1 in the pathophysiology and pharmacotherapy of clinical obesity. World J Diabetes 2016; 7:572-598. [PMID: 28031776 PMCID: PMC5155232 DOI: 10.4239/wjd.v7.i20.572] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 09/26/2016] [Accepted: 10/18/2016] [Indexed: 02/05/2023] Open
Abstract
Though the pathophysiology of clinical obesity is undoubtedly multifaceted, several lines of clinical evidence implicate an important functional role for glucagon-like peptide 1 (GLP-1) signalling. Clinical studies assessing GLP-1 responses in normal weight and obese subjects suggest that weight gain may induce functional deficits in GLP-1 signalling that facilitates maintenance of the obesity phenotype. In addition, genetic studies implicate a possible role for altered GLP-1 signalling as a risk factor towards the development of obesity. As reductions in functional GLP-1 signalling seem to play a role in clinical obesity, the pharmacological replenishment seems a promising target for the medical management of obesity in clinical practice. GLP-1 analogue liraglutide at a high dose (3 mg/d) has shown promising results in achieving and maintaining greater weight loss in obese individuals compared to placebo control, and currently licensed anti-obesity medications. Generally well tolerated, provided that longer-term data in clinical practice supports the currently available evidence of superior short- and long-term weight loss efficacy, GLP-1 analogues provide promise towards achieving the successful, sustainable medical management of obesity that remains as yet, an unmet clinical need.
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Holst JJ, Madsbad S. Mechanisms of surgical control of type 2 diabetes: GLP-1 is key factor. Surg Obes Relat Dis 2016; 12:1236-42. [PMID: 27313194 DOI: 10.1016/j.soard.2016.02.033] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Accepted: 02/23/2016] [Indexed: 01/07/2023]
Abstract
GLP-1 secretion in response to meals is dramatically increased after gastric bypass operations. GLP-1 is a powerful insulinotropic and anorectic hormone, and analogs of GLP-1 are widely used for the treatment of diabetes and recently approved also for obesity treatment. It is, therefore, reasonable to assume that the exaggerated GLP-1 secretion contributes to the antidiabetic and anorectic effects of gastric bypass. Indeed, human experiments with the GLP-1 receptor antagonist, Exendin 9-39, have shown that the improved insulin secretion, which is responsible for part of the antidiabetic effect of the operation, is reduced and or abolished after GLP-1 receptor blockade. Also the postoperative improvement of glucose tolerance is eliminated and or reduced by the antagonist, pointing to a key role for the exaggerated GLP-1 secretion. Indeed, there is evidence that the exaggerated GLP-1 secretion is also responsible for postprandial hypoglycemia sometimes observed after bypass. Other operations (biliopancreatic-diversion and or sleeve gastrectomy) appear to involve different and/or additional mechanisms, and so does experimental bariatric surgery in rodents. However, unlike bypass surgery in humans, the rodent operations are generally associated with increased energy metabolism pointing to an entirely different mechanism of action in the animals.
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Affiliation(s)
- Jens Juul Holst
- NNF Center for Basic Metabolic Research and Department of Biomedical Research, the Panum Institute, Copenhagen, Denmark.
| | - Sten Madsbad
- Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
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Lutz TA, Bueter M. The physiology underlying Roux-en-Y gastric bypass: a status report. Am J Physiol Regul Integr Comp Physiol 2014; 307:R1275-91. [PMID: 25253084 DOI: 10.1152/ajpregu.00185.2014] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Obesity and its related comorbidities can be detrimental for the affected individual and challenge public health systems worldwide. Currently, the only available treatment options leading to clinically significant and maintained body weight loss and reduction in obesity-related morbidity and mortality are based on surgical interventions. This review will focus on two main clinical effects of Roux-en-Y gastric bypass (RYGB), namely body weight loss and change in eating behavior. Animal experiments designed to understand the underlying physiological mechanisms of these post-gastric bypass effects will be discussed. Where appropriate, reference will also be made to vertical sleeve gastrectomy. While caloric malabsorption and mechanical restriction seem not to be major factors in this respect, alterations in gut hormone levels are invariably found after RYGB. However, their causal role in RYGB effects on eating and body weight has recently been challenged. Other potential factors contributing to the RYGB effects include increased bile acid concentrations and an altered composition of gut microbiota. RYGB is further associated with remarkable changes in preference for different dietary components, such as a decrease in the preference for high fat or sugar. It needs to be noted, however, that in many cases, the question about the necessity of these alterations for the success of bariatric surgery procedures remains unanswered.
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Affiliation(s)
- Thomas A Lutz
- Institute of Veterinary Physiology, Vetsuisse Faculty University of Zurich, Zurich, Switzerland; Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland; Institute of Laboratory Animal Science, University of Zurich, Zurich, Switzerland; and
| | - Marco Bueter
- Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland; Department of Surgery, Division of Visceral and Transplantation Surgery, University Hospital Zurich, Zurich, Switzerland
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Abstract
Oxyntomodulin (OXM) is a peptide hormone released from the gut in post-prandial state that activates both the glucagon-like peptide-1 receptor (GLP1R) and the glucagon receptor (GCGR) resulting in superior body weight lowering to selective GLP1R agonists. OXM reduces food intake and increases energy expenditure in humans. While activation of the GCGR increases glucose production posing a hyperglycemic risk, the simultaneous activation of the GLP1R counteracts this effect. Acute OXM infusion improves glucose tolerance in T2DM patients making dual agonists of the GCGR and GLP1R new promising treatments for diabetes and obesity with the potential for weight loss and glucose lowering superior to that of GLP1R agonists.
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Affiliation(s)
- Alessandro Pocai
- Janssen Research and Devolopment, Cardiovascular and Metabolic Disease, 1516 Welsh and McKean Roads, Spring House, PA 19477, USA
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Hansen CF, Bueter M, Theis N, Lutz T, Paulsen S, Dalbøge LS, Vrang N, Jelsing J. Hypertrophy dependent doubling of L-cells in Roux-en-Y gastric bypass operated rats. PLoS One 2013; 8:e65696. [PMID: 23776529 PMCID: PMC3679162 DOI: 10.1371/journal.pone.0065696] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Accepted: 04/29/2013] [Indexed: 12/31/2022] Open
Abstract
Background and Aims Roux-en-Y gastric bypass (RYGB) leads to a rapid remission of type 2 diabetes mellitus (T2DM), but the underlying mode of action remains incompletely understood. L-cell derived gut hormones such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are thought to play a central role in the anti-diabetic effects of RYGB; therefore, an improved understanding of intestinal endocrine L-cell adaptability is considered pivotal. Methods The full rostrocaudal extension of the gut was analyzed in rats after RYGB and in sham-operated controls ad libitum fed or food restricted to match the body weight of RYGB rats. Total number of L-cells, as well as regional numbers, densities and mucosa volumes were quantified using stereological methods. Preproglucagon and PYY mRNA transcripts were quantified by qPCR to reflect the total and relative hormone production capacity of the L-cells. Results RYGB surgery induced hypertrophy of the gut mucosa in the food exposed regions of the small intestine coupled with a doubling in the total number of L-cells. No changes in L-cell density were observed in any region regardless of surgery or food restriction. The total gene expression capacity of the entire gut revealed a near 200% increase in both PYY and preproglucagon mRNA levels in RYGB rats associated with both increased L-cell number as well as region-specific increased transcription per cell. Conclusions Collectively, these findings indicate that RYGB in rats is associated with gut hypertrophy, an increase in L-cell number, but not density, and increased PYY and preproglucagon gene expression. This could explain the enhanced gut hormone dynamics seen after RYGB.
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Affiliation(s)
- Carl Frederik Hansen
- Department of Histology, Gubra, Hørsholm, Denmark
- Department of Human Nutrition, University of Copenhagen, Frederiksberg, Denmark
| | - Marco Bueter
- Department of Visceral and Transplant Surgery, University Hospital Zurich, Zurich, Switzerland
- Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Nadine Theis
- Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Thomas Lutz
- Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland
- Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | | | | | - Niels Vrang
- Department of Histology, Gubra, Hørsholm, Denmark
| | - Jacob Jelsing
- Department of Histology, Gubra, Hørsholm, Denmark
- * E-mail:
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Abstract
Oxyntomodulin (OXM) is a peptide secreted from the L cells of the gut following nutrient ingestion. OXM is a dual agonist of the glucagon-like peptide-1 receptor (GLP1R) and the glucagon receptor (GCGR) combining the effects of GLP1 and glucagon to act as a potentially more effective treatment for obesity than GLP1R agonists. Injections of OXM in humans cause a significant reduction in weight and appetite, as well as an increase in energy expenditure. Activation of GCGR is classically associated with an elevation in glucose levels, which would be deleterious in patients with T2DM, but the antidiabetic properties of GLP1R agonism would be expected to counteract this effect. Indeed, OXM administration improved glucose tolerance in diet-induced obese mice. Thus, dual agonists of the GCGR and GLP1R represent a new therapeutic approach for diabetes and obesity with the potential for enhanced weight loss and improvement in glycemic control beyond those of GLP1R agonists.
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Affiliation(s)
- Alessandro Pocai
- Diabetes and Endocrinology, Merck Research Laboratories, Merck Sharp and Dohme Corp., Rahway, New Jersey 07065, USA.
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Aicher TD, Boyd SA, McVean M, Celeste A. Novel therapeutics and targets for the treatment of diabetes. Expert Rev Clin Pharmacol 2012; 3:209-29. [PMID: 22111568 DOI: 10.1586/ecp.10.1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The microvascular complications of insufficiently controlled diabetes (neuropathy, retinopathy and nephropathy) and the marked increased risk of macrovascular events (e.g., stroke and myocardial infarction) have a dire impact on society in both human and economic terms. In Type 1 diabetes total β-cell loss occurs. In Type 2 diabetes, partial β-cell loss occurs before diagnosis, and the progressive β-cell loss during the life of the patient increases the severity of the disease. In patients with diabetes, increased insulin resistance in the muscle and liver are key pathophysiologic defects. In addition, defects in metabolic processes in the fat, GI tract, brain, pancreatic α-cells and kidney are detrimental to the overall health of the patient. This review addresses novel therapies for these deficiencies in clinical and preclinical evaluation, emphasizing their potential to address glucose homeostasis, β-cell mass and function, and the comorbidities of cardiovascular disease and obesity.
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Affiliation(s)
- Thomas D Aicher
- Principal Research Investigator, Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA.
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Torekov SS, Madsbad S, Holst JJ. Obesity - an indication for GLP-1 treatment? Obesity pathophysiology and GLP-1 treatment potential. Obes Rev 2011; 12:593-601. [PMID: 21401851 DOI: 10.1111/j.1467-789x.2011.00860.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Obesity is common and associated with a high rate of morbidity and mortality; therefore, treatment is of great interest. At present, bariatric surgery is the only truly successful treatment of severe obesity. Mimicking one of the effects of bariatric surgery, namely the increased secretion of glucagon-like peptide (GLP)-1, by artificially increasing the levels of GLP-1 might prove successful as obesity treatment. Recent studies have shown that GLP-1 is a physiological regulator of appetite and food intake. The effect on food intake and satiety is preserved in obese subjects and GLP-1 may therefore have a therapeutic potential. The GLP-1 analogues result in a moderate average weight loss, which is clinically relevant in relation to reducing the risk of type 2 diabetes and cardiovascular disease. Inspired by the hormone profile after gastric bypass, a future strategy in obesity drug development could be to combine several hormones, and thereby produce a superior appetite suppressing hormone profile that may result in a weight loss exceeding that seen in single-agent trials. In conclusion, with the GLP-1 analogues combining a moderate weight loss with beneficial effects on metabolic and cardiovascular risk factors, it seems that we are on the right track for future treatment of obesity.
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Affiliation(s)
- S S Torekov
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
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Abstract
The rising prevalence of obesity has reached pandemic proportions, with an associated cost estimated at up to 7% of health expenditures worldwide. Bariatric surgery is currently the only effective long-term treatment for obesity and obesity-related co-morbidities in clinically severely obese patients. However, the precise physiological mechanisms underlying the postsurgical reductions in caloric intake and body weight are poorly comprehended. It has been suggested that changes in hormones involved in hunger, food intake and satiety via the neurohormonal network may contribute to the efficacy of bariatric procedures. In this review, we consider how gastrointestinal hormone concentrations, involved in appetite and body weight regulation via the gut-brain axis, are altered by different bariatric procedures. Special emphasis is placed on neurohormonal changes following Roux-en-Y gastric bypass surgery, which is the most common and effective procedure used today.
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Affiliation(s)
- C N Ochner
- New York Obesity Research Center, Department of Medicine, St Luke's-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, NY 10025, USA.
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Liu YL, Ford HE, Druce MR, Minnion JS, Field BCT, Shillito JC, Baxter J, Murphy KG, Ghatei MA, Bloom SR. Subcutaneous oxyntomodulin analogue administration reduces body weight in lean and obese rodents. Int J Obes (Lond) 2010; 34:1715-25. [PMID: 20531351 DOI: 10.1038/ijo.2010.110] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
OBJECTIVE To determine the efficacy of a long-acting oxyntomodulin (OXM) analogue, OXM6421, in inhibiting food intake and decreasing body weight in lean and diet-induced obese (DIO) rodents. RESEARCH DESIGN AND METHODS The glucagon-like peptide-1 (GLP-1) receptor binding affinity and efficacy, sensitivity to enzymatic degradation in vitro and persistence in the circulation after peripheral administration were investigated for OXM6421 and compared with native OXM. The chronic effect of OXM6421 on food intake, body weight and energy expenditure was examined in lean rats, and its anti-obesity potential was evaluated in DIO mice. RESULTS OXM6421 showed enhanced GLP-1 receptor binding affinity and cyclic adenosine monophosphate (cAMP) stimulation, and higher resistance to enzymatic degradation by dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidase (NEP) compared with native OXM. OXM6421 persisted longer in the circulation than OXM after peripheral administration. Acute administration of OXM6421 potently inhibited food intake in lean rodents, with cumulative effects lasting up to 24 h. In lean rats, daily subcutaneous (s.c.) administration of OXM6421 caused greater weight loss than the pair-fed animals, and a higher rate of oxygen consumption than both the pair-fed and the saline controls. In DIO mice, continuous s.c. infusion of OXM6421 resulted in a significant weight loss, accompanied by an improvement in glucose homeostasis and an increase in circulating adiponectin levels. Once-daily s.c. administration of OXM6421 for 21 days caused sustained weight loss in DIO mice. CONCLUSION OXM6421 induces negative energy balance in both lean and obese rodents, suggesting that long-acting OXM analogues may represent a potential therapy for obesity.
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Affiliation(s)
- Y-L Liu
- Department of Investigative Medicine, Imperial College Faculty of Medicine, Hammersmith Hospital, London, UK
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Dirksen C, Hansen DL, Madsbad S, Hvolris LE, Naver LS, Holst JJ, Worm D. Postprandial diabetic glucose tolerance is normalized by gastric bypass feeding as opposed to gastric feeding and is associated with exaggerated GLP-1 secretion: a case report. Diabetes Care 2010; 33:375-7. [PMID: 19918005 PMCID: PMC2809286 DOI: 10.2337/dc09-1374] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To examine after gastric bypass the effect of peroral versus gastroduodenal feeding on glucose metabolism. RESEARCH DESIGN AND METHODS A type 2 diabetic patient was examined on 2 consecutive days 5 weeks after gastric bypass. A standard liquid meal was given on the first day into the bypassed gastric remnant and on the second day perorally. Plasma glucose, insulin, C-peptide, glucagon, incretin hormones, peptide YY, and free fatty acids were measured. RESULTS Peroral feeding reduced 2-h postprandial plasma glucose (7.8 vs. 11.1 mmol/l) and incremental area under the glucose curve (iAUC) (0.33 vs. 0.49 mmol . l(-1) . min(-1)) compared with gastroduodenal feeding. beta-Cell function (iAUC(Cpeptide/Glu)) was more than twofold improved during peroral feeding, and the glucagon-like peptide (GLP)-1 response increased nearly fivefold. CONCLUSIONS Improvement in postprandial glucose metabolism after gastric bypass is an immediate and direct consequence of the gastrointestinal rearrangement, associated with exaggerated GLP-1 release and independent of changes in insulin sensitivity, weight loss, and caloric restriction.
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Affiliation(s)
- Carsten Dirksen
- Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark.
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Guldstrand M, Ahrén B, Näslund E, Holst JJ, Adamson U. Dissociated incretin response to oral glucose at 1 year after restrictive vs. malabsorptive bariatric surgery. Diabetes Obes Metab 2009; 11:1027-33. [PMID: 19614945 DOI: 10.1111/j.1463-1326.2009.01089.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
AIM Compare the response to oral glucose of the two incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) at 1 year after restrictive vs. malabsorptive bariatric surgery. METHODS Vertical banded gastroplasty (VBG, n = 7) or jejunoileal bypass (JIB, n = 5) was performed in 12 women, aged 26-39 years, with severe obesity [body mass index (BMI) 46.6 +/- 2.3 kg/m(2)]. After 1 year, 75 g glucose was administered and plasma levels of glucose, insulin, GIP and GLP-1 were determined regularly during the following 2 h. RESULTS At 1 year after operation, reduction in body weight, actual body weight, fasting glucose or insulin, or the glucose and insulin responses to oral glucose did not differ significantly between the groups. Similarly, fasting GIP and GLP-1 levels did not differ significantly between the groups. In contrast, the GIP and GLP-1 responses to oral glucose were different between the groups in a dissociated pattern. Thus, AUC(GIP) was significantly higher after VBG than after JIB (53 +/- 8 vs. 26 +/- 6 pmol/l/min, p = 0.003). In contrast, AUC(GLP-1) was significantly higher after JIB than after VBG (49 +/- 5 vs. 20 +/- 3 pmol/l/min, p = 0.007). CONCLUSIONS We conclude that at 1 year after bariatric surgery, the two incretins show dissociated responses in that the GIP secretion is higher after VBG whereas GLP-1 secretion is higher after JIB. This dissociated incretin response is independent from reduction in body weight, glucose tolerance or insulin secretion.
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Affiliation(s)
- M Guldstrand
- Division of Internal Medicine, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
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18
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Abstract
Desde o descobrimento da leptina, avanços consideráveis foram obtidos na caracterização dos mecanismos hipotalâmicos do controle da ingestão alimentar e, atualmente, a oxintomodulina é reconhecida como um regulador da homeostase energética. O presente artigo de revisão enfoca algumas das mais relevantes inter-relações do hormônio oxintomodulina com o apetite, a homeostase energética e aspectos de seu papel na bioquímica e fisiologia nutricional. A oxintomodulina é um peptídeo intestinal anorexígeno produzido pelas células L do intestino. Recentes estudos têm demonstrado que em longo prazo a administração de oxintomodulina reduz a ingestão alimentar e o ganho de peso. Pesquisas em humanos têm verificado que o seu uso reduz o consumo energértico em 25%. Portanto, a oxintomodulina representa uma potente terapia anti-obesidade. Entretanto, o mecanismo de ação da oxintomodulina ainda é desconhecido. Atuais evidências sugerem que tem ação via receptor do peptídeo semelhante ao glucagon 1. Além disso, a literatura mostra que, juntamente com a adoção de hábitos saudáveis e a mudança do estilo de vida, a oxintomodulina pode proporcionar menor avanço da obesidade.
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Ashrafian H, le Roux CW. Metabolic surgery and gut hormones - a review of bariatric entero-humoral modulation. Physiol Behav 2009; 97:620-31. [PMID: 19303889 DOI: 10.1016/j.physbeh.2009.03.012] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2009] [Revised: 03/11/2009] [Accepted: 03/12/2009] [Indexed: 12/12/2022]
Abstract
The global pandemic of obesity is increasing. Inappropriate food intake relative to energy expenditure results in increased adiposity. These factors are partly regulated by signals through the gut-brain and adipose-brain axes. Metabolic operations (otherwise known as Bariatric surgery) offer the most effective results for sustained metabolic improvement and weight loss. They modulate a number of gut hormones that constitute the gut-brain axis. This review summarizes the literature to-date reporting the gut hormone changes associated with these operations and their subsequent effects on appetite. Understanding the anatomical differences between each operation and how these can differentially regulate gut hormonal release can provide new treatments and targets for obesity, appetite and metabolic disorders.
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Affiliation(s)
- Hutan Ashrafian
- Department of Biosurgery and Surgical Technology, Imperial College London, UK
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20
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Abstract
A critical role for the gut in energy homeostasis has emerged. Gut hormones not only have a role in digestion but several of them have been found to modulate appetite in animals and humans. Current nonendocrine drugs for obesity are limited by their modest efficacies, and bariatric surgery is confined to use in severe cases. The discovery of important appetite-signaling pathways from the gut to the brain has led to the emergence of several gut hormone-derived drugs that are being investigated for clinical use. This article summarizes the physiology of the major gut hormones implicated in appetite regulation, and reviews clinical evidence that gives us insight into their potential as clinical treatments for obesity.
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Affiliation(s)
- Channa N Jayasena
- Department of Investigative Medicine, Imperial College London, Hammersmith Hospital, 6th Floor, Commonwealth Building, Du Cane Road, W12 0NN, London, UK
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21
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Abstract
Bariatric surgery is one of the most effective treatments for achieving long-term weight loss in morbidly obese patients. Bariatric surgery causes weight loss through substantial decline of hunger and increased satiety. Recently our understanding of neuroendocrine regulation of food intake and weight gain, especially regarding the role of gut hormones, has significantly increased. The changes in these hormones following bariatric surgery can partly explain the mechanism behind weight loss achieved through these procedures. In this paper, we review the effect bariatric procedures have on different gut hormone levels and how they in turn can alter the complex neuroendocrine regulation of energy homeostasis.
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Affiliation(s)
- R P Vincent
- Department of Chemical Pathology, King's College Hospital, London, UK
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22
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Abstract
The increasing prevalence of obesity and the associated morbidity and mortality has resulted in a major research effort to identify mechanisms that regulate appetite. It is well established that the hypothalamus and brain stem are major sites in the central nervous system (CNS) that regulate appetite. Until recently the missing element has been how information regarding food intake and energy stores is communicated to the CNS. Gut hormones have recently been found to be an important element in this regulation, communicating information regarding food intake to the CNS. Several gut hormones have been found to exert anorectic effects. These include members of the Pancreatic Polypeptide (PP)-fold family, namely PP itself and also peptide tyrosine-tyrosine (PYY), the first gut hormone shown to have appetite-inhibiting properties. The other main class of anorectic gut hormones are those derived by proteolytic processing from proglucagon, most importantly glucagon-like peptide-1 (GLP-1) and oxyntomodulin. All of these are currently being investigated as the basis of treatments to prevent the development of obesity. So far the only gastrointestinal hormone demonstrated to stimulate appetite is ghrelin. Potential sites and mechanisms of action and therapeutic use of these gastrointestinal hormones are discussed.
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Affiliation(s)
- J V Gardiner
- Department of Investigative Medicine, Imperial College Faculty of Medicine, Hammersmith Hospital, Imperial College, London, UK
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23
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Abstract
Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in these cells. The current knowledge regarding regulation of proglucagon gene expression in the gut and in the brain and mechanisms responsible for the posttranslational processing are reviewed. GLP-1 is released in response to meal intake, and the stimuli and molecular mechanisms involved are discussed. GLP-1 is extremely rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone has left the gut, raising the possibility that the actions of GLP-1 are transmitted via sensory neurons in the intestine and the liver expressing the GLP-1 receptor. Because of this, it is important to distinguish between measurements of the intact hormone (responsible for endocrine actions) or the sum of the intact hormone and its metabolites, reflecting the total L-cell secretion and therefore also the possible neural actions. The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the "ileal brake" mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these actions, GLP-1 or GLP-1 receptor agonists are currently being evaluated for the therapy of type 2 diabetes. Decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia.
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Affiliation(s)
- Jens Juul Holst
- Department of Medical Physiology, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
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24
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Korner J, Bessler M, Inabnet W, Taveras C, Holst JJ. Exaggerated glucagon-like peptide-1 and blunted glucose-dependent insulinotropic peptide secretion are associated with Roux-en-Y gastric bypass but not adjustable gastric banding. Surg Obes Relat Dis 2007; 3:597-601. [PMID: 17936091 PMCID: PMC2134840 DOI: 10.1016/j.soard.2007.08.004] [Citation(s) in RCA: 277] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2007] [Revised: 07/11/2007] [Accepted: 08/05/2007] [Indexed: 12/15/2022]
Abstract
BACKGROUND The aim of this study was to measure the circulating levels of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon in patients who had undergone adjustable gastric banding (BND) or Roux-en-Y gastric bypass (RYGB) to understand the differences in glucose and insulin regulation after these procedures. METHODS This was a cross-sectional study of 3 groups of women matched for age and body mass index: group 1, overweight controls (n = 13); group 2, BND (n = 10); and group 3, RYGB (n = 13). Venous blood was drawn with the patient in the fasted state and throughout a 3-hour period after a liquid meal. RESULTS The fasting glucose level was similar between the 2 surgery groups; however, the fasting insulin concentrations were greater in the BND (10.0 microU/mL) than in the RYGB (6.2 microU/mL; P <0.05) group. The glucose level at 60 minutes was significantly lower in the RYGB group (70 mg/dL, range 38-82) than in the BND group (83 mg/dL, range 63-98). The GLP-1 levels at 30 minutes were more than threefold greater in the RYGB group (96 pmol/L) compared with the BND and overweight control (28 pmol/L) groups. The GLP-1 and insulin concentrations correlated at 30 minutes only in the RYGB group (r = .66; P = .013). The glucose-dependent insulinotropic peptide levels at 30 minutes were lower in the RYGB group (20 pmol/L) than in the BND group (31 pmol/L) or overweight control group (33 pmol/L). The peak glucagon levels were similar among the 3 groups. CONCLUSION Exaggerated postprandial GLP-1 and blunted glucose-dependent insulinotropic peptide secretion after RYGB might contribute to the greater weight loss and improved glucose homeostasis compared with BND.
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Affiliation(s)
- Judith Korner
- Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
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25
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Wynne K, Bloom SR. The role of oxyntomodulin and peptide tyrosine-tyrosine (PYY) in appetite control. ACTA ACUST UNITED AC 2007; 2:612-20. [PMID: 17082808 DOI: 10.1038/ncpendmet0318] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2006] [Accepted: 06/12/2006] [Indexed: 01/10/2023]
Abstract
Oxyntomodulin and peptide tyrosine-tyrosine (PYY) are released from intestinal enteroendocrine cells in response to a meal. These circulating hormones are considered to be satiety signals, as they have been found to decrease food intake, body weight and adiposity in rodents. Their effect on energy homeostasis is mediated by the hypothalamus and brainstem, and several studies have demonstrated alterations in neuropeptide signaling within the arcuate nucleus. The weight loss that has been observed in animal models after repeated administration of oxyntomodulin and PYY has led to interest in developing these peptides as antiobesity therapies in humans. Indeed, preliminary studies have found that oxyntomodulin or PYY administration reduces food intake and body weight effectively in overweight human volunteers. This research suggests that modulation of these gut hormones could prove to be effective long-term therapies in the quest to combat the obesity epidemic.
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Affiliation(s)
- Katie Wynne
- Department of Metabolic Medicine, Imperial College London, and Hammersmith Hospital, UK
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26
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Abstract
The role of gastrointestinal hormones in the regulation of appetite is reviewed. The gastrointestinal tract is the largest endocrine organ in the body. Gut hormones function to optimize the process of digestion and absorption of nutrients by the gut. In this capacity, their local effects on gastrointestinal motility and secretion have been well characterized. By altering the rate at which nutrients are delivered to compartments of the alimentary canal, the control of food intake arguably constitutes another point at which intervention may promote efficient digestion and nutrient uptake. In recent decades, gut hormones have come to occupy a central place in the complex neuroendocrine interactions that underlie the regulation of energy balance. Many gut peptides have been shown to influence energy intake. The most well studied in this regard are cholecystokinin (CCK), pancreatic polypeptide, peptide YY, glucagon-like peptide-1 (GLP-1), oxyntomodulin and ghrelin. With the exception of ghrelin, these hormones act to increase satiety and decrease food intake. The mechanisms by which gut hormones modify feeding are the subject of ongoing investigation. Local effects such as the inhibition of gastric emptying might contribute to the decrease in energy intake. Activation of mechanoreceptors as a result of gastric distension may inhibit further food intake via neural reflex arcs. Circulating gut hormones have also been shown to act directly on neurons in hypothalamic and brainstem centres of appetite control. The median eminence and area postrema are characterized by a deficiency of the blood-brain barrier. Some investigators argue that this renders neighbouring structures, such as the arcuate nucleus of the hypothalamus and the nucleus of the tractus solitarius in the brainstem, susceptible to influence by circulating factors. Extensive reciprocal connections exist between these areas and the hypothalamic paraventricular nucleus and other energy-regulating centres of the central nervous system. In this way, hormonal signals from the gut may be translated into the subjective sensation of satiety. Moreover, the importance of the brain-gut axis in the control of food intake is reflected in the dual role exhibited by many gut peptides as both hormones and neurotransmitters. Peptides such as CCK and GLP-1 are expressed in neurons projecting both into and out of areas of the central nervous system critical to energy balance. The global increase in the incidence of obesity and the associated burden of morbidity has imparted greater urgency to understanding the processes of appetite control. Appetite regulation offers an integrated model of a brain-gut axis comprising both endocrine and neurological systems. As physiological mediators of satiety, gut hormones offer an attractive therapeutic target in the treatment of obesity.
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Affiliation(s)
| | | | - Steve Bloom
- Department of Metabolic Medicine, Imperial College Faculty of MedicineHammersmith Hospital, Du Cane Road, London W12 ONN, UK
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27
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Abstract
There is a growing worldwide epidemic of obesity. Obese people have a higher incidence of type 2 diabetes and cardiovascular disease, and hence present increasing social, financial and health burdens. Weight loss is always difficult to achieve through lifestyle changes alone, and currently licensed anti-obesity drug treatments, such as orlistat and sibutramine, if tolerated, only achieve modest weight loss. Therefore, there is a need to identify more potent pharmacological targets. In the last 10 years, discoveries of new hormones such as leptin and ghrelin, together with greater understanding of previously described hormones such as cholecystokinin (CCK), pancreatic polypeptide (PP), peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), have led to a rapid increase in our knowledge of the regulation of energy balance. Among the most important factors, controlling appetite and satiety are peptide hormones released from the gut. In this paper, we provide a full up-to-date overview of the current state of knowledge of this field, together with the potential of these peptides as drugs, or as other therapeutic targets, in the treatment of obesity. Finally, we propose an integrated model to describe the complex interplay of these hormones in the broader physiology of energy balance.
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Affiliation(s)
- M S B Huda
- Diabetes and Endocrinology Research Group, University Hospital Aintree, Longmoor Lane, Liverpool, UK.
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28
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29
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Abstract
The prevalence of obesity is increasing rapidly and the associated morbidity and mortality has led to an urgent need for potential therapeutic targets to reduce appetite and food intake. Gut hormones released after eating that coordinate digestive activity and promote satiety are novel potential treatments for obesity. Oxyntomodulin is a gut hormone that is produced by the L cells in the small intestine and reduces food intake. It is timely to review some of the original literature on oxyntomodulin, to evaluate what is already known about the peptide, and also to set the recent findings on its effects on food intake and bodyweight into context.Recent studies have shown that long-term peripheral administration of oxyntomodulin to rats leads to reduced food intake and reduced weight gain. Studies in humans have demonstrated that acute administration reduces food intake by 19%. When given preprandially by subcutaneous injection three times daily, oxyntomodulin resulted in a reduction in food intake and mean weight loss of 2.8kg over 4 weeks. Oxyntomodulin thus represents a potential therapy for obesity.The mechanism of action of oxyntomodulin is not known. Current evidence suggests that it acts via the glucagon-like peptide 1 (GLP-1) receptor. There may be an additional receptor in the gastric mucosa mediating its effects on gastric acid secretion. Although oxyntomodulin probably acts via the GLP-1 receptor, the two peptides differentially regulate food intake and energy expenditure in the mouse.Oxyntomodulin represents a potential therapy for obesity. Further work will help to clarify its mechanisms of action.
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Affiliation(s)
- Maralyn R Druce
- Department of Metabolic Medicine, Hammersmith Hospital, Imperial College London, London, UK
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30
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Abstract
Short bowel syndrome occurs when there is insufficient length of the small intestine to maintain adequate nutrition and/or hydration status without supplemental support. This syndrome most frequently occurs following extensive surgical resection of the intestine, and the extent of adaptation depends on the anatomy of the resected bowel and the amount of bowel remaining. Following resection, the intestinal tissue undergoes morphologic and functional changes to compensate for the lost function of the resected bowel. These changes are mediated by multiple interactive factors, including intraluminal and parenteral nutrients, gastrointestinal secretions, hormones, cytokines, and growth factors, many of which have been well characterized in animal models. The amount of small bowel remaining is the most important predictor of adaptive potential; neither structural nor functional adaptative changes have been demonstrated in humans or animal models with more extreme resections resulting in an end-jejunostomy. The current understanding of these processes has led to the recent use of supplemental hormones, such as growth hormone and glucagon-like peptide 2, in intestinal rehabilitation programs and may lead to the development of pharmacologic agents designed to augment the innate adaptive response.
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Affiliation(s)
- Jason J Cisler
- Division of Gastroenterology, Feinburg School of Medicine, Northwestern University, Chicago, IL, USA
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31
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Abstract
Our knowledge of the physiological systems controlling energy homeostasis has increased dramatically over the last decade. The roles of peripheral signals from adipose tissue, pancreas, and the gastrointestinal tract reflecting short- and long-term nutritional status are now being described. Such signals influence central circuits in the hypothalamus, brain stem, and limbic system to modulate neuropeptide release and hence food intake and energy expenditure. This review discusses the peripheral hormones and central neuronal pathways that contribute to control of appetite.
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Affiliation(s)
- Sarah Stanley
- Endocrine Unit, Imperial College Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK
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32
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Wynne K, Park AJ, Small CJ, Patterson M, Ellis SM, Murphy KG, Wren AM, Frost GS, Meeran K, Ghatei MA, Bloom SR. Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double-blind, randomized, controlled trial. Diabetes 2005; 54:2390-5. [PMID: 16046306 DOI: 10.2337/diabetes.54.8.2390] [Citation(s) in RCA: 291] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
This study investigated the effect of subcutaneously administered oxyntomodulin on body weight in healthy overweight and obese volunteers. Participants self-administered saline or oxyntomodulin subcutaneously in a randomized, double-blind, parallel-group protocol. Injections were self-administered for 4 weeks, three times daily, 30 min before each meal. The volunteers were asked to maintain their regular diet and level of physical exercise during the study period. Subjects' body weight, energy intake, and levels of adipose hormones were assessed at the start and end of the study. Body weight was reduced by 2.3 +/- 0.4 kg in the treatment group over the study period compared with 0.5 +/- 0.5 kg in the control group (P = 0.0106). On average, the treatment group had an additional 0.45-kg weight loss per week. The treatment group demonstrated a reduction in leptin and an increase in adiponectin. Energy intake by the treatment group was significantly reduced by 170 +/- 37 kcal (25 +/- 5%) at the initial study meal (P = 0.0007) and by 250 +/- 63 kcal (35 +/- 9%) at the final study meal (P = 0.0023), with no change in subjective food palatability. Oxyntomodulin treatment resulted in weight loss and a change in the levels of adipose hormones consistent with a loss of adipose tissue. The anorectic effect was maintained over the 4-week period. Oxyntomodulin represents a potential therapy for obesity.
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Affiliation(s)
- Katie Wynne
- Department of Metabolic Medicine, Imperial College Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK
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34
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Baggio LL, Huang Q, Brown TJ, Drucker DJ. Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure. Gastroenterology 2004; 127:546-58. [PMID: 15300587 DOI: 10.1053/j.gastro.2004.04.063] [Citation(s) in RCA: 270] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Gut-derived peptides including ghrelin, cholecystokinin (CCK), peptide YY (PYY), glucagon-like peptide (GLP-1), and GLP-2 exert overlapping actions on energy homeostasis through defined G-protein-coupled receptors (GPCRs). The proglucagon-derived peptide (PGDP) oxyntomodulin (OXM) is cosecreted with GLP-1 and inhibits feeding in rodents and humans; however, a distinct receptor for OXM has not been identified. METHODS We examined the mechanisms mediating oxyntomodulin action using stable cell lines expressing specific PGDP receptors in vitro and both wild-type and knockout mice in vivo. RESULTS OXM activates signaling pathways in cells through glucagon or GLP-1 receptors (GLP-1R) but transiently inhibits food intake in vivo exclusively through the GLP-1R. Both OXM and the GLP-1R agonist exendin-4 (Ex-4) activated neuronal c-fos expression in the paraventricular nucleus of the hypothalamus, the area postrema, and the nucleus of the solitary tract following intraperitoneal (i.p.) injection. However, OXM transiently inhibited food intake in wild-type mice following intracerebroventricular (i.c.v.) but not i.p. administration, whereas Ex-4 produced a more potent and sustained inhibition of food intake following both i.c.v. and i.p. administration. The anorectic effects of OXM were preserved in Gcgr(-/-) mice but abolished in GLP-1R(-/-) mice. Although central Ex-4 and OXM inhibited feeding via a GLP-1R-dependent mechanism, Ex-4 but not OXM reduced VO2 and respiratory quotient in wild-type mice. CONCLUSIONS These findings demonstrate that structurally distinct PGDPs differentially regulate food intake and energy expenditure by interacting with a GLP-1R-dependent pathway. Hence ligand-specific activation of a common GLP-1R increases the complexity of gut-central nervous system pathways regulating energy homeostasis and metabolic expenditure.
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MESH Headings
- Amino Acid Sequence
- Animals
- Binding, Competitive
- Brain/metabolism
- Cells, Cultured
- Cricetinae
- Dose-Response Relationship, Drug
- Eating/drug effects
- Energy Metabolism/drug effects
- Exenatide
- Glucagon/genetics
- Glucagon/metabolism
- Glucagon/pharmacology
- Glucagon-Like Peptide 1
- Glucagon-Like Peptide 2
- Glucagon-Like Peptide-1 Receptor
- Glucagon-Like Peptides/metabolism
- Glucagon-Like Peptides/pharmacology
- Injections, Intraperitoneal
- Injections, Intraventricular
- Iodine Radioisotopes
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Molecular Sequence Data
- Oxyntomodulin
- Peptide Fragments/metabolism
- Peptide Fragments/pharmacology
- Peptides/metabolism
- Peptides/pharmacology
- Proglucagon
- Protein Precursors/genetics
- Protein Precursors/metabolism
- Protein Precursors/pharmacology
- Proto-Oncogene Proteins c-fos/metabolism
- Rats
- Receptors, G-Protein-Coupled/genetics
- Receptors, G-Protein-Coupled/metabolism
- Receptors, Glucagon/agonists
- Receptors, Glucagon/genetics
- Receptors, Glucagon/metabolism
- Venoms/metabolism
- Venoms/pharmacology
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Affiliation(s)
- Laurie L Baggio
- Department of Medicine, Banting and Best Diabetes Centre, Toronto General Hospital, University of Toronto, Ontario, Canada
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35
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Abstract
Glucagon-like peptide 2 (GLP-2) is a member of family of peptides derived from the proglucagon gene expressed in the intestines, pancreas and brain. Tissue-specific posttranslational processing of proglucagon leads to GLP-2 and GLP-1 secretion from the intestine and glucagon secretion from the pancreas. GLP-2 and GLP-1 are co-secreted from the enteroendocrine L-cells located in distal intestine in response to enteral nutrient ingestion, especially carbohydrate and fat. GLP-2 secretion is mediated by direct nutrient stimulation of the L-cells and indirect action from enteroendocrine and neural inputs, including GIP, gastrin-releasing peptide (GRP) and the vagus nerve. GLP-2 is secreted as a 33-amino acid peptide and is rapidly cleaved by dipeptidylpeptidase IV (DPP-IV) to a truncated peptide which acts as a weak agonist with competitive antagonistic properties. GLP-2 acts to enhance nutrient absorption by inhibiting gastric motility and secretion and stimulating nutrient transport. GLP-2 also suppresses food intake when infused centrally. The trophic actions of GLP-2 are specific for the intestine and occur via stimulation of crypt cell proliferation and suppression of apoptosis in mucosal epithelial cells. GLP-2 reduces gut permeability, bacterial translocation and proinflammatory cytokine expression under conditions of intestinal inflammation and injury. The effects of GLP-2 are mediated by a G-protein-linked receptor that is localized to the intestinal mucosa and hypothalamus. The intestinal localization of the GLP-2R to neural and endocrine cells, but not enterocytes, suggests that its actions are mediated indirectly via a secondary signaling mechanism. The implications of GLP-2 in domestic animal production are largely unexplored. However, GLP-2 may have therapeutic application in treatment of gastrointestinal injury and diarrheal diseases that occur in developing neonatal and weanling animals.
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Affiliation(s)
- D G Burrin
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, 1100 Bates Street, Houston, TX 77030, USA.
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36
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Abstract
Malabsorption of both nonessential and essential nutrients, fluid, and electrolytes will, if not compensated for by increased intake, lead to diminished body stores and to subclinical and eventually clinical deficiencies. By definition, intestinal failure prevails when parenteral support is necessary to maintain nutritional equilibrium. After intestinal resection, adaptation, a progressive recovery from the malabsorptive disorder, may be seen. Research has focused on optimizing remnant intestinal function through dietary or pharmacologic interventions. In this review, factors responsible for the morphologic and functional changes in the adaptive processes are described. Results of clinical trials employing either growth hormone and glutamine or glucagon-like peptide-2 in short bowel patients are presented.
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Affiliation(s)
- Palle Bekker Jeppesen
- Department of Medicine CA-2121, Section of Gastroenterology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
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37
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Chao SC, Lee JYY. Brittle nails and dyspareunia as first clues to recurrences of malignant glucagonoma. Br J Dermatol 2002; 146:1071-4. [PMID: 12072081 DOI: 10.1046/j.1365-2133.2002.04673.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Glucagonoma syndrome is a paraneoplastic syndrome in which the occurrence and resolution of the characteristic necrolytic migratory erythema lesions parallel the course of the underlying glucagonoma. Nail abnormalities and dyspareunia are rarely reported in this syndrome. We describe a case of glucagonoma syndrome in which recurrent brittle nails and dyspareunia gave the patient the first clues of the recurrence of glucagonoma. It is possible that the significance of onychoschizia and dyspareunia has been overlooked in glucagonoma syndrome because patients might not report these problems to their doctors. Our case illustrates the importance of examining the nail and genital mucosa in patients with glucagonoma syndrome and including this syndrome in the differential diagnosis of onychoschizia and dyspareunia.
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Affiliation(s)
- S-C Chao
- Department of Dermatology, National Cheng-Kung University Hospital, 138 Sheng-Li Road, 704 Tainan, Taiwan
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38
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Abstract
The glucagon-like peptides (GLP-1 and GLP-2) are proglucagon-derived peptides cosecreted from gut endocrine cells in response to nutrient ingestion. GLP-1 acts as an incretin to lower blood glucose via stimulation of insulin secretion from islet beta cells. GLP-1 also exerts actions independent of insulin secretion, including inhibition of gastric emptying and acid secretion, reduction in food ingestion and glucagon secretion, and stimulation of beta-cell proliferation. Administration of GLP-1 lowers blood glucose and reduces food intake in human subjects with type 2 diabetes. GLP-2 promotes nutrient absorption via expansion of the mucosal epithelium by stimulation of crypt cell proliferation and inhibition of apoptosis in the small intestine. GLP-2 also reduces epithelial permeability, and decreases meal-stimulated gastric acid secretion and gastrointestinal motility. Administration of GLP-2 in the setting of experimental intestinal injury is associated with reduced epithelial damage, decreased bacterial infection, and decreased mortality or gut injury in rodents with chemically induced enteritis, vascular-ischemia reperfusion injury, and dextran sulfate-induced colitis. GLP-2 also attenuates chemotherapy-induced mucositis via inhibition of drug-induced apoptosis in the small and large bowel. GLP-2 improves intestinal adaptation and nutrient absorption in rats after major small bowel resection, and in humans with short bowel syndrome. The actions of GLP-2 are mediated by a distinct GLP-2 receptor expressed on subsets of enteric nerves and enteroendocrine cells in the stomach and small and large intestine. The beneficial actions of GLP-1 and GLP-2 in preclinical and clinical studies of diabetes and intestinal disease, respectively, has fostered interest in the potential therapeutic use of these gut peptides. Nevertheless, the actions of the glucagon-like peptides are limited in duration by enzymatic inactivation via cleavage at the N-terminal penultimate alanine by dipeptidyl peptidase IV (DP IV). Hence, inhibitors of DP IV activity, or DP IV-resistant glucagon-like peptide analogues, may be alternative therapeutic approaches for treatment of human diseases.
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Affiliation(s)
- Daniel J Drucker
- The Banting and Best Diabetes Centre, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
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Ljungmann K, Hartmann B, Kissmeyer-Nielsen P, Flyvbjerg A, Holst JJ, Laurberg S. Time-dependent intestinal adaptation and GLP-2 alterations after small bowel resection in rats. Am J Physiol Gastrointest Liver Physiol 2001; 281:G779-85. [PMID: 11518690 DOI: 10.1152/ajpgi.2001.281.3.g779] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Existing data on morphological adaptation after small bowel resection are obtained by potentially biased methods. Using stereological techniques, we examined segments of bowel on days 0, 4, 7, 14, and 28 after 80% jejunoileal resection or sham operation in rats and correlated intestinal growth with plasma levels of glucagon-like peptide-2 (GLP-2). In the jejunum and ileum of the resected rats, the mucosal weight increased by 120 and 115% during the first week, and the weight of muscular layer increased by 134 and 83%, compared with sham-operated controls. The luminal surface area increased by 190% in the jejunum and by 155% in the ileum after 28 days. The GLP-2 level was increased by 130% during the entire study period in the resected rats. Small bowel resection caused a pronounced and persistent transmural growth response in the remaining small bowel, with the most prominent growth occurring in the jejunal part. The significantly elevated GLP-2 level is consistent with an important role of GLP-2 in the adaptive response.
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Affiliation(s)
- K Ljungmann
- Surgical Research Unit, Department of Surgery L, Aarhus University Hospital, DK-8000 Aarhus C, Denmark.
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Verdich C, Toubro S, Buemann B, Lysgård Madsen J, Juul Holst J, Astrup A. The role of postprandial releases of insulin and incretin hormones in meal-induced satiety--effect of obesity and weight reduction. Int J Obes (Lond) 2001; 25:1206-14. [PMID: 11477506 DOI: 10.1038/sj.ijo.0801655] [Citation(s) in RCA: 306] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2000] [Revised: 10/31/2000] [Accepted: 01/30/2001] [Indexed: 12/26/2022]
Abstract
BACKGROUND Previous studies have indicated that the secretion of the intestinal satiety hormone glucagon-like peptide-1 (GLP-1) is attenuated in obese subjects. OBJECTIVE To compare meal-induced response of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in obese and lean male subjects, to investigate the effect of a major weight reduction in the obese subjects, and to look for an association between these hormones and ad libitum food intake. METHOD Plasma concentrations of intestinal hormones and appetite sensations were measured prior to, and every 30 min for 180 min after, ingestion of a 2.5 MJ solid test meal. Gastric emptying was estimated scintigraphically. An ad libitum lunch was served 3 h after the test meal. SUBJECTS Nineteen non-diabetic obese (body mass index (BMI) 34.1--43.8 kg/m(2)) and 12 lean (BMI 20.4--24.7 kg/m(2)) males. All obese subjects were re-examined after a mean stabilised weight loss of 18.8 kg (95% CI 14.4--23.2). RESULTS Total area under the GLP-1 response curve (AUC(total, GLP-1)) was lower in obese before and after the weight loss compared to lean subjects (P<0.05), although weight loss improved the response from 80 to 88% of that of the lean subjects (P=0.003). The GIP response was similar in obese and lean subjects. However, after the weight loss both AUC(total, GIP) and AUC(incremental, GIP) were lowered (P<0.05). An inverse correlation was observed between AUC(incremental, GIP) and energy intake at the subsequent ad libitum meal in all groups. In lean subjects ad libitum energy intake was largely predicted by the insulin response to the preceding meal (r(2)=0.67, P=0.001). CONCLUSION Our study confirmed previous findings of a reduced postprandial GLP-1 response in severely obese subjects. Following weight reduction, GLP-1 response in the obese subjects apparently rose to a level between that of obese and lean subjects. The data suggests that postprandial insulin and GIP responses are key players in short-term appetite regulation.
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Affiliation(s)
- C Verdich
- Research Department of Human Nutrition, Centre for Advanced Food Studies, The Royal Veterinary and Agricultural University, Frederiksberg, Denmark.
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Kollman KA, Goulet O, Vanderhoof JA. Saccharomyces boulardii does not stimulate mucosal hyperplasia after intestinal resection in the rat. J Pediatr Gastroenterol Nutr 2001; 32:454-7. [PMID: 11396813 DOI: 10.1097/00005176-200104000-00012] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND Polyamines have been shown to be important regulators of the intestinal adaptation process after massive bowel resection. Saccharomyces boulardii is yeast that has the ability to synthesize polyamines. Therefore. S. boulardii may be useful in the treatment of short bowel syndrome. METHODS Twenty 150-g male Sprague-Dawley rats were subjected to 80% jejunoileal resection. Another 20 animals received transection and closure and served as pair fed controls. One half of the resected rats and one half of the controls were given S. boulardii 25 mg/day. RESULTS After 2 weeks, mucosal mass (mg/cm bowel) did not differ between treated and non-treated animals despite the presence of a marked resection effect. Mucosal DNA, protein, and sucrase activity likewise did not differ. Subsequently, the experiment was repeated four times the original dose (100 mg/day) and found comparable results. In the proximal bowel, mucosal mass was 92+/-6 mg/cm in treated animals versus 107+/-8 mg/cm in untreated rats. In the distal small bowel, comparable values were 85+/-5 mg/cm and 88+/-4 mg/cm. Again, mucosal DNA, protein, and sucrase activity levels paralleled these results. CONCLUSIONS Although S. boulardii may stimulate polyamine synthesis, it does not seem to be helpful in augmenting gut adaptation in this animal model of short bowel syndrome.
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Affiliation(s)
- K A Kollman
- Department of Pediatrics, University of Nebraska Medical Center/Creighton University, Omaha 68198-5160, USA
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42
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Abstract
The medical risks of obesity increase exponentially as weight increases, and these risks are reduced by sustained weight loss. Behavior modification and dieting provide an approximately 6% loss of body weight at 1 year. Fenfluramine provides an approximately 8% weight loss at 1 year, which can be doubled to 16% when a drug such as phentermine, which works through a different biochemical mechanism, is added to it. This amount of weight loss is insufficient for many severely obese individuals. It was with these facts in mind that the National Institutes of Health Consensus Conference in 1992 recommended that obesity surgery is an appropriate treatment for patients with a body mass index greater than 40 kg/m2 who had failed in attempts at medical treatment and for patients with a body mass index greater than 35 kg/m2 with severe complications of obesity. Vertically banded gastroplasty and Roux-en-Y gastric bypass are the two operations presently recommended because of their relative safety and effectiveness. This article reviews previous procedures that have provided insight into the mechanisms by which these surgeries cause weight loss. The presently used surgeries and their results also are reviewed because until medical therapy improves substantially, surgery remains the most reasonable treatment option for most morbidly obese patients.
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Affiliation(s)
- F L Greenway
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, USA
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Tappenden KA, Thomson AB, Wild GE, McBurney MI. Short-chain fatty acids increase proglucagon and ornithine decarboxylase messenger RNAs after intestinal resection in rats. JPEN J Parenter Enteral Nutr 1996; 20:357-62. [PMID: 8887905 DOI: 10.1177/0148607196020005357] [Citation(s) in RCA: 74] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND Intestinal adaptation is a complex physiological process that is not completely understood. Systemic administration of short-chain fatty acids (SCFAs) has been shown to facilitate adaptation to small bowel resection; however the mechanisms underlying this phenomena are unknown. METHODS Forty-six male Sprague-Dawley rats underwent an 80% jejunoileal resection and jugular catheterization. After surgery, rats were randomly assigned to receive standard total parenteral nutrition (TPN) or an isoenergetic, isonitrogenous TPN supplemented with SCFAs. On day 3 or 7 after surgery, ileal samples were removed for determination of mucosal wet weight, DNA, RNA, and protein concentrations. Total cellular RNA was extracted for use in Northern blot analysis to quantify proglucagon and ornithine decarboxylase messenger RNAs (mRNAs). RESULTS Total, mucosal, and submucosal weights were increased (p < .05) in the SCFA group both 3 and 7 days after surgery. Ileal DNA and RNA concentrations were increased (p < .05) in the SCFA group at both time points; however ileal protein concentration did not differ between groups until 7 days after resection. Levels of proglucagon and ornithine decarboxylase messenger RNAs were higher (p < .05) in the SCFA group at both time points. CONCLUSION The upregulation of proglucagon and ornithine decarboxylase gene expression may be the mechanism by which SCFAs facilitate intestinal adaptation.
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Affiliation(s)
- K A Tappenden
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Canada
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Abstract
This article discusses the management of short bowel syndrome from the time of intestinal resection until the patient either recovers free of supplemental parenteral and enteral nutrition or progresses to the point of needing intestinal transplantation. The importance of aggressive use of enteral feedings is emphasized, especially in relation to the process of intestinal adaptation. An approach to the various complications of short bowel syndrome, especially small bowel bacterial overgrowth, is discussed. Surgical options short of transplantation also are described. Intestinal transplantation and its present and future roles in the management of patients with short bowel syndrome are discussed.
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Affiliation(s)
- J A Vanderhoof
- Department of Pediatrics, University of Nebraska Medical Center, Omaha, USA
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Abstract
Studies were performed on 20 male adult rats to investigate the effects of chronic intermittent infusion of lipid and physiological emulsifier into the distal small intestine on stomach to caecum transit time (SCTT) of the head of a test meal. SCTT was measured using environmental hydrogen analysis. Ileal lipid infusion normally delays gastric emptying and small intestinal transit (p < 0.001), but chronic intermittent infusion of lipid, given three times a week gradually reduced the delay in transit time until by four weeks it was no longer than control values. The lipid induced delay did not return during the four weeks after the chronic infusion had finished. Intermittent infusion of physiological emulsifier into the distal small intestine for four weeks did not change the control SCTT or the acute response to an ileal lipid infusion. SCTT of the head of the meal did not change in the four weeks after the physiological emulsifier infusion had stopped. In conclusion these results show that infusing rats intermittently with lipid for four weeks results in desensitisation of the mechanisms by which distal small intestinal lipid regulate SCTT of the head of a meal. This adaptation is not reversed within four weeks of withdrawal of the lipid infusion. These results emphasise the importance of assessing recent dietary history when assessing gastric emptying and small bowel transit times.
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Affiliation(s)
- N J Brown
- Department of Biomedical Science, The University, Sheffield
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Miholic J, Orskov C, Holst JJ, Kotzerke J, Meyer HJ. Emptying of the gastric substitute, glucagon-like peptide-1 (GLP-1), and reactive hypoglycemia after total gastrectomy. Dig Dis Sci 1991; 36:1361-70. [PMID: 1914756 DOI: 10.1007/bf01296800] [Citation(s) in RCA: 117] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Postprandial glucagon-like peptide-1 (GLP-1), pancreatic glucagon, and insulin were measured in 27 tumor-free patients 43 months (median) after total gastrectomy and in four controls using a 99technetium-labeled 100-g carbohydrate solid test meal. Emptying of the gastric substitute was measured by scintigraphy. Fourteen patients suffered from early dumping symptoms, and five of them also reported symptoms suggestive of reactive hypoglycemia (late dumping). The median emptying half-time (T1/2) of the gastric substitute was 480 sec. Sigstad's dumping score was 8.5 +/- 1.6 (mean +/- SE) in patients with rapid emptying (T1/2 less than 480 sec), and 3.0 +/- 1.5 in patients with slow emptying of the gastric substitute (P = 0.02). The peak postprandial concentration of GLP-1 was 44 +/- 20 pmol/liter in controls, 172 +/- 50 in patients without reactive hypoglycemia, and 502 +/- 116 in patients whose glucose fell below 3.8 mmol/liter during the second postprandial hour. Plasma GLP-1 concentrations peaked at 15 min, and insulin concentrations at 30 min after the end of the meal. A close correlation between integrated GLP-1 responses and integrated insulin responses (r = 0.68) was observed. Multiple regression revealed that three factors were significantly associated with the integrated glucose concentrations during the second hour (60-120 min): Early (first 30 min) integrated GLP-1 (inverse correlation; P = 0.006), age (P = 0.006), and early integrated pancreatic glucagon (P = 0.005). There was a close (inverse) relationship of T1/2 with early integrated GLP-1 and pancreatic glucagon, but not with insulin. Gel filtration of pooled postprandial plasma of gastrectomized individuals revealed that all glucagon-like immunoreactivity eluted at Kd 0.30 (Kd, coefficient of distribution), the elution position of glicentin. Almost all of the GLP-1 like immunoreactivity eluted at Kd 0.60, the elution position of gut GLP-1. The authors contend that GLP-1-induced insulin release and inhibition of pancreatic glucagon both contribute to the reactive hypoglycemia encountered in some patients following gastric surgery. Rapid emptying seems to be one causative factor for the exaggerated GLP-1 release in these subjects.
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Affiliation(s)
- J Miholic
- Klinik für Abdominal- und Transplantationschirurgie, Medizinische Hochschule Hannover, Germany
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Bristol JB, Ghatei MA, Smith JH, Bloom SR, Williamson RC. Elevated plasma enteroglucagon alone fails to alter distal colonic carcinogenesis in rats. Gastroenterology 1987; 92:617-24. [PMID: 3817385 DOI: 10.1016/0016-5085(87)90009-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The effect of physiologic increases of plasma enteroglucagon, induced by massive bypass or resection of small bowel, on large bowel cell turnover and carcinogenesis was studied in rats in which the distal colon was isolated as a mucous fistula. After injections of azoxymethane, either 85% end-to-side jejunoileal bypass, 85% jejunoileal resection, or sham bypass was performed. Controls underwent colonic transection and resuture, azoxymethane treatment, and then sham bypass. Thirty weeks later the plasma enteroglucagon level had almost trebled after jejunoileal bypass (p less than 0.001) and almost doubled after jejunoileal resection (p less than 0.002) when compared with sham bypass; sham values did not differ from controls. The median number of tumors per rat in the distal (defunctioned) colon fell from 2 to 0 (p less than 0.05). Segmental weight fell by 45% (p less than 0.001) and crypt cell production rate by 75% (p less than 0.001). Neither tumor yield nor adaptation was affected by jejunoileal bypass or jejunoileal resection. Plasma enteroglucagon has no effect on colonic cell turnover or carcinogenesis in the absence of luminal content.
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Savage AP, Gornacz GE, Adrian TE, Ghatei MA, Goodlad RA, Wright NA, Bloom SR. Is raised plasma peptide YY after intestinal resection in the rat responsible for the trophic response? Gut 1985; 26:1353-8. [PMID: 3841330 PMCID: PMC1433118 DOI: 10.1136/gut.26.12.1353] [Citation(s) in RCA: 50] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The relationship between the adaptive response and plasma PYY concentrations after small bowel resection has been investigated. Seventy five per cent proximal small bowel resection resulted in a rise in plasma PYY at six days from 28 +/- 3.1 to 85 +/- 12.3 pmol/l (p less than 0.001) and this difference was maintained to 48 days. Plasma PYY correlates both with crypt cell production rate (CCPR) in the ileum and with plasma enteroglucagon levels. In a second study, PYY or saline was infused over a 12 day period. There were no significant changes in intestinal wet weight or CCPR in any part of the bowel studied. This indicates that it is unlikely that PYY exerts a major trophic effect on the gastrointestinal tract.
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50
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