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Wang R, Mijiti S, Xu Q, Liu Y, Deng C, Huang J, Yasheng A, Tian Y, Cao Y, Su Y. The Potential Mechanism of Remission in Type 2 Diabetes Mellitus After Vertical Sleeve Gastrectomy. Obes Surg 2024; 34:3071-3083. [PMID: 38951388 DOI: 10.1007/s11695-024-07378-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 06/13/2024] [Accepted: 06/19/2024] [Indexed: 07/03/2024]
Abstract
In recent years, there has been a gradual increase in the prevalence of obesity and type 2 diabetes mellitus (T2DM), with bariatric surgery remaining the most effective treatment strategy for these conditions. Vertical sleeve gastrectomy (VSG) has emerged as the most popular surgical procedure for bariatric/metabolic surgeries, effectively promoting weight loss and improving or curing T2DM. The alterations in the gastrointestinal tract following VSG may improve insulin secretion and resistance by increasing incretin secretion (especially GLP-1), modifying the gut microbiota composition, and through mechanisms dependent on weight loss. This review focuses on the potential mechanisms through which the enhanced action of incretin and metabolic changes in the digestive system after VSG may contribute to the remission of T2DM.
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Affiliation(s)
- Rongfei Wang
- Department of Gastrointestinal Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, No.57 Mei Hua East Road, Xiang Zhou District, Zhuhai, 519000, Guangdong, China
| | - Salamu Mijiti
- Department of General Surgery, The First People's Hospital of Kashi, Autonomous Region, Kashi, 844000, Xinjiang Uygur, China
| | - Qilin Xu
- Department of General Surgery, The First People's Hospital of Kashi, Autonomous Region, Kashi, 844000, Xinjiang Uygur, China
| | - Yile Liu
- Department of Gastrointestinal Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, No.57 Mei Hua East Road, Xiang Zhou District, Zhuhai, 519000, Guangdong, China
| | - Chaolun Deng
- Department of Gastrointestinal Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, No.57 Mei Hua East Road, Xiang Zhou District, Zhuhai, 519000, Guangdong, China
| | - Jiangtao Huang
- Department of Gastrointestinal Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, No.57 Mei Hua East Road, Xiang Zhou District, Zhuhai, 519000, Guangdong, China
| | - Abudoukeyimu Yasheng
- Department of General Surgery, The First People's Hospital of Kashi, Autonomous Region, Kashi, 844000, Xinjiang Uygur, China
| | - Yunping Tian
- Department of General Surgery, The First People's Hospital of Kashi, Autonomous Region, Kashi, 844000, Xinjiang Uygur, China.
| | - Yanlong Cao
- Department of General Surgery, The First People's Hospital of Kashi, Autonomous Region, Kashi, 844000, Xinjiang Uygur, China.
| | - Yonghui Su
- Department of Gastrointestinal Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, No.57 Mei Hua East Road, Xiang Zhou District, Zhuhai, 519000, Guangdong, China.
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Huang X, Zhao Y, Liu T, Wu D, Shu J, Yue W, Zhang W, Liu S. β-Cell Function and Insulin Dynamics in Obese Patients With and Without Diabetes After Sleeve Gastrectomy. Diabetes 2024; 73:572-584. [PMID: 37257028 DOI: 10.2337/db22-1048] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 05/24/2023] [Indexed: 06/02/2023]
Abstract
Improved β-cell function seems to be essential for better glucose homeostasis after Roux-en-Y gastric bypass but is less studied after sleeve gastrectomy (SG). We evaluated the effects of SG on β-cell function in obese patients with diabetes (DM group) and without (control group) in response to both oral and intravenous glucose stimulation. The DM group demonstrated impaired insulin sensitivity and insulin response to glucose before surgery. The insulin sensitivity index of both groups significantly improved after SG. In addition, the insulin response to glucose (early insulinogenic index in oral glucose tolerance test and acute insulin response to glucose in an intravenous glucose tolerance test) increased in the DM group but decreased in the control group. As a result, β-cell function improved significantly in both groups after SG since the disposition index (DI) increased in both. However, the DI of the DM group was not restored to the level of control group up to 1 year after SG. Our results support that obese patients, with and without diabetes, could benefit from SG in β-cell function. For obese patients at risk for or who have been diagnosed with diabetes, interventions should be recommended early to preserve or restore β-cell function, and SG could be an effective choice. Further studies are needed for long-term effects. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Xin Huang
- Division of Bariatric and Metabolic Surgery, Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Yian Zhao
- School of Clinical Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Teng Liu
- Division of Bariatric and Metabolic Surgery, Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Dong Wu
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Jiaxin Shu
- School of Clinical Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wenwen Yue
- School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wenjing Zhang
- School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shaozhuang Liu
- Division of Bariatric and Metabolic Surgery, Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
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Mashayekhi M, Nian H, Mayfield D, Devin JK, Gamboa JL, Yu C, Silver HJ, Niswender K, Luther JM, Brown NJ. Weight Loss-Independent Effect of Liraglutide on Insulin Sensitivity in Individuals With Obesity and Prediabetes. Diabetes 2024; 73:38-50. [PMID: 37874653 PMCID: PMC10784656 DOI: 10.2337/db23-0356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Accepted: 10/16/2023] [Indexed: 10/26/2023]
Abstract
Metabolic effects of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and not fully recapitulated by increasing endogenous GLP-1. We tested the hypothesis that GLP-1 receptor (GLP-1R) agonists exert weight loss-independent, GLP-1R-dependent effects that differ from effects of increasing endogenous GLP-1. Individuals with obesity and prediabetes were randomized to receive for 14 weeks the GLP-1R agonist liraglutide, a hypocaloric diet, or the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin. The GLP-1R antagonist exendin(9-39) and placebo were administered in a two-by-two crossover study during mixed-meal tests. Liraglutide and diet, but not sitagliptin, caused weight loss. Liraglutide improved insulin sensitivity measured by HOMA for insulin resistance (HOMA-IR), the updated HOMA model (HOMA2), and the Matsuda index after 2 weeks, prior to weight loss. Liraglutide decreased fasting and postprandial glucose levels, and decreased insulin, C-peptide, and fasting glucagon levels. In contrast, diet-induced weight loss improved insulin sensitivity by HOMA-IR and HOMA2, but not the Matsuda index, and did not decrease glucose levels. Sitagliptin increased endogenous GLP-1 and GIP values without altering insulin sensitivity or fasting glucose levels, but decreased postprandial glucose and glucagon levels. Notably, sitagliptin increased GIP without altering weight. Acute GLP-1R antagonism increased glucose levels in all groups, increased the Matsuda index and fasting glucagon level during liraglutide treatment, and increased endogenous GLP-1 values during liraglutide and sitagliptin treatments. Thus, liraglutide exerts rapid, weight loss-independent, GLP-1R-dependent effects on insulin sensitivity that are not achieved by increasing endogenous GLP-1. ARTICLE HIGHLIGHTS Metabolic benefits of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and are not fully achieved by increasing endogenous GLP-1 through dipeptidyl peptidase 4 (DPP-4) inhibition. We investigated weight loss-independent, GLP-1 receptor (GLP-1R)-dependent metabolic effects of liraglutide versus a hypocaloric diet or the DPP-4 inhibitor sitagliptin. GLP-1R antagonism with exendin(9-39) was used to assess GLP-1R-dependent effects during mixed meals. Liraglutide improved insulin sensitivity and decreased fasting and postprandial glucose prior to weight loss, and these benefits were reversed by exendin(9-39). GLP-1R agonists exert rapid, weight loss-independent, GLP-1R-dependent effects on insulin sensitivity not achieved by increasing endogenous GLP-1.
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Affiliation(s)
- Mona Mashayekhi
- Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN
| | - Hui Nian
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN
| | - Dustin Mayfield
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN
| | - Jessica K. Devin
- UCHealth Endocrinology, Yampa Valley Medical Center, Steamboat Springs, CO
| | - Jorge L. Gamboa
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN
| | - Chang Yu
- Department of Population Health, NYU Grossman School of Medicine, New York, NY
| | - Heidi J. Silver
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN
- Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN
| | - Kevin Niswender
- Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN
| | - James M. Luther
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN
| | - Nancy J. Brown
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT
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Bottino R, Carbone A, Formisano T, D'Elia S, Orlandi M, Sperlongano S, Molinari D, Castaldo P, Palladino A, Barbareschi C, Tolone S, Docimo L, Cimmino G. Cardiovascular Effects of Weight Loss in Obese Patients with Diabetes: Is Bariatric Surgery the Additional Arrow in the Quiver? Life (Basel) 2023; 13:1552. [PMID: 37511927 PMCID: PMC10381712 DOI: 10.3390/life13071552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 07/01/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
Obesity is an increasingly widespread disease worldwide because of lifestyle changes. It is associated with an increased risk of cardiovascular disease, primarily type 2 diabetes mellitus, with an increase in major cardiovascular adverse events. Bariatric surgery has been shown to be able to reduce the incidence of obesity-related cardiovascular disease and thus overall mortality. This result has been shown to be the result of hormonal and metabolic effects induced by post-surgical anatomical changes, with important effects on multiple hormonal and molecular axes that make this treatment more effective than conservative therapy in determining a marked improvement in the patient's cardiovascular risk profile. This review, therefore, aimed to examine the surgical techniques currently available and how these might be responsible not only for weight loss but also for metabolic improvement and cardiovascular benefits in patients undergoing such procedures.
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Affiliation(s)
- Roberta Bottino
- Cardiology Unit, Azienda Ospedaliera Universitaria Luigi Vanvitelli, Piazza Miraglia 2, 80138 Napoli, Italy
| | - Andreina Carbone
- Cardiology Unit, Azienda Ospedaliera Universitaria Luigi Vanvitelli, Piazza Miraglia 2, 80138 Napoli, Italy
| | - Tiziana Formisano
- Cardiology Unit, Azienda Ospedaliera Universitaria Luigi Vanvitelli, Piazza Miraglia 2, 80138 Napoli, Italy
| | - Saverio D'Elia
- Cardiology Unit, Azienda Ospedaliera Universitaria Luigi Vanvitelli, Piazza Miraglia 2, 80138 Napoli, Italy
| | - Massimiliano Orlandi
- Cardiology Unit, Azienda Ospedaliera Universitaria Luigi Vanvitelli, Piazza Miraglia 2, 80138 Napoli, Italy
| | - Simona Sperlongano
- Cardiology Unit, Azienda Ospedaliera Universitaria Luigi Vanvitelli, Piazza Miraglia 2, 80138 Napoli, Italy
- Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Daniele Molinari
- Cardiology Unit, Azienda Ospedaliera Universitaria Luigi Vanvitelli, Piazza Miraglia 2, 80138 Napoli, Italy
| | - Pasquale Castaldo
- Cardiology Unit, Azienda Ospedaliera Universitaria Luigi Vanvitelli, Piazza Miraglia 2, 80138 Napoli, Italy
| | - Alberto Palladino
- Cardiology Unit, Azienda Ospedaliera Universitaria Luigi Vanvitelli, Piazza Miraglia 2, 80138 Napoli, Italy
| | - Consiglia Barbareschi
- Cardiology Unit, Azienda Ospedaliera Universitaria Luigi Vanvitelli, Piazza Miraglia 2, 80138 Napoli, Italy
| | - Salvatore Tolone
- Department of Medical, Surgical, Neurologic, Metabolic and Aging Sciences, General, Mini-Invasive and Obesity Surgery Unit, University of Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Ludovico Docimo
- Department of Medical, Surgical, Neurologic, Metabolic and Aging Sciences, General, Mini-Invasive and Obesity Surgery Unit, University of Campania Luigi Vanvitelli, 80131 Naples, Italy
| | - Giovanni Cimmino
- Cardiology Unit, Azienda Ospedaliera Universitaria Luigi Vanvitelli, Piazza Miraglia 2, 80138 Napoli, Italy
- Department of Translational Medical Sciences, Section of Cardiology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy
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Hindsø M, Hedbäck N, Svane MS, Møller A, Martinussen C, Jørgensen NB, Dirksen C, Gasbjerg LS, Kristiansen VB, Hartmann B, Rosenkilde MM, Holst JJ, Madsbad S, Bojsen-Møller KN. The Importance of Endogenously Secreted GLP-1 and GIP for Postprandial Glucose Tolerance and β-Cell Function After Roux-en-Y Gastric Bypass and Sleeve Gastrectomy Surgery. Diabetes 2023; 72:336-347. [PMID: 36478039 DOI: 10.2337/db22-0568] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 12/04/2022] [Indexed: 12/13/2022]
Abstract
Enhanced secretion of glucagon-like peptide 1 (GLP-1) seems to be essential for improved postprandial β-cell function after Roux-en-Y gastric bypass (RYGB) but is less studied after sleeve gastrectomy (SG). Moreover, the role of the other major incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is relatively unexplored after bariatric surgery. We studied the effects of separate and combined GLP-1 receptor (GLP-1R) and GIP receptor (GIPR) blockade during mixed-meal tests in unoperated (CON), SG-operated, and RYGB-operated people with no history of diabetes. Postprandial GLP-1 concentrations were highest after RYGB but also higher after SG compared with CON. In contrast, postprandial GIP concentrations were lowest after RYGB. The effect of GLP-1R versus GIPR blockade differed between groups. GLP-1R blockade reduced β-cell glucose sensitivity and increased or tended to increase postprandial glucose responses in the surgical groups but had no effect in CON. GIPR blockade reduced β-cell glucose sensitivity and increased or tended to increase postprandial glucose responses in the CON and SG groups but had no effect in the RYGB group. Our results support that GIP is the most important incretin hormone in unoperated people, whereas GLP-1 and GIP are equally important after SG, and GLP-1 is the most important incretin hormone after RYGB.
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Affiliation(s)
- Morten Hindsø
- Department of Endocrinology, Copenhagen University Hospital, Hvidovre, Denmark
| | - Nora Hedbäck
- Department of Endocrinology, Copenhagen University Hospital, Hvidovre, Denmark
| | - Maria S Svane
- Department of Endocrinology, Copenhagen University Hospital, Hvidovre, Denmark
- Department of Surgical Gastroenterology, Copenhagen University Hospital, Hvidovre, Denmark
| | - Andreas Møller
- Department of Endocrinology, Copenhagen University Hospital, Hvidovre, Denmark
| | | | - Nils B Jørgensen
- Department of Endocrinology, Copenhagen University Hospital, Hvidovre, Denmark
| | - Carsten Dirksen
- Department of Endocrinology, Copenhagen University Hospital, Hvidovre, Denmark
| | - Lærke S Gasbjerg
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Viggo B Kristiansen
- Department of Surgical Gastroenterology, Copenhagen University Hospital, Hvidovre, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sten Madsbad
- Department of Endocrinology, Copenhagen University Hospital, Hvidovre, Denmark
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Nakamura Y, Horie I, Kanetaka K, Eguchi S, Nakamichi S, Hongo R, Takashima M, Kawakami A, Abiru N. Exenatide challenge in oral glucose tolerance test is insufficient for predictions of glucose metabolism and insulin secretion after sleeve gastrectomy (SG) in obese patients with type 2 diabetes: a pilot study to establish a preoperative model to estimate β-cell function following augmented glucagon-like peptide-1 secretion after SG. Endocr J 2022; 69:1457-1465. [PMID: 35896344 DOI: 10.1507/endocrj.ej22-0224] [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] [Indexed: 12/30/2022] Open
Abstract
The postoperative increase in glucagon-like peptide-1 (GLP-1) is the main factor to improve glucose metabolism following sleeve gastrectomy (SG) in obese patients with type 2 diabetes. We investigated whether the β-cell responsiveness to an injection of exogenous GLP-1 in the preoperative period could determine the postoperative glucose tolerance in 18 patients underwent SG. In the preoperative period, a regular oral glucose tolerance test (OGTT) and an exenatide-challenge during OGTT (Ex-OGTT) were performed to evaluate the β-cell function and its responsiveness to GLP-1. The postoperative glucose tolerance was evaluated by another regular OGTT performed at 3 months after SG. The significant decrease in glucose levels with enhanced secretions of insulin and GLP-1 was observed in OGTT at 3 months after SG. The area under the curve of glucose from 0 to 120 minutes (AUC glucose0-120 min) and the insulinogenic index (I.I.) in OGTT at 3 months post-SG were significantly improved compared to those in preoperative period, but comparable with those in Ex-OGTT. AUC glucose0-120 min and I.I. in OGTT at 3 months post-SG were significantly correlated with not only those in Ex-OGTT, but also those in the preoperative regular OGTT. Conversely, the correlations calculated by the Spearman's ρ were stronger in the latter than the former. This exenatide-challenge protocol might be useful to estimate glucose tolerance and insulin secretion after SG, however, it may be insufficient to improve predictability of a patient who is likely to achieve a significant benefit on glucose metabolism from receiving SG.
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Affiliation(s)
- Yuta Nakamura
- Department of Endocrinology and Metabolism, Division of Advanced Preventive Medical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan
| | - Ichiro Horie
- Department of Endocrinology and Metabolism, Division of Advanced Preventive Medical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan
| | - Kengo Kanetaka
- Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan
| | - Susumu Eguchi
- Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan
| | - Seiko Nakamichi
- Department of General Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan
| | - Ryoko Hongo
- Department of Nutrition Science, Faculty of Nursing and Nutrition, University of Nagasaki, Nagasaki 851-2195, Japan
| | - Miwa Takashima
- Nutritional Management Division, Nagasaki University Hospital, Nagasaki 852-8501, Japan
| | - Atsushi Kawakami
- Department of Endocrinology and Metabolism, Division of Advanced Preventive Medical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan
| | - Norio Abiru
- Department of Endocrinology and Metabolism, Division of Advanced Preventive Medical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan
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Ding H, Zhang Y, Ma X, Zhang Z, Xu Q, Liu C, Li B, Dong S, Li L, Zhu J, Zhong M, Zhang G. Bariatric surgery for diabetic comorbidities: A focus on hepatic, cardiac and renal fibrosis. Front Pharmacol 2022; 13:1016635. [PMID: 36339532 PMCID: PMC9634081 DOI: 10.3389/fphar.2022.1016635] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 10/06/2022] [Indexed: 07/29/2024] Open
Abstract
Continuously rising trends in diabetes render this disease spectrum an epidemic proportion worldwide. As the disease progresses, the pathological effects of diabetes may impair the normal function of several vital organs, eventually leading to increase the risk of other diabetic comorbidities with advanced fibrosis such as non-alcoholic fatty liver disease, diabetic cardiomyopathy, and diabetic kidney disease. Currently, lifestyle changes and drug therapies of hypoglycemic and lipid-lowering are effective in improving multi-organ function, but therapeutic efficacy is difficult to maintain due to poor compliance and drug reactions. Bariatric surgery, including sleeve gastrectomy and Roux-en-Y gastric bypass surgery, has shown better results in terms of prognosis for diabetes through long-term follow-up. Moreover, bariatric surgery has significant long-term benefits on the function of the heart, liver, kidneys, and other organs through mechanisms associated with reversal of tissue fibrosis. The aim of this review is to describe the impact of type 2 diabetes mellitus on hepatic, cardiac and renal fibrosis and to summarize the potential mechanisms by which bariatric surgery improves multiple organ function, particularly reversal of fibrosis.
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Affiliation(s)
- Huanxin Ding
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China
| | - Yun Zhang
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Xiaomin Ma
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Zhongwen Zhang
- Department of Endocrinology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Qian Xu
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Chuxuan Liu
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China
| | - Bingjun Li
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Shuohui Dong
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China
| | - Linchuan Li
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Jiankang Zhu
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Mingwei Zhong
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Guangyong Zhang
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China
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8
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Knerr PJ, Mowery SA, Douros JD, Premdjee B, Hjøllund KR, He Y, Kruse Hansen AM, Olsen AK, Perez-Tilve D, DiMarchi RD, Finan B. Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice. Mol Metab 2022; 63:101533. [PMID: 35809773 PMCID: PMC9305623 DOI: 10.1016/j.molmet.2022.101533] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/18/2022] [Accepted: 06/18/2022] [Indexed: 12/19/2022] Open
Abstract
Objective Pharmacological strategies that engage multiple mechanisms-of-action have demonstrated synergistic benefits for metabolic disease in preclinical models. One approach, concurrent activation of the glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon (Gcg) receptors (i.e. triagonism), combines the anorectic and insulinotropic activities of GLP-1 and GIP with the energy expenditure effect of glucagon. While the efficacy of triagonism in preclinical models is known, the relative contribution of GcgR activation remains unassessed. This work aims to addresses that central question. Methods Herein, we detail the design of unimolecular peptide triagonists with an empirically optimized receptor potency ratio. These optimized peptide triagonists employ a protraction strategy permitting once-weekly human dosing. Additionally, we assess the effects of these peptides on weight-reduction, food intake, glucose control, and energy expenditure in an established DIO mouse model compared to clinically relevant GLP-1R agonists (e.g. semaglutide) and dual GLP-1R/GIPR agonists (e.g. tirzepatide). Results Optimized triagonists normalize body weight in DIO mice and enhance energy expenditure in a manner superior to that of GLP-1R mono-agonists and GLP-1R/GIPR co-agonists. Conclusions These pre-clinical data suggest unimolecular poly-pharmacology as an effective means to target multiple mechanisms contributing to obesity and further implicate GcgR activation as the differentiating factor between incretin receptor mono- or dual-agonists and triagonists.
Details the design of unimolecular peptide triagonists for GLP-1R/GIPR/GCGR. Optimal weight-loss is achieved when receptor potency ratio is weighted toward GCGR vs GLP-1R or GIPR. These agonists are protracted for once-weekly human dosing. Optimized triagonists normalizes body weight & enhance energy expenditure in mice. Efficacy of optimized triagonists is superior to GLP-1R & GLP-1R/GIPR agonists.
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Affiliation(s)
- Patrick J Knerr
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA
| | | | | | | | | | - Yantao He
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA
| | | | | | - Diego Perez-Tilve
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | | | - Brian Finan
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA.
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9
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Zhu H, Cai H, Wang X, Chen T, Zhen C, Zhang Z, Ruan X, Li G. Sodium-glucose co-transporter 1 (SGLT1) differentially regulates gluconeogenesis and GLP-1 receptor (GLP-1R) expression in different diabetic rats: a preliminary validation of the hypothesis of "SGLT1 bridge" as an indication for "surgical diabetes". ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:481. [PMID: 35571394 PMCID: PMC9096370 DOI: 10.21037/atm-22-1769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 04/20/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND Sodium-glucose co-transporter 1 (SGLT1) may play a synergistic role in gluconeogenesis (GNG) and glucagon-like peptide-1 (GLP-1) expression. We proposed the hypothesis of a "SGLT1 bridge" as an indication for "surgical diabetes" that was preliminary validated in the present study. METHODS We selected nonobese diabetic Goto-Kakizaki (GK) rats and Zuker diabetic fat (ZDF) rats to represent advanced and early diabetes, respectively. Based on glucose gavage with or without SGLT1 inhibitor phlorizin, the rats were divided into 4 groups: Gk-Glu, GK-P, ZDF-Glu, and ZDF-P. The expressions of SGLT1, GLP-1 receptor (GLP-1R), glucose-6 phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase-1 (Pck1) were determined by immunohistochemistry (IHC) or quantitative reverse transcription polymerase chain reaction (RT-qPCR), and the effects of phlorizin were analyzed. RESULTS Glucose tolerance was worse in GK rats and the homeostasis model assessment-insulin resistance (HOMA-IR) was higher in ZDF rats, indicating different pathophysiological conditions between the different diabetic rats. GK rats showed higher activity of duodenal SGLT1 (P=0.022) and jejunal SGLT1 mRNA expression (P=0.000) and lower SGLT1 mRNA expression in the liver (P=0.000) and pancreas (P=0.000). Phlorizin effectively inhibited the activity of duodenal SGLT1 in both GK rats (P=0.000) and ZDF rats (P=0.000). In ZDF rats, the expression of GLP-1R mRNA was downregulated in the jejunum (P=0.001) and upregulated in the pancreas (P=0.021) by phlorizin, but there were no regulatory effects on GLP-1R mRNA in the jejunum and pancreas of GK rats. As for the regulatory effects on GNG, phlorizin upregulated Pck1 mRNA in the duodenum (P=0.000) and the jejunum (P=0.038), whereas it downregulated hepatic G6Pase mRNA in ZDF rats (P=0.005) and Pck1 mRNA expression in GK rats (P=0.001), suggesting that SGLT1 inhibitor may have upregulated intestinal GNG in ZDF rats and downregulated hepatic GNG in both ZDF and GK rats. CONCLUSIONS SGLT1 showed synergistic regulatory effects on the entero-insular axis (EIA) and the gut-brain-liver axis (GBLA), preliminarily validating the hypothesis of a "SGLT1 bridge". The distinct expression of SGLT1 and its differentially regulatory effects on diabetic rats with different pathophysiological conditions may provide probable potential indications involved in the "Surgical Diabetes" that is supposed as the inclusion for diabetic surgery.
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Affiliation(s)
- Hengliang Zhu
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of General Surgery, Shenzhen University General Hospital & Shenzhen University Clinical Medical Academy, Shenzhen University, Shenzhen, China
| | - Huajie Cai
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaokun Wang
- Department of Gastrointestinal & Hernia Surgery, Ganzhou People’s Hospital, Ganzhou, China
| | - Tao Chen
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chaohui Zhen
- Department of General Surgery, Shenzhen University General Hospital & Shenzhen University Clinical Medical Academy, Shenzhen University, Shenzhen, China
| | - Zhenzhan Zhang
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaojiao Ruan
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Guoxin Li
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, China
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10
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Evans RM, Wei Z. Interorgan crosstalk in pancreatic islet function and pathology. FEBS Lett 2022; 596:607-619. [PMID: 35014695 DOI: 10.1002/1873-3468.14282] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 12/16/2021] [Accepted: 12/28/2021] [Indexed: 12/14/2022]
Abstract
Pancreatic β cells secrete insulin in response to glucose, a process that is regulated at multiple levels, including a network of input signals from other organ systems. Impaired islet function contributes to the pathogenesis of type 2 diabetes mellitus (T2DM), and targeting inter-organ communications, such as GLP-1 signalling, to enhance β-cell function has been proven to be a successful therapeutic strategy in the last decade. In this review, we will discuss recent advances in inter-organ communication from the metabolic, immune and neural system to pancreatic islets, their biological implication in normal pancreas endocrine function and their role in the (mal)adaptive responses of islet to nutrition-induced stress.
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Affiliation(s)
- Ronald M Evans
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Zong Wei
- Department of Physiology and Biomedical Engineering, Mayo Clinic Arizona, Scottsdale, AZ, USA
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11
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Zhou M, Wang L, Zhou L, Chang X, Zhu X. Novel Insight into the Mechanism of Metabolic Surgery Causing the Diversity in Glycemic Status in Type 2 Diabetes. Exp Clin Endocrinol Diabetes 2022; 130:484-492. [PMID: 34979572 DOI: 10.1055/a-1708-3214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Metabolic surgery results in diverse glycemic status in patients with type 2 diabetes (T2D), including hyperglycemia without remission, significant amelioration of hyperglycemia with partial remission, complete restoration of euglycemia, or with prolonged remission, hyperglycemia recurrence in relapses after remission, or post-bariatric hypoglycemia. Unfortunately, it is not known how metabolic surgery leads to this diverse consequence. Here, we discuss the diversity of glycemic status associated with metabolic surgery and the potential mechanisms of T2D remission. We also highlight the relationship between the change in low-grade inflammation and T2D remission after metabolic surgery. We hypothesize that the level of inflammatory and anti-inflammatory cytokines controls the efficacy of metabolic surgery in patients with T2D. This hypothesis may provide further insight into the mechanism of the beneficial effects of metabolic surgery patients with T2D.
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Affiliation(s)
- Mengxiao Zhou
- Key Laboratory of Clinical Diagnostics, North University of Hebei, Zhangjiakou, China.,Department of Blood Transfusion, Forth Hospital of Shijiazhuang, Shijiazhuang, China
| | - Lijuan Wang
- Department of Day Care Unit, Gansu Hospital of Traditional Chinese Medicine, Lanzhou, China
| | - Lujin Zhou
- Key Laboratory of Clinical Diagnostics, North University of Hebei, Zhangjiakou, China
| | - Xiaotong Chang
- Key Laboratory of Clinical Diagnostics, North University of Hebei, Zhangjiakou, China
| | - Xiaobo Zhu
- Key Laboratory of Clinical Diagnostics, North University of Hebei, Zhangjiakou, China
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12
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Gasbjerg LS, Bari EJ, Christensen M, Knop FK. Exendin(9-39)NH 2 : Recommendations for clinical use based on a systematic literature review. Diabetes Obes Metab 2021; 23:2419-2436. [PMID: 34351033 DOI: 10.1111/dom.14507] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 07/23/2021] [Accepted: 07/28/2021] [Indexed: 12/25/2022]
Abstract
AIM To present an overview of exendin(9-39)NH2 usage as a scientific tool in humans and provide recommendations for dosage and infusion regimes. METHODS We systematically searched the literature on exendin(9-39)NH2 and included for review 44 clinical studies reporting use of exendin(9-39)NH2 in humans. RESULTS Exendin(9-39)NH2 binds to the orthosteric binding site of the glucagon-like peptide-1 (GLP-1) receptor with high affinity. The plasma elimination half-life of exendin(9-39)NH2 after intravenous administration is ~30 minutes, requiring ~2.5 hours of constant infusion before steady-state plasma concentrations can be expected. Studies utilizing infusions with exendin(9-39)NH2 in humans have applied varying regimens (priming with a bolus or constant infusion) and dosages (continuous infusion rate range 30-900 pmol/kg/min) with subsequent differences in effects. Administration of exendin(9-39)NH2 in healthy individuals, patients with diabetes, obese patients, and patients who have undergone bariatric surgery significantly increases fasting and postprandial levels of glucose and glucagon, but has inconsistent effects on circulating concentrations of insulin and C-peptide, gastric emptying, appetite sensations, and food intake. Importantly, exendin(9-39)NH2 induces secretion of all L cell products (ie, in addition to GLP-1, also peptide YY, glucagon-like peptide-2, oxyntomodulin, and glicentin) complicating use of exendin(9-39)NH2 as a tool to study the isolated effect of GLP-1. CONCLUSIONS Exendin(9-39)NH2 is selective for the GLP-1 receptor, with numerous and complex whole-body effects. To obtain GLP-1 receptor blockade in humans, we recommend an initial high-dose infusion, followed by a continuous infusion rate aiming at a ratio of exendin(9-39)NH2 to GLP-1 of 2000:1. Highlights Exendin(9-39)NH2 is a competitive antagonist of the human GLP-1 receptor. Exendin(9-39)NH2 has been used as a tool to delineate human GLP-1 physiology since 1998. Exendin(9-39)NH2 induces secretion of GLP-1 and other L cell products. Reported effects of exendin(9-39)NH2 on insulin levels and food intake are inconsistent. Here, we provide recommendations for the use of exendin(9-39)NH2 in clinical studies.
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Affiliation(s)
- Laerke Smidt Gasbjerg
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Emilie Johanning Bari
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Mikkel Christensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
- Copenhagen Center for Translational Research, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip Krag Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Centre Copenhagen, Gentofte, Denmark
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13
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Ji Y, Lee H, Kaura S, Yip J, Sun H, Guan L, Han W, Ding Y. Effect of Bariatric Surgery on Metabolic Diseases and Underlying Mechanisms. Biomolecules 2021; 11:1582. [PMID: 34827579 PMCID: PMC8615605 DOI: 10.3390/biom11111582] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/11/2021] [Accepted: 10/15/2021] [Indexed: 12/17/2022] Open
Abstract
Obesity is a highly prevalent public health concern, attributed to multifactorial causes and limited in treatment options. Several comorbidities are closely associated with obesity such as the development of type 2 diabetes mellitus (T2DM), cardiovascular and cerebrovascular diseases, and nonalcoholic fatty liver disease (NAFLD). Bariatric surgery, which can be delivered in multiple forms, has been remarked as an effective treatment to decrease the prevalence of obesity and its associated comorbidities. The different types of bariatric surgery create a variety of new pathways for food to metabolize in the body and truncate the stomach's caliber. As a result, only a small quantity of food is tolerated, and the body mass index noticeably decreases. This review describes the improvements of obesity and its comorbidities following bariatric surgery and their mechanism of improvement. Additionally, endocrine function improvements after bariatric surgery, which contributes to the patients' health improvement, are described, including the role of glucagon-like peptide-1 (GLP-1), fibroblast growth factors 19 and 21 (FGF-19, FGF-21), and pancreatic peptide YY (PYY). Lastly, some of the complications of bariatric surgery, including osteoporosis, iron deficiency/anemia, and diarrhea, as well as their potential mechanisms, are described.
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Affiliation(s)
- Yu Ji
- Department of General Surgery, Beijing Luhe Clinical Institute, Capital Medical University, Beijing 101149, China;
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA; (H.L.); (S.K.); (L.G.); (Y.D.)
- John D. Dingell VA Medical Center, 4646 John R Street (11R), Detroit, MI 48201, USA
| | - Hangil Lee
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA; (H.L.); (S.K.); (L.G.); (Y.D.)
| | - Shawn Kaura
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA; (H.L.); (S.K.); (L.G.); (Y.D.)
| | - James Yip
- Department of General Surgery, Wayne State University School of Medicine, Detroit, MI 48201, USA;
| | - Hao Sun
- Central Laboratory, Beijing Luhe Clinical Institute, Capital Medical University, Beijing 101149, China;
| | - Longfei Guan
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA; (H.L.); (S.K.); (L.G.); (Y.D.)
- John D. Dingell VA Medical Center, 4646 John R Street (11R), Detroit, MI 48201, USA
- Department of General Surgery, Wayne State University School of Medicine, Detroit, MI 48201, USA;
- China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing 101149, China
| | - Wei Han
- Department of General Surgery, Beijing Luhe Clinical Institute, Capital Medical University, Beijing 101149, China;
| | - Yuchuan Ding
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA; (H.L.); (S.K.); (L.G.); (Y.D.)
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A pilot study about the development and characterization of a Roux en Y gastric bypass model in obese Yucatan minipigs. Sci Rep 2021; 11:20190. [PMID: 34642370 PMCID: PMC8511153 DOI: 10.1038/s41598-021-98575-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 07/21/2021] [Indexed: 11/30/2022] Open
Abstract
Performing the Roux-en-Y gastric bypass (RYGBP) in obese Yucatan minipigs provides an opportunity to explore the mechanisms behind the effects of this surgery in controlled environmental and nutritional conditions. We hypothesized that RYGBP in these minipigs would induce changes at multiple levels, as in obese humans. We sought to characterize RYGBP in a diet-induced obese minipig model, compared with a pair-fed sham group. After inducing obesity with an ad libitum high-fat/high-sugar diet, we performed RYGBP (n = 7) or sham surgery (n = 6). Oral glucose tolerance tests (OGTT) were performed before and after surgery. Histological analyses were conducted to compare the alimentary limb at sacrifice with tissue sampled during RYGBP surgery. One death occurred in the RYGBP group at postoperative day (POD) 3. Before sacrifice, weight loss was the same across groups. GLP-1 secretion (OGTT) was significantly higher at 15, 30 and 60 min at POD 7, and at 30 and 60 min at POD 30 in the RYGBP group. Incremental insulin area under the curve increased significantly after RYGBP (p = 0.02). RYGBP induced extensive remodeling of the alimentary limb. Results show that RYGBP can be safely performed in obese minipigs, and changes mimic those observed in humans.
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15
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State Scientific Institution “Center for Innovative Medical Technologies of the National Academy of Sciences of Ukraine”, Kiev, Ukraine, Todurov I, Kosiukhno S, State Scientific Institution “Center for Innovative Medical Technologies of the National Academy of Sciences of Ukraine”, Kiev, Ukraine, Perekhrestenko O, State Scientific Institution “Center for Innovative Medical Technologies of the National Academy of Sciences of Ukraine”, Kiev, Ukraine, Kalashnikov O, State Scientific Institution “Center for Innovative Medical Technologies of the National Academy of Sciences of Ukraine”, Kiev, Ukraine, Potapov O, State Scientific Institution “Center for Innovative Medical Technologies of the National Academy of Sciences of Ukraine”, Kiev, Ukraine, Plehutsa О, State Scientific Institution “Center for Innovative Medical Technologies of the National Academy of Sciences of Ukraine”, Kiev, Ukraine. DYNAMICS OF GLUCAGON-LIKE PEPTIDE-1 AFTER LAPAROSCOPIC SLEEVE GASTRECTOMY IN PATIENTS WITH TYPE 2 DIABETES MELLITUS ASSOCIATIONS WITH OBESITY. FIZIOLOHICHNYĬ ZHURNAL 2021; 67:44-51. [DOI: 10.15407/fz67.04.044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Laparoscopic sleeve gastrectomy (LSG) proved to be a valuable procedure for treating obesity complicated by type 2 diabetes mellitus (T2DM). The mechanism of T2DM resolution after LSG is not yet clearly defined. The objective of the study was to investigate the effect of LSG on the secretion of GLP-1 in patients with T2DM associated with obesity. Plasma GLP-1 levels were evaluated by starvation and 15, 30, 60 and 90 min after the standard carbohydrate preload for breakfast, which included 125 ml of balanced high energy Nutricia Nutridrink Protein. Evaluations were made on the eve of the procedure, for 4 days and 3 months after the operation. In 7 patients with T2DM were diagnosed for the first time, in 3 patients with diabetic history 2 years, in 1 patient – 3.5 years and in 1 patient – 10 years. Mean glycated hemoglobin before surgery was 7.7 ± 1.6%, 3 months after LSG – 5.9 ± 0.4%. The concentration of GLP-1 in 30 minutes before surgery was 6.7 ± 0.9 ng/ml. On the 4th day after LSG, the mean level of GLP-1 was 9.6 ± 0.2 ng/ml, which statistically differed from its level in the pre-operative period, and after 3 months the mean level of GLP-1 statistically increased to 13.7 ± 0.3 ng/ml. Thus LSG leads to an early and significant increase in post-prandial secretion GLP-1 in T2DM patients associated with obesity. The rapid postoperative improvement in signs of carbohydrate metabolism indicates the importance of the incretin effect LSG in the implementation of early compensation mechanisms for T2DM and explains the metabolic activity of this operation.
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16
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Jin ZL, Liu W. Progress in treatment of type 2 diabetes by bariatric surgery. World J Diabetes 2021; 12:1187-1199. [PMID: 34512886 PMCID: PMC8394224 DOI: 10.4239/wjd.v12.i8.1187] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/29/2021] [Accepted: 07/06/2021] [Indexed: 02/06/2023] Open
Abstract
The incidence of type 2 diabetes (T2D) is increasing at an alarming rate worldwide. Bariatric surgical procedures, such as the vertical sleeve gastrectomy and Roux-en-Y gastric bypass, are the most efficient approaches to obtain substantial and durable remission of T2D. The benefits of bariatric surgery are realized through the consequent increased satiety and alterations in gastrointestinal hormones, bile acids, and the intestinal microbiota. A comprehensive understanding of the mechanisms by which various bariatric surgical procedures exert their benefits on T2D could contribute to the design of better non-surgical treatments for T2D. In this review, we describe the classification and evolution of bariatric surgery and explore the multiple mechanisms underlying the effect of bariatric surgery on insulin resistance. Based upon our summarization of the current knowledge on the underlying mechanisms, we speculate that the gut might act as a new target for improving T2D. Our ultimate goal with this review is to provide a better understanding of T2D pathophysiology in order to support development of T2D treatments that are less invasive and more scalable.
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Affiliation(s)
- Zhang-Liu Jin
- Department of General Surgery & Department of Biliopancreatic and Metabolic Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Wei Liu
- Department of General Surgery & Department of Biliopancreatic and Metabolic Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
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17
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Brierley DI, de Lartigue G. Reappraising the role of the vagus nerve in GLP-1-mediated regulation of eating. Br J Pharmacol 2021; 179:584-599. [PMID: 34185884 PMCID: PMC8714868 DOI: 10.1111/bph.15603] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 06/03/2021] [Accepted: 06/16/2021] [Indexed: 12/19/2022] Open
Abstract
Here, we provide a focused review of the evidence for the roles of the vagus nerve in mediating the regulatory effects of peripherally and centrally produced GLP-1 on eating behaviour and energy balance. We particularly focus on recent studies which have used selective genetic, viral, and transcriptomic approaches to provide important insights into the anatomical and functional organisation of GLP-1-mediated gut-brain signalling pathways. A number of these studies have challenged canonical ideas of how GLP-1 acts in the periphery and the brain to regulate eating behaviour, with important implications for the development of pharmacological treatments for obesity.
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Affiliation(s)
- Daniel I Brierley
- Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK
| | - Guillaume de Lartigue
- Center for Integrative Cardiovascular and Metabolic Disease, University of Florida, Gainesville, Florida, USA
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Calcaterra V, Cena H, Pelizzo G, Porri D, Regalbuto C, Vinci F, Destro F, Vestri E, Verduci E, Bosetti A, Zuccotti G, Stanford FC. Bariatric Surgery in Adolescents: To Do or Not to Do? CHILDREN (BASEL, SWITZERLAND) 2021; 8:453. [PMID: 34072065 PMCID: PMC8204230 DOI: 10.3390/children8060453] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/04/2021] [Accepted: 05/25/2021] [Indexed: 01/19/2023]
Abstract
Pediatric obesity is a multifaceted disease that can impact physical and mental health. It is a complex condition that interweaves biological, developmental, environmental, behavioral, and genetic factors. In most cases lifestyle and behavioral modification as well as medical treatment led to poor short-term weight reduction and long-term failure. Thus, bariatric surgery should be considered in adolescents with moderate to severe obesity who have previously participated in lifestyle interventions with unsuccessful outcomes. In particular, laparoscopic sleeve gastrectomy is considered the most commonly performed bariatric surgery worldwide. The procedure is safe and feasible. The efficacy of this weight loss surgical procedure has been demonstrated in pediatric age. Nevertheless, there are barriers at the patient, provider, and health system levels, to be removed. First and foremost, more efforts must be made to prevent decline in nutritional status that is frequent after bariatric surgery, and to avoid inadequate weight loss and weight regain, ensuring successful long-term treatment and allowing healthy growth. In this narrative review, we considered the rationale behind surgical treatment options, outcomes, and clinical indications in adolescents with severe obesity, focusing on LSG, nutritional management, and resolution of metabolic comorbidities.
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Affiliation(s)
- Valeria Calcaterra
- Pediatric and Adolescent Unit, Department of Internal Medicine, University of Pavia, 27100 Pavia, Italy;
- Pediatric Department, “V. Buzzi” Children’s Hospital, 20154 Milan, Italy; (E.V.); (A.B.); (G.Z.)
| | - Hellas Cena
- Clinical Nutrition and Dietetics Service, Unit of Internal Medicine and Endocrinology, ICS Maugeri IRCCS, 27100 Pavia, Italy; (H.C.); (D.P.)
- Laboratory of Dietetics and Clinical Nutrition, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia, Italy
| | - Gloria Pelizzo
- Pediatric Surgery Department, “V. Buzzi” Children’s Hospital, 20154 Milan, Italy; (F.D.); (E.V.)
| | - Debora Porri
- Clinical Nutrition and Dietetics Service, Unit of Internal Medicine and Endocrinology, ICS Maugeri IRCCS, 27100 Pavia, Italy; (H.C.); (D.P.)
- Laboratory of Dietetics and Clinical Nutrition, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia, Italy
| | - Corrado Regalbuto
- Pediatric Unit, Fond. IRCCS Policlinico S. Matteo and University of Pavia, 27100 Pavia, Italy; (C.R.); (F.V.)
| | - Federica Vinci
- Pediatric Unit, Fond. IRCCS Policlinico S. Matteo and University of Pavia, 27100 Pavia, Italy; (C.R.); (F.V.)
| | - Francesca Destro
- Pediatric Surgery Department, “V. Buzzi” Children’s Hospital, 20154 Milan, Italy; (F.D.); (E.V.)
| | - Elettra Vestri
- Pediatric Surgery Department, “V. Buzzi” Children’s Hospital, 20154 Milan, Italy; (F.D.); (E.V.)
| | - Elvira Verduci
- Pediatric Department, “V. Buzzi” Children’s Hospital, 20154 Milan, Italy; (E.V.); (A.B.); (G.Z.)
- Department of Health Sciences, University of Milan, 20146 Milan, Italy
| | - Alessandra Bosetti
- Pediatric Department, “V. Buzzi” Children’s Hospital, 20154 Milan, Italy; (E.V.); (A.B.); (G.Z.)
| | - Gianvincenzo Zuccotti
- Pediatric Department, “V. Buzzi” Children’s Hospital, 20154 Milan, Italy; (E.V.); (A.B.); (G.Z.)
- “L. Sacco” Department of Biomedical and Clinical Science, University of Milan, 20146 Milan, Italy
| | - Fatima Cody Stanford
- Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA;
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Do Gut Hormones Contribute to Weight Loss and Glycaemic Outcomes after Bariatric Surgery? Nutrients 2021; 13:nu13030762. [PMID: 33652862 PMCID: PMC7996890 DOI: 10.3390/nu13030762] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/18/2021] [Accepted: 02/20/2021] [Indexed: 02/07/2023] Open
Abstract
Bariatric surgery is an effective intervention for management of obesity through treating dysregulated appetite and achieving long-term weight loss maintenance. Moreover, significant changes in glucose homeostasis are observed after bariatric surgery including, in some cases, type 2 diabetes remission from the early postoperative period and postprandial hypoglycaemia. Levels of a number of gut hormones are dramatically increased from the early period after Roux-en-Y gastric bypass and sleeve gastrectomy—the two most commonly performed bariatric procedures—and they have been suggested as important mediators of the observed changes in eating behaviour and glucose homeostasis postoperatively. In this review, we summarise the current evidence from human studies on the alterations of gut hormones after bariatric surgery and their impact on clinical outcomes postoperatively. Studies which assess the role of gut hormones after bariatric surgery on food intake, hunger, satiety and glucose homeostasis through octreotide use (a non-specific inhibitor of gut hormone secretion) as well as with exendin 9–39 (a specific glucagon-like peptide-1 receptor antagonist) are reviewed. The potential use of gut hormones as biomarkers of successful outcomes of bariatric surgery is also evaluated.
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Hindsø M, Svane MS, Hedbäck N, Holst JJ, Madsbad S, Bojsen-Møller KN. The role of GLP-1 in postprandial glucose metabolism after bariatric surgery: a narrative review of human GLP-1 receptor antagonist studies. Surg Obes Relat Dis 2021; 17:1383-1391. [PMID: 33771461 DOI: 10.1016/j.soard.2021.01.041] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 12/22/2020] [Accepted: 01/28/2021] [Indexed: 12/14/2022]
Abstract
The Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) bariatric procedures lead to remission or improvement of type 2 diabetes. A weight loss-independent augmentation of postprandial insulin secretion contributes to the improvement in glycemic control after RYGB and is associated with a ∼10-fold increase in plasma concentrations of the incretin hormone glucagon-like peptide-1 (GLP-1). However, the physiologic importance of the markedly increased postprandial GLP-1 secretion after RYGB has been much debated. The effect of GLP-1 receptor blockade after RYGB has been investigated in 12 studies. The studies indicate a shift toward a more prominent role for GLP-1 in postprandial β-cell function after RYGB. The effect of GLP-1 receptor antagonism on glucose tolerance after RYGB is more complex and is associated with important methodological challenges. The postprandial GLP-1 response is less enhanced after SG compared with RYGB. However, the effect of GLP-1 receptor blockade after SG has been examined in 1 study only and needs further investigation.
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Affiliation(s)
- Morten Hindsø
- Department of Endocrinology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.
| | - Maria S Svane
- Department of Endocrinology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Nora Hedbäck
- Department of Endocrinology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, University of Copenhagen and Novo Nordisk Foundation Center for Basic Metabolic Research, Copenhagen, Denmark
| | - Sten Madsbad
- Department of Endocrinology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
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21
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Piché ME, Tardif I, Auclair A, Poirier P. Effects of bariatric surgery on lipid-lipoprotein profile. Metabolism 2021; 115:154441. [PMID: 33248063 DOI: 10.1016/j.metabol.2020.154441] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 11/06/2020] [Accepted: 11/20/2020] [Indexed: 12/13/2022]
Abstract
Most patients with severe obesity will present some lipid-lipoprotein abnormalities. The atherogenic dyslipidemia associated with severe obesity is characterized by elevated fasting and postprandial triglyceride levels, low high-density lipoprotein cholesterol concentrations, and increased proportion of small and dense low-density lipoproteins. Bariatric surgery has been proven safe and successful in terms of long-term weight loss and improvement in obesity co-existing metabolic conditions including lipid-lipoprotein abnormalities. Nevertheless, bariatric surgery procedures are not all equivalent. We conducted a comprehensive critical analysis of the literature related to severe obesity, bariatric surgery and lipid-lipoprotein metabolism/profile. In this review, we described the metabolic impacts of different bariatric surgery procedures on the lipid-lipoprotein profile, and the mechanisms linking bariatric surgery and dyslipidemia remission based on recent epidemiological, clinical and preclinical studies. Further mechanistic studies are essential to assess the potential of bariatric/metabolic surgery in the management of lipid-lipoprotein abnormalities associated with severe obesity. Understanding the beneficial effects of various bariatric surgery procedures on the lipid-lipoprotein metabolism and profile may result in a wider acceptance of this strategy as a long-term metabolic treatment of lipid-lipoprotein abnormalities in severe obesity and help clinician to develop an individualized and optimal approach in the management of dyslipidemia associated with severe obesity. BRIEF SUMMARY: Abnormal lipid-lipoprotein profile is frequent in patients with severe obesity. Significant improvements in lipid-lipoprotein profile following bariatric surgery occur early in the postoperative period, prior to weight loss, and persists throughout the follow-up. The mechanisms that facilitate the remission of dyslipidemia after bariatric surgery, may involve positive effects on adipose tissue distribution/function, insulin sensitivity, liver fat content/function and lipid-lipoprotein metabolism.
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Affiliation(s)
- Marie-Eve Piché
- Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, Quebec, Canada; Faculty of Medicine, Laval University, Quebec, Canada
| | - Isabelle Tardif
- Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, Quebec, Canada
| | - Audrey Auclair
- Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, Quebec, Canada
| | - Paul Poirier
- Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, Quebec, Canada; Faculty of Pharmacy, Laval University, Quebec, Canada.
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22
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Kittah E, Camilleri M, Jensen MD, Vella A. A Pilot Study Examining the Effects of GLP-1 Receptor Blockade Using Exendin-(9,39) on Gastric Emptying and Caloric Intake in Subjects With and Without Bariatric Surgery. Metab Syndr Relat Disord 2020; 18:406-412. [PMID: 32833560 DOI: 10.1089/met.2020.0049] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Background: Obesity causes significant morbidity and mortality and continues to be a significant public health concern. Unfortunately, lifestyle modification and pharmacotherapy do not produce durable results. This has led to bariatric surgical procedures playing an increasingly prominent role in the management of medically complicated obesity. Roux-en-Y gastric bypass and sleeve gastrectomy are the most commonly performed bariatric surgeries in North America and produce mechanical restriction with accelerated gastrointestinal transit accompanied by increased postprandial secretion of glucagon-like peptide-1 (GLP-1). GLP-1 is a gastrointestinal hormone that delays gastric emptying and causes satiety and weight loss. This raises the possibility that the postprandial rise in GLP-1 might affect feeding behavior over and above the mechanical restriction produced by bariatric surgery. Methods: We, therefore, sought to determine the effects of GLP-1 receptor blockade using exendin-9,39-a competitive antagonist of the actions of GLP-1 at its receptor-on caloric intake and gastrointestinal transit in subjects after sleeve gastrectomy and after Roux-en-Y gastric bypass compared with weight-matched controls. Results: GLP-1 receptor blockade did not alter caloric intake in people after bariatric surgery. However, caloric intake was decreased in age-, weight- and sex-matched control subjects, and the mechanisms require further study. Conclusions: Given the known effects of GLP-1 on gastric accommodation, future studies should ascertain effects of GLP-1 receptor blockade on gastric accommodation, which might be a useful and novel strategy to decrease caloric intake in humans with an intact upper gastrointestinal tract. The Clinical Trial Resigtration number is NCT02779075.
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Affiliation(s)
- Esi Kittah
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
| | - Michael Camilleri
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Michael D Jensen
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
| | - Adrian Vella
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
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Abstract
PURPOSE OF REVIEW The prevalence of pediatric obesity and its associated complications is increasing around the world. Treatment of obesity is challenging and metabolic and bariatric surgery (MBS) is currently the most effective treatment for this condition. At this time, vertical sleeve gastrectomy (VSG) is the most commonly performed bariatric procedure in adolescents. However, knowledge regarding the efficacy, safety, and durability of VSG in adolescents is still evolving. This review summarizes the most recent updates in the field of MBS particularly VSG in adolescents. RECENT FINDINGS MBS is recommended to treat moderate to severe obesity, especially when complicated by comorbidities. The use of VSG for weight loss is increasing among adolescents and produces similar weight loss at five years in both adolescents and adults. The physiologic mechanisms causing weight loss after VSG are multifactorial and still being investigated. The complication rate after VSG ranges between 0 and 17.5%. SUMMARY VSG appears to be a well-tolerated and effective procedure in adolescents. However, it continues to be underutilized despite the increasing prevalence of moderate to severe obesity in adolescents. It is thus important to educate providers regarding its benefits and safety profile.
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Affiliation(s)
- Vibha Singhal
- Pediatric Endocrinology, Massachusetts General Hospital for Children
- Neuroendocrine Unit, Massachusetts General Hospital
- MGH Weight Center
| | | | - Madhusmita Misra
- Pediatric Endocrinology, Massachusetts General Hospital for Children
- Neuroendocrine Unit, Massachusetts General Hospital
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Iqbal Z, Adam S, Ho JH, Syed AA, Ammori BJ, Malik RA, Soran H. Metabolic and cardiovascular outcomes of bariatric surgery. Curr Opin Lipidol 2020; 31:246-256. [PMID: 32618731 DOI: 10.1097/mol.0000000000000696] [Citation(s) in RCA: 13] [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: 01/19/2023]
Abstract
PURPOSE OF REVIEW Bariatric surgery is an effective therapy for morbid obesity that also improves weight-related metabolic parameters and reduces morbidity and mortality. The purpose of this review is to consolidate our current understanding of metabolic, macrovascular and microvascular benefits of bariatric surgery and to provide an update. RECENT FINDINGS Early resolution of insulin resistance and type 2 diabetes mellitus (T2DM) varies by type of bariatric surgery and appears to be mediated by changes in secretion of gut hormones, metabolism of bile acids, expression of glucose transporters and the gut microbiome. Dyslipidaemia, atherosclerosis, microvascular complications of obesity and diabetes, systemic and tissue-level inflammation show evidence of regression and hypertension improves significantly after bariatric surgery. SUMMARY Bariatric surgery leads to improvements in obesity-related metabolic comorbidities such as dyslipidaemia, HDL functionality, hypertension, T2DM, insulin resistance and inflammation. It slows the atherosclerotic process and reduces cardiovascular and all-cause mortality. Recent data have demonstrated regression of the microvascular complications of obesity and diabetes including the regeneration of small nerve fibres. The magnitude of change in short-term metabolic effects depends on the surgical procedure whilst longer term effects are related to the amount of sustained excess weight loss.
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Affiliation(s)
- Zohaib Iqbal
- Faculty of Biology, Medicine and Health, University of Manchester
- Cardiovascular Trials Unit, Manchester University NHS Foundation Trust
| | - Safwaan Adam
- Faculty of Biology, Medicine and Health, University of Manchester
- The Christie Hospital NHS Foundation Trust, Manchester
| | - Jan H Ho
- Faculty of Biology, Medicine and Health, University of Manchester
- Cardiovascular Trials Unit, Manchester University NHS Foundation Trust
| | - Akheel A Syed
- Faculty of Biology, Medicine and Health, University of Manchester
- Department of Diabetes, Endocrinology and Obesity Medicine
| | - Basil J Ammori
- Faculty of Biology, Medicine and Health, University of Manchester
- Department of Surgery, Salford Royal NHS Foundation Trust, Salford, UK
| | - Rayaz A Malik
- Faculty of Biology, Medicine and Health, University of Manchester
- Weill-Cornell Medicine-Qatar, Doha, Qatar
| | - Handrean Soran
- Faculty of Biology, Medicine and Health, University of Manchester
- The Christie Hospital NHS Foundation Trust, Manchester
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25
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Davis EM, Sandoval DA. Glucagon‐Like Peptide‐1: Actions and Influence on Pancreatic Hormone Function. Compr Physiol 2020; 10:577-595. [DOI: 10.1002/cphy.c190025] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Gasbjerg LS, Bergmann NC, Stensen S, Christensen MB, Rosenkilde MM, Holst JJ, Nauck M, Knop FK. Evaluation of the incretin effect in humans using GIP and GLP-1 receptor antagonists. Peptides 2020; 125:170183. [PMID: 31693916 DOI: 10.1016/j.peptides.2019.170183] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 10/22/2019] [Accepted: 10/24/2019] [Indexed: 02/07/2023]
Abstract
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) potentiate glucose-induced insulin secretion and are therefore thought to be responsible for the incretin effect. The magnitude of the incretin effect, defined as the fraction of postprandial insulin secretion stimulated by intestinal factors, has been reported to be up to ∼60% in healthy individuals. In several pathological conditions but especially in patients with type 2 diabetes, the incretin effect is severely reduced or even absent. In line with this, the insulinotropic effects of GIP and GLP-1 are impaired in patients with type 2 diabetes, even when administered in supraphysiological doses. In healthy individuals, GIP has been proposed to be the most important incretin hormone of the two, but the individual contribution of the two is difficult to determine. However, using incretin hormone receptor antagonists: the novel GIP receptor antagonist GIP(3-30)NH2 and the widely used GLP-1 receptor antagonist exendin(9-39)NH2, we can now distinguish between the effects of the two hormones. In this review, we present and discuss studies in which the individual contribution of GIP and GLP-1 to the incretin effect in healthy individuals have been estimated and discuss the limitations of using incretin hormone receptor antagonists.
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Affiliation(s)
- Lærke S Gasbjerg
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Natasha C Bergmann
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Signe Stensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Mikkel B Christensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Michael Nauck
- Diabetes Division, St. Josef Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Gentofte, Denmark
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Abstract
PURPOSE OF REVIEW We seek to characterize the impact of bariatric surgery on diabetes mellitus by recalling its history, examining the clinical data, exploring the putative mechanisms of action, and anticipating its future. RECENT FINDINGS Results of clinical trials reveal that bariatric surgery induces remission of diabetes in 33-90% of individuals at 1-year post-treatment versus 0-39% of medically managed. Remission rates decrease over time but remain higher in surgically treated individuals. Investigations have revealed numerous actions of surgery including effects on intestinal physiology, neuronal signaling, incretin hormone secretion, bile acid metabolism, and microbiome changes. Bariatric surgery improves control of diabetes through both weight-dependent and weight-independent actions. These various mechanisms help explain the difference between individuals treated surgically vs. medically. They also explain differing effects of various bariatric surgery procedure types. Understanding how surgery affects diabetes will help optimize utilization of the therapy for both disease prevention and treatment.
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Affiliation(s)
- Alison H Affinati
- Division of Metabolism, Endocrinology and Diabetes (MEND), Department of Internal Medicine, Michigan Medicine, University of Michigan, 24 Frank Lloyd Wright Drive, Lobby G, Suite 1500, Ann Arbor, MI, 48106-0482, USA
| | - Nazanene H Esfandiari
- Division of Metabolism, Endocrinology and Diabetes (MEND), Department of Internal Medicine, Michigan Medicine, University of Michigan, 24 Frank Lloyd Wright Drive, Lobby G, Suite 1500, Ann Arbor, MI, 48106-0482, USA
| | - Elif A Oral
- Division of Metabolism, Endocrinology and Diabetes (MEND), Department of Internal Medicine, Michigan Medicine, University of Michigan, 24 Frank Lloyd Wright Drive, Lobby G, Suite 1500, Ann Arbor, MI, 48106-0482, USA
| | - Andrew T Kraftson
- Division of Metabolism, Endocrinology and Diabetes (MEND), Department of Internal Medicine, Michigan Medicine, University of Michigan, 24 Frank Lloyd Wright Drive, Lobby G, Suite 1500, Ann Arbor, MI, 48106-0482, USA.
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Wang Y, Guo X, Lu X, Mattar S, Kassab G. Mechanisms of Weight Loss After Sleeve Gastrectomy and Adjustable Gastric Banding: Far More Than Just Restriction. Obesity (Silver Spring) 2019; 27:1776-1783. [PMID: 31545007 DOI: 10.1002/oby.22623] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Accepted: 07/15/2019] [Indexed: 12/18/2022]
Abstract
Obesity has reached global epidemic proportions in recent decades. Bariatric surgery is currently accepted as most effective in alleviating morbid obesity and related disorders. Sleeve gastrectomy (SG) and adjustable gastric banding (AGB) have gained popularity since the beginning of this century because of their efficacy, safety, and simplicity. SG, in particular, has emerged as the most popular bariatric procedure because of its simpler concept and shorter operative time compared with gastric bypass. Caloric restriction, however, cannot account for the sustained weight loss and improved glucose metabolism seen following SG and AGB. Other mechanisms, including changes in gastrointestinal hormone secretion, rearrangement of hypothalamic and vagal control, alteration in energy expenditure, and re-regulation of bile acid metabolism and the intestinal flora environment, are thought to contribute to the postoperative benefits. This review focuses on clinical and experimental literature addressing the potential mechanisms for SG and AGB procedures in human and animal models. Understanding such mechanisms can provide important insight into how current gastric restrictive procedures work and how future treatments of obesity, both surgical and nonsurgical, can be developed.
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Affiliation(s)
- Yanmin Wang
- California Medical Innovations Institute, San Diego, California, USA
| | - Xiaomei Guo
- California Medical Innovations Institute, San Diego, California, USA
| | - Xiao Lu
- California Medical Innovations Institute, San Diego, California, USA
| | - Samer Mattar
- Swedish Weight Loss Services, Seattle, Washington, USA
| | - Ghassan Kassab
- California Medical Innovations Institute, San Diego, California, USA
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Kokkinos A, Tsilingiris D, le Roux CW, Rubino F, Mantzoros CS. Will medications that mimic gut hormones or target their receptors eventually replace bariatric surgery? Metabolism 2019; 100:153960. [PMID: 31412266 DOI: 10.1016/j.metabol.2019.153960] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 07/31/2019] [Accepted: 08/05/2019] [Indexed: 02/07/2023]
Abstract
Bariatric surgery is currently the most effective therapeutic modality through which sustained beneficial effects on weight loss and metabolic improvement are achieved. During recent years, indications for bariatric surgery have been expanded to include cases of poorly controlled type 2 (T2DM) diabetes mellitus in lesser extremes of body weight. A spectrum of the beneficial effects of surgery is attributed to robust changes of postprandial gut peptide responses that are observed post operatively. Consolidated knowledge regarding gut peptide physiology as well as emerging new evidence shedding light on the mode of action of previously overlooked gut hormones provide appealing potential obesity and T2DM therapeutic perspectives. The accumulation of evidence from the effect of exogenous administration of native gut peptides alone or in combinations to humans as well as the development of mimetic agents exerting agonistic effects on combinations of gut hormone receptors pave the way for future integrated gut peptide-based treatments, which may mimic the effects of bariatric surgery.
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Affiliation(s)
- Alexander Kokkinos
- First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.
| | - Dimitrios Tsilingiris
- First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Carel W le Roux
- Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland
| | - Francesco Rubino
- Department of Metabolic and Bariatric Surgery, Diabetes and Nutritional Science Division, King's College Hospital, London, United Kingdom
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, USA
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30
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Du J, Hu C, Bai J, Peng M, Wang Q, Zhao N, Wang Y, Wang G, Tao K, Wang G, Xia Z. Intestinal Glucose Absorption Was Reduced by Vertical Sleeve Gastrectomy via Decreased Gastric Leptin Secretion. Obes Surg 2019; 28:3851-3861. [PMID: 29915972 DOI: 10.1007/s11695-018-3351-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND The unique effects of gastric resection after vertical sleeve gastrectomy (VSG) on type 2 diabetes mellitus remain unclear. This work aimed to investigate the effects of VSG on gastric leptin expression and intestinal glucose absorption in high-fat diet-induced obesity. METHODS Male C57BL/6J mice were fed a high-fat diet (HFD) to induce obesity. HFD mice were randomized into VSG and sham-operation groups, and the relevant parameters were measured at 8 weeks postoperation. RESULTS Higher gastric leptin expression and increased intestinal glucose transport were observed in the HFD mice. Furthermore, VSG reduced gastric leptin expression and the intestinal absorption of alimentary glucose. Both exogenous leptin replenishment during the oral glucose tolerance test (OGTT) and the addition of leptin into the everted isolated jejunum loops in vitro restored the glucose transport capacity in VSG-operated mice, and this effect was abolished when the glucose transporter GLUT2 was blocked with phloretin. Moreover, phloretin almost completely suppressed glucose transport in the HFD mice. Intestinal immunohistochemistry in the obese mice showed increased GLUT2 and diminished sodium glucose co-transporter 1 (SGLT-1) in the apical membrane of enterocytes. Decreased GLUT2 and enhanced SGLT1 were observed following VSG. VSG also reduced the phosphorylation status of protein kinase C isoenzyme β II (PKCβ II) in the jejunum, which was stimulated by the combination of leptin and glucose. CONCLUSION Our data demonstrated that the decreased secretion of gastric leptin in VSG results in a decrease in intestinal glucose absorption via modulation of GLUT2 translocation.
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Affiliation(s)
- Jinpeng Du
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Chaojie Hu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Jie Bai
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Miaomiao Peng
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Qingbo Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Ning Zhao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Yu Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Guobin Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Kaixiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Geng Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China.
| | - Zefeng Xia
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China.
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31
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Douros JD, Tong J, D’Alessio DA. The Effects of Bariatric Surgery on Islet Function, Insulin Secretion, and Glucose Control. Endocr Rev 2019; 40:1394-1423. [PMID: 31241742 PMCID: PMC6749890 DOI: 10.1210/er.2018-00183] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 04/23/2019] [Indexed: 01/19/2023]
Abstract
Although bariatric surgery was developed primarily to treat morbid obesity, evidence from the earliest clinical observations to the most recent clinical trials consistently demonstrates that these procedures have substantial effects on glucose metabolism. A large base of research indicates that bariatric surgeries such as Roux-en-Y gastric bypass (RYGB), vertical sleeve gastrectomy (VSG), and biliopancreatic diversion (BPD) improve diabetes in most patients, with effects frequently evident prior to substantial weight reduction. There is now unequivocal evidence from randomized controlled trials that the efficacy of surgery is superior to intensive life-style/medical management. Despite advances in the clinical understanding and application of bariatric surgery, there remains only limited knowledge of the mechanisms by which these procedures confer such large changes to metabolic physiology. The improvement of insulin sensitivity that occurs with weight loss (e.g., the result of diet, illness, physical training) also accompanies bariatric surgery. However, there is evidence to support specific effects of surgery on insulin clearance, hepatic glucose production, and islet function. Understanding the mechanisms by which surgery affects these parameters of glucose regulation has the potential to identify new targets for therapeutic discovery. Studies to distinguish among bariatric surgeries on key parameters of glucose metabolism are limited but would be of considerable value to assist clinicians in selecting specific procedures and investigators in delineating the resulting physiology. This review is based on literature related to factors governing glucose metabolism and insulin secretion after the commonly used RYGB and VSG, and the less frequently used BPD and adjustable gastric banding.
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Affiliation(s)
- Jonathan D Douros
- Division of Endocrinology, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
| | - Jenny Tong
- Division of Endocrinology, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
| | - David A D’Alessio
- Division of Endocrinology, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
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32
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Bypassed and Preserved Stomach Resulted in Superior Glucose Control in Sprague-Dawley Rats with Streptozotocin-Induced Diabetes. Sci Rep 2019; 9:9981. [PMID: 31292518 PMCID: PMC6620334 DOI: 10.1038/s41598-019-46418-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 06/28/2019] [Indexed: 12/18/2022] Open
Abstract
Recent studies suggest the possibility of the stomach playing a role in diabetes remission after bariatric surgery. In this study, we investigated whether bypassing the stomach alleviates diabetes in diabetic rodent model. Eighteen moderately obese and diabetic Sprague-Dawley rats were randomly assigned to Esophagoduodenostomy with or without gastric preservation (EDG and EDNG/total gastrectomy, respectively), and SHAM groups. Bodyweight, food intake, fasting glucose level, oral glucose tolerance test result (OGTT), and hormone levels (insulin, glucagon-like peptide-1, ghrelin, gastrin and glucagon) were measured preoperative and postoperatively. Postoperatively, bodyweight and food intake did not differ significantly between the EDG and EDNG groups. Postoperative fasting blood glucose and OGTT results declined significantly in the EDG and EDNG group when compared with the respective preoperative levels. Postoperative glucose control improvements in EDNG group was significantly inferior when compared to EDG. Compared preoperatively, postoperative plasma ghrelin and gastrin levels declined significantly in EDNG group. Preoperative and postoperative plasma GLP-1 level did not differ significantly among all the groups. Postoperatively, EDG group had significantly higher insulin and lower glucagon levels when compared with SHAM. In conclusion, bypassing and preserving the stomach resulted in superior glucose control improvements than total gastrectomy.
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Miras AD, Pérez-Pevida B, Aldhwayan M, Kamocka A, McGlone ER, Al-Najim W, Chahal H, Batterham RL, McGowan B, Khan O, Greener V, Ahmed AR, Petrie A, Scholtz S, Bloom SR, Tan TM. Adjunctive liraglutide treatment in patients with persistent or recurrent type 2 diabetes after metabolic surgery (GRAVITAS): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2019; 7:549-559. [PMID: 31174993 DOI: 10.1016/s2213-8587(19)30157-3] [Citation(s) in RCA: 110] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 04/20/2019] [Accepted: 04/22/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Many patients with type 2 diabetes do not achieve sustained diabetes remission after metabolic (bariatric) surgery for the treatment of obesity. Liraglutide, a glucagon-like peptide-1 analogue, improves glycaemic control and reduces bodyweight in patients with type 2 diabetes. Our aim was to assess the safety and efficacy of liraglutide 1·8 mg in patients with persistent or recurrent type 2 diabetes after metabolic surgery. METHODS In the GRAVITAS randomised double-blind, placebo-controlled trial, we enrolled adults who had undergone Roux-en-Y gastric bypass or vertical sleeve gastrectomy and had persistent or recurrent type 2 diabetes with HbA1c levels higher than 48 mmol/mol (6·5%) at least 1 year after surgery from five hospitals in London, UK. Participants were randomly assigned (2:1) via a computer-generated sequence to either subcutaneous liraglutide 1·8 mg once daily or placebo, both given together with a reduced-calorie diet, aiming for a 500 kcal per day deficit from baseline energy intake, and increased physical activity. The primary outcome was the change in HbA1c from baseline to the end of the study period at 26 weeks, assessed in patients who completed the trial. Safety was assessed in the safety analysis population, consisting of all participants who received either liraglutide or placebo. This trial is registered with EudraCT, number 2014-003923-23, and the ISRCTN registry, number ISRCTN13643081. FINDINGS Between Jan 29, 2016, and May 2, 2018, we assigned 80 patients to receive either liraglutide (n=53) or placebo (n=27). 71 (89%) participants completed the study and were included in the principal complete-cases analysis. In a multivariable linear regression analysis, with baseline HbA1c levels and surgery type as covariates, liraglutide treatment was associated with a difference of -13·3 mmol/mol (-1·22%, 95% CI -19·7 to -7·0; p=0·0001) in HbA1c change from baseline to 26 weeks, compared with placebo. Type of surgery had no significant effect on the outcome. 24 (45%) of 53 patients assigned to liraglutide and 11 (41%) of 27 assigned to placebo reported adverse effects: these were mainly gastrointestinal and in line with previous experience with liraglutide. There was one death during the study in a patient assigned to the placebo group, which was considered unrelated to study treatment. INTERPRETATION These findings support the use of adjunctive liraglutide treatment in patients with persistent or recurrent type 2 diabetes after metabolic surgery. FUNDING JP Moulton Foundation.
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Affiliation(s)
- Alexander Dimitri Miras
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London and Imperial College Healthcare NHS Trust, London, UK
| | - Belén Pérez-Pevida
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London and Imperial College Healthcare NHS Trust, London, UK
| | - Madhawi Aldhwayan
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London and Imperial College Healthcare NHS Trust, London, UK
| | - Anna Kamocka
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London and Imperial College Healthcare NHS Trust, London, UK
| | - Emma Rose McGlone
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London and Imperial College Healthcare NHS Trust, London, UK
| | - Werd Al-Najim
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London and Imperial College Healthcare NHS Trust, London, UK; Diabetes Complications Research Centre, Conway Institute, University College Dublin, Dublin, Ireland
| | - Harvinder Chahal
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London and Imperial College Healthcare NHS Trust, London, UK
| | - Rachel L Batterham
- Centre for Obesity Research, Rayne Institute, Department of Medicine, University College London, London, UK; Bariatric Centre for Weight Management and Metabolic Surgery and National Institute for Health Research Biomedical Research Centre, University College London Hospital, London, UK
| | - Barbara McGowan
- Diabetes and Endocrinology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Omar Khan
- Surgery, St George's University Hospitals NHS Trust, London, UK
| | - Veronica Greener
- Diabetes and Endocrinology, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK
| | - Ahmed R Ahmed
- Department of Surgery & Cancer, Imperial College London and Imperial College Healthcare NHS Trust, London, UK
| | - Aviva Petrie
- Eastman Dental Institute, University College London, London, UK
| | - Samantha Scholtz
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London and Imperial College Healthcare NHS Trust, London, UK
| | - Stephen R Bloom
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London and Imperial College Healthcare NHS Trust, London, UK
| | - Tricia M Tan
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London and Imperial College Healthcare NHS Trust, London, UK.
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Svane MS, Bojsen-Møller KN, Martinussen C, Dirksen C, Madsen JL, Reitelseder S, Holm L, Rehfeld JF, Kristiansen VB, van Hall G, Holst JJ, Madsbad S. Postprandial Nutrient Handling and Gastrointestinal Hormone Secretion After Roux-en-Y Gastric Bypass vs Sleeve Gastrectomy. Gastroenterology 2019; 156:1627-1641.e1. [PMID: 30742833 DOI: 10.1053/j.gastro.2019.01.262] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 01/04/2019] [Accepted: 01/14/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) induce substantial weight loss and improve glycemic control in patients with type 2 diabetes, but it is not clear whether these occur via the same mechanisms. We compared absorption rates of glucose and protein, as well as profiles of gastro-entero-pancreatic hormones, in patients who had undergone SG or RYGB vs controls. METHODS We performed a cross-sectional study of 12 patients who had undergone sleeve gastrectomy, 12 patients who had undergone RYGB, and 12 individuals who had undergone neither surgery (controls), all in Denmark. Study participants were matched for body mass index, age, sex, and postoperative weight loss, and all had stable weights. They received continuous infusions of stable isotopes of glucose, glycerol, phenylalanine, tyrosine, and urea before and during a mixed meal containing labeled glucose and intrinsically phenylalanine-labeled caseinate. Blood samples were collected for 6 hours, at 10- to 60-minute intervals, and analyzed. RESULTS The systemic appearance of ingested glucose was faster after RYGB and SG vs controls; the peak glucose appearance rate was 64% higher after RYGB, and 23% higher after SG (both P < .05); the peak phenylalanine appearance rate from ingested casein was 118% higher after RYGB (P < .01), but similar between patients who had undergone SG and controls. Larger, but more transient increases in levels of plasma glucose and amino acids were accompanied by higher secretion of insulin, glucagon-like peptide 1, peptide YY, and cholecystokinin after RYGB, whereas levels of ghrelin were lower after SG, compared with RYGB and controls. Total 6-hour oral recovery of ingested glucose and protein was comparable among groups. CONCLUSIONS Postprandial glucose and protein absorption and gastro-entero-pancreatic hormone secretions differ after SG and RYGB. RYGB was characterized by accelerated absorption of glucose and amino acids, whereas protein metabolism after SG did not differ significantly from controls, suggesting that different mechanisms explain improved glycemic control and weight loss after these surgical procedures. ClinicalTrials.gov ID NCT03046186.
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Affiliation(s)
- Maria S Svane
- Department of Endocrinology, Copenhagen University Hospital Hvidovre, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark
| | - Kirstine N Bojsen-Møller
- Department of Endocrinology, Copenhagen University Hospital Hvidovre, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark
| | - Christoffer Martinussen
- Department of Endocrinology, Copenhagen University Hospital Hvidovre, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark
| | - Carsten Dirksen
- Department of Endocrinology, Copenhagen University Hospital Hvidovre, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark
| | - Jan L Madsen
- Department of Clinical Physiology and Nuclear Medicine, Centre for Functional Imaging and Research, Copenhagen University Hospital Hvidovre, Denmark
| | - Søren Reitelseder
- Institute of Sports Medicine Copenhagen, Bispebjerg Hospital, Copenhagen, Denmark
| | - Lars Holm
- Institute of Sports Medicine Copenhagen, Bispebjerg Hospital, Copenhagen, Denmark; School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, United Kingdom
| | - Jens F Rehfeld
- Department of Clinical Biochemistry, Rigshospitalet, Denmark
| | - Viggo B Kristiansen
- Department of Surgical Gastroenterology, Copenhagen University Hospital Hvidovre, Denmark
| | - Gerrit van Hall
- Clinical Metabolomics Core Facility, Rigshospitalet, Denmark; Department of Biomedical Sciences, University of Copenhagen, Denmark
| | - Jens J Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark; Department of Biomedical Sciences, University of Copenhagen, Denmark.
| | - Sten Madsbad
- Department of Endocrinology, Copenhagen University Hospital Hvidovre, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark; Department of Biomedical Sciences, University of Copenhagen, Denmark.
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Halpern B, Mancini MC. Metabolic surgery for the treatment of type 2 diabetes in patients with BMI lower than 35 kg/m 2 : Why caution is still needed. Obes Rev 2019; 20:633-647. [PMID: 30821085 DOI: 10.1111/obr.12837] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 12/17/2018] [Accepted: 12/21/2018] [Indexed: 12/13/2022]
Abstract
Bariatric surgery has shifted from being a risky procedure to an evidence-based one, with proven benefits on all-cause mortality, cardiovascular disease, cancer, and diabetes control. The procedure has an overall positive result on type 2 diabetes mellitus (T2DM), with a substantial number of patients achieving disease remission. This has resulted in several studies assessing possible weight-independent effects of bariatric surgery on glycemic improvement, in addition to recommendation of the procedure to patients with class 1 obesity and T2DM, for whom the procedure was classically not indicated, and adoption of a new term, "metabolic surgery," to highlight the overall metabolic benefit of the procedure beyond weight loss. Recently, the Diabetes Surgery Summit (DSS) has included metabolic surgery in its T2DM treatment algorithm. Although the discussion brought by this consensus is highly relevant, the recommendation of metabolic surgery for patients with uncontrolled T2DM and a body mass index of 30 to 35 kg/m2 still lacks enough evidence. This article provides an overall view of the metabolic benefits of bariatric/metabolic surgery in patients with class 1 obesity, compares the procedure against clinical treatment, and presents our rationale for defending caution on recommending the procedure to less obese individuals.
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Affiliation(s)
- Bruno Halpern
- Obesity Group, Department of Endocrinology and Metabolism, Clinics Hospital, University of São Paulo Medical School, São Paulo, Brazil
| | - Marcio Correa Mancini
- Obesity Group, Department of Endocrinology and Metabolism, Clinics Hospital, University of São Paulo Medical School, São Paulo, Brazil
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Sandoval DA. Mechanisms for the metabolic success of bariatric surgery. J Neuroendocrinol 2019; 31:e12708. [PMID: 30882956 PMCID: PMC9205614 DOI: 10.1111/jne.12708] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 03/11/2019] [Accepted: 03/13/2019] [Indexed: 12/14/2022]
Abstract
To date, bariatric surgery remains the most effective strategy for the treatment of obesity and its comorbidities. However, given the enormity of the obesity epidemic, and sometimes variable results, it is not a feasible strategy for the treatment of all obese patients. A simple PubMed search for 'bariatric surgery' reveals over 28 000 papers that have been published since the 1940s when the first bariatric surgeries were performed. However, there is still an incomplete understanding of the mechanisms for the weight loss and metabolic success of surgery. An understanding of the mechanisms is important because it may lead to greater understanding of the pathophysiology of obesity and thus surgery-alternative strategies for the treatment of all obese patients. In this review, the potential mechanisms that underlie the success of surgery are discussed, with a focus on the potential endocrine, neural and other circulatory factors (eg, bile acids) that have been proposed to play a role.
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Rollins KA, Opitz L, Arnold M, Simon E, Neubauer H, Wolfrum S. The L cell transcriptome is unaffected by vertical sleeve gastrectomy but highly dependent upon position within the gastrointestinal tract. Peptides 2019; 113:22-34. [PMID: 30660763 DOI: 10.1016/j.peptides.2019.01.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 12/07/2018] [Accepted: 01/09/2019] [Indexed: 12/31/2022]
Abstract
Altered GLP-1 secretion from L cells has been implicated in the development of type 2 diabetes mellitus and its resolution following bariatric surgery. However, changes in L cell gene expression, which may form the basis for altered functionality after high fat diet (HFD) or bariatric surgery, have either not been investigated or have given conflicting results. We developed a gcg-DTR-eGFP reporter mouse to isolate ileal and colonic L cells from HFD fed insulin resistant mice and mice showing improved glucose tolerance following vertical sleeve gastrectomy (VSG). Transcriptomic sequencing and identification of genes differentially expressed in response to HFD or VSG revealed small changes with HFD, primarily in immune related genes, but no regulation following VSG. In contrast, large differences were observed between ileal and colonic L cells due to the differential expression of genes involved in nutrient transport and metabolism, reflecting to some extent the differences in the surrounding epithelium. We showed that, in line with the gene expression data, colonic and ileal L cells exhibit differing GLP-1 responses to nutrients (glucose and the gly-sar dipeptide) and hormones (vasopressin). Thus, we hypothesise that colonic and ileal L cells have different physiological roles, with ileal L cells contributing more to postprandial glucose homeostasis by responding to dietary nutrients and colonic cells responding more to non-dietary stimulants.
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Affiliation(s)
- Katherine A Rollins
- Laboratory of Organic Chemistry, ETH Zurich, Schorenstrasse 16, 8603, Schwerzenbach, Switzerland.
| | - Lennart Opitz
- Functional Genomics Center Zurich, University of Zurich/ETH Zurich, Winterthurerstrasse 190, 8057, Zürich, Switzerland.
| | - Myrtha Arnold
- Physiology and Behavior Laboratory, ETH Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland.
| | - Eric Simon
- Boehringer Ingelheim Pharma GmbH & Co KG, Target Discovery Research Department, Birkendorfer Strasse 65, 88397, Biberach/Riss, Germany.
| | - Heike Neubauer
- Boehringer Ingelheim Pharma GmbH & Co KG, Cardiometabolic Diseases Research Department, Birkendorfer Strasse 65, 88397, Biberach/Riss, Germany.
| | - Susanne Wolfrum
- Laboratory of Organic Chemistry, ETH Zurich, Schorenstrasse 16, 8603, Schwerzenbach, Switzerland.
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Laursen TL, Hagemann CA, Wei C, Kazankov K, Thomsen KL, Knop FK, Grønbæk H. Bariatric surgery in patients with non-alcoholic fatty liver disease - from pathophysiology to clinical effects. World J Hepatol 2019; 11:138-149. [PMID: 30820265 PMCID: PMC6393715 DOI: 10.4254/wjh.v11.i2.138] [Citation(s) in RCA: 118] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 11/01/2018] [Accepted: 12/05/2018] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is increasingly recognized as a significant liver disease, and it covers the disease spectrum from simple steatosis with a risk of development of non-alcoholic steatohepatitis (NASH) to fibrosis, subsequent cirrhosis, end-stage liver failure, and liver cancer with a potential need for liver transplantation. NAFLD and NASH are closely related to obesity, metabolic syndrome, and type 2 diabetes (T2D). The role of gut hormones, especially glucagon-like peptide 1 (GLP-1), is important in NAFLD. Bariatric surgery has the potential for inducing great weight loss and may improve the symptoms of metabolic syndrome and T2D. Recent data demonstrated significant effects of bariatric surgery on GLP-1 and other gut hormones and important lipid metabolic and inflammatory abnormalities in the pathophysiology of NAFLD. Therefore, bariatric surgery may reverse the pathological liver changes in NAFLD and NASH patients. In the present review, we describe NAFLD and NASH pathophysiology and the primary effects of bariatric surgery on metabolic pathways. We performed a systematic review of the beneficial and harmful effects and focused on changes in liver disease severity in NAFLD and NASH patients. The specific focus was liver histopathology as assessed by the invasive liver biopsy. Additionally, we reviewed several non-invasive methods used for the assessment of liver disease severity following bariatric surgery.
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Affiliation(s)
- Tea L Laursen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark
| | - Christoffer A Hagemann
- Gubra ApS, Hørsholm 2970, Denmark
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup 2900, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Chunshan Wei
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, the Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, China
| | - Konstantin Kazankov
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark
| | - Karen L Thomsen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark
| | - Filip K Knop
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup 2900, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark
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Zhu H, Wang H, Zheng Z, Ye B, Ruan X, Zheng X, Li G. Ileal transposition rapidly improves glucose tolerance and gradually improves insulin resistance in non-obese type 2 diabetic rats. Gastroenterol Rep (Oxf) 2018; 6:291-297. [PMID: 30430018 PMCID: PMC6225830 DOI: 10.1093/gastro/goy027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 03/04/2018] [Accepted: 06/26/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Many studies have confirmed that ileal transposition can improve type 2 diabetes mellitus (T2DM), accompanied by increased glucagon-like peptide-1 (GLP-1). We performed the experiment on diabetic rats to evaluate the effects and mechanisms of ileal transposition on the glycemic metabolism. METHODS Twenty Goto-Kakizaki (GK) rats were randomly divided into the ileal transposition group (IT group) and the sham operation group (Sham group). Weight, food intake, fasting plasma glucose (FPG), fasting insulin (F-ins), oral glucose tolerance test (OGTT) and GLP-1 were determined at baseline and 1, 4, 8, 16 and 24 weeks post-operatively. The homeostasis model assessment-insulin resistance (HOMA-IR) index and the area under the curve (AUC) during OGTT were measured. Histological determination of the GLP-1 receptor (GLP-1R) was performed on the pancreas and ileum 24 weeks post-operatively. RESULTS In comparison with the Sham group, the IT group showed a higher GLP-1 level and lower AUC at 4, 8, 16 and 24 weeks post-operatively (all P < 0.05) and a lower FPG, F-ins levels and HOMA-IR at 8, 16 and 24 weeks post-operatively (all P < 0.05). Compared with baseline levels, the plasma GLP-1, AUC and FPG levels decreased significantly at each post-operative time point in the IT group (all P < 0.05), but not in the Sham group (all P > 0.05); F-ins and HOMA-IR significantly decreased at 8, 16 and 24 weeks post-operatively in the IT group (all P < 0.05). GLP-1R expression in the IT group was significantly higher than that of the Sham group in both the pancreas and the ileum at 24 weeks post-operatively (P < 0.05). CONCLUSIONS Ileal transposition ameliorated glucose metabolism without reduction in weight or food intake in GK rats, which may be induced by the increased GLP-1 expression. However, the delayed improvement of insulin resistance, accompanied by decreased plasma insulin levels, might not directly result from the increased GLP-1.
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Affiliation(s)
- Hengliang Zhu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Gastrointestinal Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Huaiming Wang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zhihai Zheng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Bailiang Ye
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiaojiao Ruan
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiaofeng Zheng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Guoxin Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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Douros JD, Lewis AG, Smith EP, Niu J, Capozzi M, Wittmann A, Campbell J, Tong J, Wagner C, Mahbod P, Seeley R, D'Alessio DA. Enhanced Glucose Control Following Vertical Sleeve Gastrectomy Does Not Require a β-Cell Glucagon-Like Peptide 1 Receptor. Diabetes 2018; 67:1504-1511. [PMID: 29759973 PMCID: PMC6054432 DOI: 10.2337/db18-0081] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 05/04/2018] [Indexed: 12/12/2022]
Abstract
Bariatric surgeries, including vertical sleeve gastrectomy (VSG), resolve diabetes in 40-50% of patients. Studies examining the molecular mechanisms underlying this effect have centered on the role of the insulinotropic glucagon-like peptide 1 (GLP-1), in great part because of the ∼10-fold rise in its circulating levels after surgery. However, there is currently debate over the role of direct β-cell signaling by GLP-1 to mediate improved glucose tolerance following surgery. In order to assess the importance of β-cell GLP-1 receptor (GLP-1R) for improving glucose control after VSG, a mouse model of this procedure was developed and combined with a genetically modified mouse line allowing an inducible, β-cell-specific Glp1r knockdown (Glp1rβ-cell-ko). Mice with VSG lost ∼20% of body weight over 30 days compared with sham-operated controls and had a ∼60% improvement in glucose tolerance. Isolated islets from VSG mice had significantly greater insulin responses to glucose than controls. Glp1r knockdown in β-cells caused glucose intolerance in diet-induced obese mice compared with obese controls, but VSG improved glycemic profiles to similar levels during oral and intraperitoneal glucose challenges in Glp1rβ-cell-ko and Glp1rWT mice. Therefore, even though the β-cell GLP-1R seems to be important for maintaining glucose tolerance in obese mice, in these experiments it is dispensable for the improvement in glucose tolerance after VSG. Moreover, the metabolic physiology activated by VSG can overcome the deficits in glucose regulation caused by lack of β-cell GLP-1 signaling in obesity.
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Affiliation(s)
- Jonathan D Douros
- Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC
| | - Alfor G Lewis
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, and Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH
- Department of Surgery, University of Michigan, Ann Arbor, MI
| | - Eric P Smith
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, and Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH
| | - JingJing Niu
- Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC
| | - Megan Capozzi
- Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC
| | - April Wittmann
- Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC
| | - Jonathan Campbell
- Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC
| | - Jenny Tong
- Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, and Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH
- Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University, Durham, NC
| | - Constance Wagner
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, and Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH
| | - Parinaz Mahbod
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, and Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH
| | - Randy Seeley
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, and Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH
- Department of Surgery, University of Michigan, Ann Arbor, MI
| | - David A D'Alessio
- Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, and Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH
- Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University, Durham, NC
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Ma J, Vella A. What Has Bariatric Surgery Taught Us About the Role of the Upper Gastrointestinal Tract in the Regulation of Postprandial Glucose Metabolism? Front Endocrinol (Lausanne) 2018; 9:324. [PMID: 29997575 PMCID: PMC6028568 DOI: 10.3389/fendo.2018.00324] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Accepted: 05/31/2018] [Indexed: 02/06/2023] Open
Abstract
The interaction between the upper gastrointestinal tract and the endocrine system is important in the regulation of metabolism and of weight. The gastrointestinal tract has a heterogeneous cellular content and comprises a variety of cells that elaborate paracrine and endocrine mediators that collectively form the entero-endocrine system. The advent of therapy that utilizes these pathways as well as the association of bariatric surgery with diabetes remission has (re-)kindled interest in the role of the gastrointestinal tract in glucose homeostasis. In this review, we will use the changes wrought by bariatric surgery to provide insights into the various gut-pancreas interactions that maintain weight, regulate satiety, and limit glucose excursions after meal ingestion.
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Affiliation(s)
- Jing Ma
- Division of Endocrinology and Metabolism, Shanghai Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic College of Medicine, Rochester, NY, United States
| | - Adrian Vella
- Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic College of Medicine, Rochester, NY, United States
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Smith EP, Polanco G, Yaqub A, Salehi M. Altered glucose metabolism after bariatric surgery: What's GLP-1 got to do with it? Metabolism 2018; 83:159-166. [PMID: 29113813 DOI: 10.1016/j.metabol.2017.10.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2017] [Revised: 10/20/2017] [Accepted: 10/25/2017] [Indexed: 01/20/2023]
Abstract
Bariatric surgery is an effective treatment for obesity. The two widely performed weight-loss procedures, Roux-en-Y gastric bypass (GB) and sleeve gastrectomy (SG), alter postprandial glucose pattern and enhance gut hormone secretion immediately after surgery before significant weight loss. This weight-loss independent glycemic effects of GB has been attributed to an accelerated nutrient transit from stomach pouch to the gut and enhanced secretion of insulinotropic gut factors; in particular, glucagon-like peptide-1 (GLP-1). Meal-induced GLP-1 secretion is as much as tenfold higher in patients after GB compared to non-surgical individuals and inhibition of GLP-1 action during meals reduces postprandial hyperinsulinemia after GB two to three times more than that in persons without surgery. Moreover, in a subgroup of patients with the late complication of postprandial hyperinsulinemic hypoglycemia after GB, GLP1R blockade reverses hypoglycemia by reducing meal stimulated insulin secretion. The role of enteroinsular axis activity after SG, an increasingly popular alternative to GB, is less understood but, similar to GB, SG accelerates nutrient delivery to the intestine, improves glucose tolerance, and increases postprandial GLP-1 secretion. This review will focus on the current evidence for and against the role of GLP-1 on glycemic effects of GB and will also highlight differences between GB and SG.
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Affiliation(s)
- Eric P Smith
- Division of Endocrinology, Diabetes & Metabolism, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
| | - Georgina Polanco
- Division of Endocrinology, Diabetes & Metabolism, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Abid Yaqub
- Division of Endocrinology, Diabetes & Metabolism, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Marzieh Salehi
- Division of Endocrinology, Diabetes & Metabolism, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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Shah M, Pham A, Gershuni V, Mundi MS. Curing Diabetes Through Bariatric Surgery: Evolution of Our Understanding. CURRENT SURGERY REPORTS 2018. [DOI: 10.1007/s40137-018-0209-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Hannon TS, Kahn SE, Utzschneider KM, Buchanan TA, Nadeau KJ, Zeitler PS, Ehrmann DA, Arslanian SA, Caprio S, Edelstein SL, Savage PJ, Mather KJ. Review of methods for measuring β-cell function: Design considerations from the Restoring Insulin Secretion (RISE) Consortium. Diabetes Obes Metab 2018; 20:14-24. [PMID: 28493515 PMCID: PMC6095472 DOI: 10.1111/dom.13005] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 05/04/2017] [Accepted: 05/06/2017] [Indexed: 01/09/2023]
Abstract
The Restoring Insulin Secretion (RISE) study was initiated to evaluate interventions to slow or reverse the progression of β-cell failure in type 2 diabetes (T2D). To design the RISE study, we undertook an evaluation of methods for measurement of β-cell function and changes in β-cell function in response to interventions. In the present paper, we review approaches for measurement of β-cell function, focusing on methodologic and feasibility considerations. Methodologic considerations included: (1) the utility of each technique for evaluating key aspects of β-cell function (first- and second-phase insulin secretion, maximum insulin secretion, glucose sensitivity, incretin effects) and (2) tactics for incorporating a measurement of insulin sensitivity in order to adjust insulin secretion measures for insulin sensitivity appropriately. Of particular concern were the capacity to measure β-cell function accurately in those with poor function, as is seen in established T2D, and the capacity of each method for demonstrating treatment-induced changes in β-cell function. Feasibility considerations included: staff burden, including time and required methodological expertise; participant burden, including time and number of study visits; and ease of standardizing methods across a multicentre consortium. After this evaluation, we selected a 2-day measurement procedure, combining a 3-hour 75-g oral glucose tolerance test and a 2-stage hyperglycaemic clamp procedure, augmented with arginine.
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Affiliation(s)
- Tamara S Hannon
- Departments of Pediatrics (T. S. H.) and Medicine (K. J. M.), Indiana University School of Medicine, Indianapolis, Indiana
| | - Steven E Kahn
- VA Puget Sound Health Care System and Department of Medicine, University of Washington, Seattle, Washington
| | - Kristina M Utzschneider
- VA Puget Sound Health Care System and Department of Medicine, University of Washington, Seattle, Washington
| | - Thomas A Buchanan
- University of Southern California Keck School of Medicine/Kaiser Permanente Southern California, Department of Medicine, Los Angeles, California
| | - Kristen J Nadeau
- University of Colorado Denver/Children's Hospital Colorado, Department of Pediatrics, Denver, Colorado
| | - Philip S Zeitler
- University of Colorado Denver/Children's Hospital Colorado, Department of Pediatrics, Denver, Colorado
| | | | - Silva A Arslanian
- Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Department of Pediatrics, Pittsburgh, Pennsylvania
| | - Sonia Caprio
- Department of Pediatrics, Yale University, New Haven, Connecticut
| | - Sharon L Edelstein
- George Washington University Biostatistics Center (RISE Coordinating Center), Rockville, Maryland
| | - Peter J Savage
- National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland
| | - Kieren J Mather
- Departments of Pediatrics (T. S. H.) and Medicine (K. J. M.), Indiana University School of Medicine, Indianapolis, Indiana
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Hutch CR, Sandoval D. The Role of GLP-1 in the Metabolic Success of Bariatric Surgery. Endocrinology 2017; 158:4139-4151. [PMID: 29040429 PMCID: PMC5711387 DOI: 10.1210/en.2017-00564] [Citation(s) in RCA: 160] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 10/04/2017] [Indexed: 12/15/2022]
Abstract
Two of the most popular bariatric procedures, vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB), are commonly considered metabolic surgeries because they are thought to affect metabolism in a weight loss-independent manner. In support of this classification, improvements in glucose homeostasis, insulin sensitivity, and even discontinuation of type 2 diabetes mellitus (T2DM) medication can occur before substantial postoperative weight loss. The mechanisms that underlie this effect are unknown. However, one of the common findings after VSG and RYGB in both animal models and humans is the sharp postprandial rise in several gut peptides, including the incretin and satiety peptide glucagonlike peptide-1 (GLP-1). The increase in endogenous GLP-1 signaling has been considered a primary pathway leading to postsurgical weight loss and improvements in glucose metabolism. However, the degree to which GLP-1 and other gut peptides are responsible for the metabolic successes after bariatric surgery is continually debated. In this review we discuss the mechanisms underlying the increase in GLP-1 and its potential role in the metabolic improvements after bariatric surgery, including remission of T2DM. Understanding the role of changes in gut peptides, or lack thereof, will be crucial in understanding the critical factors necessary for the metabolic success of bariatric surgery.
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Affiliation(s)
- Chelsea R. Hutch
- Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109
| | - Darleen Sandoval
- Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109
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Sleeve Gastrectomy Decreases Body Weight, Whole-Body Adiposity, and Blood Pressure Even in Aged Diet-Induced Obese Rats. Obes Surg 2017; 26:1549-58. [PMID: 26439733 DOI: 10.1007/s11695-015-1919-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Aging and obesity are two conditions associated with increased risk of cardiovascular disease. Our aim was to analyze whether an advanced age affects the beneficial effects of sleeve gastrectomy on weight loss and blood pressure in an experimental model of diet-induced obesity (DIO). METHODS Young (6-month-old) and old (18-month-old) male Wistar DIO rats (n = 101) were subjected to surgical (sham operation and sleeve gastrectomy) or dietary interventions (pair-fed to the amount of food eaten by sleeve gastrectomized animals). Systolic (SBP), diastolic (DBP), and mean (MBP) blood pressure values and heart rate (HR) were recorded in conscious, resting animals by non-invasive tail-cuff plethysmography before and 4 weeks after surgical or dietary interventions. RESULTS Aging was associated with higher (P < 0.05) body weight and subcutaneous and perirenal fat mass as well as mild cardiac hypertrophy. Sleeve gastrectomy induced a reduction in body weight, whole-body adiposity, and serum total ghrelin in both young and old DIO rats. The younger group achieved a higher excess weight loss than the older group (164 ± 60 vs. 82 ± 17 %, P < 0.05). A significant (P < 0.05) decrease in insulin resistance, SBP, DBP, MBP, and HR without changes in heart weight was observed after sleeve gastrectomy independently of age. CONCLUSION Our results provide evidence for the effectiveness of sleeve gastrectomy without increased operative risk in body weight and blood pressure reduction even in aged animals via endocrine changes that go beyond the mere caloric restriction.
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Li F, Sheng C, Song K, Zhang M, Bu L, Yang P, Sheng H, Li H, Qu S. Preventative Sleeve Gastrectomy Contributes to Maintaining β Cell Function in db/db Diabetic Mouse. Obes Surg 2017; 26:2402-10. [PMID: 26916639 DOI: 10.1007/s11695-016-2112-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND We used the leptin-receptor (LPR)-deficient mice model (db/db), a spontaneous model of type 2 diabetes with early β cell dysfunction to determine whether a preventative sleeve gastrectomy (SG) is an effective technique for the treatment of β cell failure. METHODS The animals operated at an early stage of life, prior to metabolic alterations, were used to study the molecular mechanisms of β cell function improvement after a SG. RESULTS β cell function was significantly increased, and islet morphology remained normal, after the SG. The expression of Glut2, Pdx1, MafA, and Nkx6.1 were significantly increased after the SG. The expression of GLP-1 in the colonic tissue, as well as GLP-1R and PKC in islets, was significantly increased after the SG. CONCLUSIONS β cell dysfunction can be ameliorated by a preventative SG for db/db mice. Maintaining the GLP-1 pathway and key transcript factor (TF) activation contributes to the improvement of β cell function after a preventative SG.
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Affiliation(s)
- Feng Li
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tong-Ji University, 301 Middle Yan-Chang Road, ShangHai, 200072, China.
| | - Chunjun Sheng
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tong-Ji University, 301 Middle Yan-Chang Road, ShangHai, 200072, China
| | - Kexiu Song
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tong-Ji University, 301 Middle Yan-Chang Road, ShangHai, 200072, China
| | - Manna Zhang
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tong-Ji University, 301 Middle Yan-Chang Road, ShangHai, 200072, China
| | - Le Bu
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tong-Ji University, 301 Middle Yan-Chang Road, ShangHai, 200072, China
| | - Peng Yang
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tong-Ji University, 301 Middle Yan-Chang Road, ShangHai, 200072, China
| | - Hui Sheng
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tong-Ji University, 301 Middle Yan-Chang Road, ShangHai, 200072, China
| | - Hong Li
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tong-Ji University, 301 Middle Yan-Chang Road, ShangHai, 200072, China
| | - Shen Qu
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tong-Ji University, 301 Middle Yan-Chang Road, ShangHai, 200072, China.
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Abstract
A logical cure for type 1 diabetes (T1D) involves replacing the lost insulin-producing cells with new ones, preferably cells from a well-characterized and unlimited source of human insulin-producing cells. This straightforward and simple solution to provide a cure for T1D is immensely attractive but entails at least two inherent and thus far unresolved hurdles: 1) provision of an unlimited source of functional human insulin-producing cells and 2) prevention of rejection without the side effects of systemic immunosuppression. Generation of transplantable insulin-producing cells from human embryonic stem cells or induced pluripotent stem cells is at present close to reality, and we are currently awaiting the first clinical studies. Focus is now directed to foster development of novel means to control the immune system to enable large-scale clinical application. Encapsulation introduces a physical barrier that prevents access of immune cells to the transplanted cells but also hinders blood vessel ingrowth. Therefore, oxygen, nutrient, and hormonal passage over the encapsulation membrane is solely dependent on diffusion over the immune barrier, contributing to delays in glucose sensing and insulin secretion kinetics. This Perspective focuses on the physiological possibilities and limitations of an encapsulation strategy to establish near-normoglycemia in subjects with T1D, assuming that glucose-responsive insulin-producing cells are available for transplantation.
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Affiliation(s)
- Olle Korsgren
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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Cavin JB, Bado A, Le Gall M. Intestinal Adaptations after Bariatric Surgery: Consequences on Glucose Homeostasis. Trends Endocrinol Metab 2017; 28:354-364. [PMID: 28209316 DOI: 10.1016/j.tem.2017.01.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Revised: 01/16/2017] [Accepted: 01/17/2017] [Indexed: 12/25/2022]
Abstract
The gastrointestinal (GI) tract can play a direct role in glucose homeostasis by modulating the digestion and absorption of carbohydrates and by producing the incretin hormones. In recent years, numerous studies have focused on intestinal adaptation following bariatric surgeries. Changes in the number of incretin (glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide) producing cells have been reported, which could result in the modified hormonal response seen after surgery. In addition, the rate of absorption and the intestinal regions exposed to sugars may affect the time course of appearance of glucose in the blood. This review gives new insights into the direct role of the GI tract in the metabolic outcomes of bariatric surgery, in the context of glucose homeostasis.
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Affiliation(s)
- Jean-Baptiste Cavin
- Inserm UMR 1149, UFR de Médecine Paris Diderot, Université Paris Diderot, Sorbonne Paris Cité, DHU Unity AP-HP, F-75890 Paris, France
| | - André Bado
- Inserm UMR 1149, UFR de Médecine Paris Diderot, Université Paris Diderot, Sorbonne Paris Cité, DHU Unity AP-HP, F-75890 Paris, France
| | - Maude Le Gall
- Inserm UMR 1149, UFR de Médecine Paris Diderot, Université Paris Diderot, Sorbonne Paris Cité, DHU Unity AP-HP, F-75890 Paris, France.
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50
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Vidal J, Corcelles R, Jiménez A, Flores L, Lacy AM. Metabolic and Bariatric Surgery for Obesity. Gastroenterology 2017; 152:1780-1790. [PMID: 28193516 DOI: 10.1053/j.gastro.2017.01.051] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Revised: 01/26/2017] [Accepted: 01/26/2017] [Indexed: 01/06/2023]
Abstract
Metabolic and bariatric surgery (MBS) leads to weight loss in obese individuals and reduces comorbidities such as type 2 diabetes. MBS is superior to medical therapy in reducing hyperglycemia in persons with type 2 diabetes, and has been associated with reduced mortality and incidences of cardiovascular events and cancer in obese individuals. New guidelines have been proposed for the use of MBS in persons with type 2 diabetes. We review the use of MBS as a treatment for obesity and obesity-related conditions and, based on recent evidence, propose that health care systems make the appropriate changes to increase accessibility for eligible patients.
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Affiliation(s)
- Josep Vidal
- Obesity Unit, Endocrinology and Nutrition Department, Hospital Clinic Universitari, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain.
| | - Ricard Corcelles
- Obesity Unit, Gastrointestinal Surgery Department, Hospital Clinic Universitari, Barcelona, Spain
| | - Amanda Jiménez
- Obesity Unit, Endocrinology and Nutrition Department, Hospital Clinic Universitari, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain
| | - Lílliam Flores
- Obesity Unit, Endocrinology and Nutrition Department, Hospital Clinic Universitari, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
| | - Antonio M Lacy
- Obesity Unit, Endocrinology and Nutrition Department, Hospital Clinic Universitari, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain; Obesity Unit, Gastrointestinal Surgery Department, Hospital Clinic Universitari, Barcelona, Spain
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