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      Mechanisms in bariatric surgery: Gut hormones, diabetes resolution, and weight loss

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          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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          Glucose Sensing in L Cells: A Primary Cell Study

          Summary Glucagon-like peptide-1 (GLP-1) is an enteric hormone that stimulates insulin secretion and improves glycaemia in type 2 diabetes. Although GLP-1-based treatments are clinically available, alternative strategies to increase endogenous GLP-1 release from L cells are hampered by our limited physiological understanding of this cell type. By generating transgenic mice with L cell-specific expression of a fluorescent protein, we studied the characteristics of primary L cells by electrophysiology, fluorescence calcium imaging, and expression analysis and show that single L cells are electrically excitable and glucose responsive. Sensitivity to tolbutamide and low-millimolar concentrations of glucose and α-methylglucopyranoside, assessed in single L cells and by hormone secretion from primary cultures, suggested that GLP-1 release is regulated by the activity of sodium glucose cotransporter 1 and ATP-sensitive K+ channels, consistent with their high expression levels in purified L cells by quantitative RT-PCR. These and other pathways identified using this approach will provide exciting opportunities for future physiological and therapeutic exploration.
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            Gut hormones as mediators of appetite and weight loss after Roux-en-Y gastric bypass.

            To evaluate the physiologic importance of the satiety gut hormones. Controversy surrounds the physiologic role of gut hormones in the control of appetite. Bariatric surgery remains the most effective treatment option for obesity, and gut hormones are implicated in the reduction of appetite and weight after Roux-en-Y gastric bypass. We correlated peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) changes within the first week after gastric bypass with changes in appetite. We also evaluated the gut hormone responses of patients with good or poor weight loss after gastric bypass. Finally, we inhibited the gut hormone responses in gastric bypass patients and then evaluated appetite and food intake. Postprandial PYY and GLP-1 profiles start rising as early as 2 days after gastric bypass (P < 0.05). Changes in appetite are evident within days after gastric bypass surgery (P < 0.05), and unlike other operations, the reduced appetite continues. However, in patients with poor weight loss after gastric bypass associated with increased appetite, the postprandial PYY and GLP-1 responses are attenuated compared with patients with good weight loss (P < 0.05). Inhibiting gut hormone responses, including PYY and GLP-1 after gastric bypass, results in return of appetite and increased food intake (P < 0.05). The attenuated appetite after gastric bypass is associated with elevated PYY and GLP-1 concentrations, and appetite returns when the release of gut hormones is inhibited. The results suggest a role for gut hormones in the mechanism of weight loss after gastric bypass and may have implications for the treatment of obesity.
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              Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes.

              The incretin effect is attenuated in patients with type 2 diabetes mellitus, partly as a result of impaired beta cell responsiveness to glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The aim of the present study was to investigate whether 4 weeks of near-normalisation of the blood glucose level could improve insulin responses to GIP and GLP-1 in patients with type 2 diabetes. Eight obese patients with type 2 diabetes with poor glycaemic control (HbA(1c) 8.6 +/- 1.3%), were investigated before and after 4 weeks of near-normalisation of blood glucose (mean blood glucose 7.4 +/- 1.2 mmol/l) using insulin treatment. Before and after insulin treatment the participants underwent three hyperglycaemic clamps (15 mmol/l) with infusion of GLP-1, GIP or saline. Insulin responses were evaluated as the incremental area under the plasma C-peptide curve. Before and after near-normalisation of blood glucose, the C-peptide responses did not differ during the early phase of insulin secretion (0-10 min). The late phase C-peptide response (10-120 min) increased during GIP infusion from 33.0 +/- 8.5 to 103.9 +/- 24.2 (nmol/l) x (110 min)(-1) (p < 0.05) and during GLP-1 infusion from 48.7 +/- 11.8 to 126.6 +/- 32.5 (nmol/l) x (110 min)(-1) (p < 0.05), whereas during saline infusion the late-phase response did not differ before vs after near-normalisation of blood glucose (40.2 +/- 11.2 vs 46.5 +/- 12.7 [nmol/l] x [110 min](-1)). Near-normalisation of blood glucose for 4 weeks improves beta cell responsiveness to both GLP-1 and GIP by a factor of three to four. No effect was found on beta cell responsiveness to glucose alone. CLINICALTRIALS.GOV ID NO.: NCT 00612950. This study was supported by The Novo Nordisk Foundation, The Medical Science Research Foundation for Copenhagen.
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                Author and article information

                Contributors
                Journal
                Surg Obes Relat Dis
                Surg Obes Relat Dis
                Surgery for Obesity and Related Diseases
                Elsevier
                1550-7289
                1878-7533
                1 May 2018
                May 2018
                : 14
                : 5
                : 708-714
                Affiliations
                [a ]NNF Center for Basic Metabolic Research and Dept. Biomedical Sciences, the Panum Institute, University of Copenhagen, Copenhagen, Denmark
                [b ]Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
                Author notes
                [* ]Correspondence: Jens Juul Holst, M.D., Department of Biomedical Sciences, The Panum Institute, University of Copenhagen, 2200 Copenhagen N, Denmark. jjholst@ 123456sund.ku.dk
                Article
                S1550-7289(18)30124-2
                10.1016/j.soard.2018.03.003
                5974695
                29776493
                e8891618-59cf-4af2-802d-4c73d97e52dc
                © 2018 American Society for Metabolic and Bariatric Surgery. All rights reserved.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 16 February 2018
                : 4 March 2018
                Categories
                Article

                glp-1,pyy,insulin resistance,carbohydrate absorption,protein absorption,paracetamol absorption

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