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Movahednasab M, Dianat-Moghadam H, Khodadad S, Nedaeinia R, Safabakhsh S, Ferns G, Salehi R. GLP-1-based therapies for type 2 diabetes: from single, dual and triple agonists to endogenous GLP-1 production and L-cell differentiation. Diabetol Metab Syndr 2025; 17:60. [PMID: 39962520 PMCID: PMC11834518 DOI: 10.1186/s13098-025-01623-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Accepted: 02/02/2025] [Indexed: 02/20/2025] Open
Abstract
Glucagon-like peptide-1 (GLP-1) is an incretin peptide hormone mainly secreted by enteroendocrine intestinal L-cells. GLP-1 is also secreted by α-cells of the pancreas and the central nervous system (CNS). GLP-1 secretion is stimulated by nutrient intake and exerts its effects on glucose homeostasis by stimulating insulin secretion, gastric emptying confiding the food intake, and β-cell proliferation. The insulinotropic effects of GLP-1, and the reduction of its effects in type 2 diabetes mellitus (T2DM), have made GLP-1 an attractive option for the treatment of T2DM. Furthermore, GLP-1-based medications such as GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, have been shown to improve diabetes control in preclinical and clinical trials with human subjects. Importantly, increasing the endogenous production of GLP-1 by different mechanisms or by increasing the number of intestinal L-cells that tend to produce this hormone may be another effective therapeutic approach to managing T2DM. Herein, we briefly describe therapeutic agents/compounds that enhance GLP-1 function. Then, we will discuss the approaches that can increase the endogenous production of GLP-1 through various stimuli. Finally, we introduce the potential of L-cell differentiation as an attractive future therapeutic approach to increase GLP-1 production as an attractive therapeutic alternative for T2DM.
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Affiliation(s)
- Maedeh Movahednasab
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hassan Dianat-Moghadam
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sana Khodadad
- Department of Genetics and Molecular Biology, School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Reza Nedaeinia
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Saeid Safabakhsh
- Micronesian Institute for Disease Prevention and Research, 736 Route 4, Suite 103, Sinajana, GU, 96910, USA
| | - Gordon Ferns
- Division of Medical Education, Brighton & Sussex Medical School, Falmer, Brighton, Sussex, BN1 9PH, UK
| | - Rasoul Salehi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran.
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He C, Jiang M, Xiong Q, Huang Z. Investigation of the mechanism of chenodeoxycholic acid in treating acute lung injury through network pharmacology and experimental validation. Sci Rep 2025; 15:5814. [PMID: 39962185 PMCID: PMC11833071 DOI: 10.1038/s41598-025-90155-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 02/11/2025] [Indexed: 02/20/2025] Open
Abstract
Network pharmacology and molecular simulation techniques were employed to predict the potential targets and signaling pathways of chenodeoxycholic acid in the treatment of acute lung injury. Subsequently, its therapeutic effects on acute lung injury were preliminarily validated using animal experiments. The target of Chenodeoxycholic acid in the treatment of acute lung injury was predicted using network pharmacology. Key active ingredients and core targets were further validated using molecular docking studies. Lipopolysaccharide was used to establish a mouse model of acute lung injury to study the effect of chenodeoxycholic acid on acute lung injury. A total of 73 potential targets of Chenodeoxycholic acid for the treatment of acute lung injury were identified, primarily HSP90AA1, STAT3, HSP90AB1, EP300, and NFKB1. These core targets influence pathways associated with bile secretion, prostate cancer, and receptor activation in chemical carcinogenesis. These targets modulate various processes, including steroid metabolism, steroid biosynthesis, and intracellular receptor signaling pathways, thus contributing to the treatment of acute lung injury. Molecular docking results indicated that Chenodeoxycholic acid exhibited strong binding affinity for the core targets, with docking energies ranging from -5.6729 to -7.4138 kcal/mol. The reliability of the results was further verified by molecular dynamics simulations. Results from animal experiments demonstrated that Chenodeoxycholic acid effectively ameliorated pathological injury to lung tissue in mice with acute lung injury, decreased levels of IL-6 and TNF-α (P < 0.01), and increased levels of IL-10 (P < 0.01). The mRNA expression levels of EP300, HSP90AB1, MTOR, and STAT3 were inhibited, while the mRNA expression level of NR1H4 was significantly increased (P < 0.01). Chenodeoxycholic acid can effectively improve acute lung injury.
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Affiliation(s)
- Chong He
- Department of Emergency, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Mengmeng Jiang
- Department of Emergency, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Qian Xiong
- Department of Emergency, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Zuoxi Huang
- Department of Gastrointestinal Surgery, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, Jiangxi, China.
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Gether IM, Andersen ES, Foghsgaard S, Ellegaard AM, Kelstrup L, Sonne DP, Brønden A, Gillum MP, Holst JJ, Hartmann B, Rehfeld JF, Vilsbøll T, Knop FK. Increased gallbladder emptying and reduced GLP-1 response in pregnancy with and without gestational diabetes mellitus. Diabetes Obes Metab 2025; 27:697-709. [PMID: 39543983 DOI: 10.1111/dom.16064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 10/28/2024] [Accepted: 10/29/2024] [Indexed: 11/17/2024]
Abstract
AIM Gestational diabetes mellitus (GDM) has been associated with reduced postprandial glucagon-like peptide 1 (GLP-1) responses. As pregnancy induces changes in gallbladder motility and bile acids stimulate GLP-1 secretion, we investigated postprandial gallbladder emptying and GLP-1 responses in women with GDM. METHODS Women with and without GDM underwent two 240-min mixed meal tests; one during third trimester of pregnancy and one 3-6 months postpartum. We evaluated ultrasonography-assessed gallbladder emptying, plasma concentrations of glucometabolic hormones including GLP-1, paracetamol absorption (proxy for gastric emptying) and circulating factors known to affect gallbladder dynamics. RESULTS Fifteen women with GDM and 15 pregnant women with normal glucose tolerance (NGT) (baseline median age 31 (interquartile range 29;33) versus 32 (28;33) years, body mass index (BMI) 27.2 (24.7;30.7) versus 28.4 (26.2;31.0) kg/m2, HbA1c 30 (29;32) versus 30 (28;31) mmol/mol) were included. No differences in postprandial gallbladder emptying or GLP-1 responses were observed between women with and without GDM, neither during pregnancy nor postpartum. Pregnancy increased fasting gallbladder volumes by 69 (30;122)% and 103 (59;156)% and postprandial gallbladder emptying by 77 (28;236)% and 99 (37;190)% compared with postpartum in women with and without GDM, respectively. Postprandial GLP-1 responses were reduced by 60 (3;82)% and 81 (11;90)% during pregnancy compared with postpartum in women with and without GDM, respectively. CONCLUSION Pregnancy-induced changes in gallbladder motility seem to play no or a limited role in previously reported GDM-associated reduced postprandial GLP-1 responses as gallbladder emptying was greater and postprandial GLP-1 response was lower in pregnancy than postpartum regardless of GDM status.
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Affiliation(s)
- Ida M Gether
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
| | - Emilie S Andersen
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Signe Foghsgaard
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Gynaecology and Obstetrics, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark
| | - Anne-Marie Ellegaard
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
| | - Louise Kelstrup
- Department of Gynaecology and Obstetrics, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark
| | - David P Sonne
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Pharmacology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark
| | - Andreas Brønden
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Pharmacology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark
| | - Matthew P Gillum
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens F Rehfeld
- Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Matye DJ, Wang H, Wang Y, Xiong L, Li T. Bile acid sequestrant inhibits gluconeogenesis via inducing hepatic cysteine dioxygenase type 1 to reduce cysteine availability. Am J Physiol Gastrointest Liver Physiol 2025; 328:G166-G178. [PMID: 39819116 DOI: 10.1152/ajpgi.00353.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 11/28/2024] [Accepted: 12/11/2024] [Indexed: 01/19/2025]
Abstract
Bile acid sequestrants such as cholestyramine (ChTM) are gut-restricted bile acid-binding resins that block intestine bile acid absorption and attenuate hepatic bile acid signaling. Bile acid sequestrants induce hepatic bile acid synthesis to promote cholesterol catabolism and are cholesterol-lowering drugs. Bile acid sequestrants also reduce blood glucose in clinical trials and are approved drugs for treating hyperglycemia in type-2 diabetes. However, the mechanisms mediating the glucose-lowering effect of bile acid sequestrants are still incompletely understood. Here we showed that ChTM treatment decreased hepatic glucose production in Western diet-fed mice with paradoxically induced hepatic gluconeogenic genes. Cysteine dioxygenase type 1 (CDO1) mediates cysteine conversion to taurine and its expression is repressed by bile acids. We show that ChTM induced hepatic CDO1 and selectively reduced hepatic cysteine availability. Knockdown of liver CDO1 increased liver cysteine and glucose production in mice, whereas hepatocytes cultured in cystine-deficient medium showed reduced glucose production. By using dietary protein-restricted and cystine-modified Western diets that selectively alter hepatic cysteine availability, we found that reduced hepatic cysteine availability strongly inhibited glucose production in mice. Interestingly, chronic dietary protein restriction also prevented Western diet-induced obesity, which was fully reversed by restoring dietary cystine intake alone. Consistently, reduced cysteine availability dose-dependently inhibited adipogenesis in vitro. In conclusion, we report that the glucose-lowering effect of bile acid sequestrants is mediated by a CDO1-induced hepatic cysteine restriction mimetic effect. Furthermore, the anti-obesity effect of dietary protein restriction is largely mediated by reduced dietary cysteine intake.NEW & NOTEWORTHY Hepatic cysteine availability is a key driver of hepatic gluconeogenesis. Bile acid sequestrant inhibits gluconeogenesis by inducing CDO1-mediated cysteine catabolism to reduce cysteine availability. Dietary protein restriction causes hepatic cysteine deficiency without overall amino acid deficiency. The glucose-lowering effect of dietary protein restriction is largely mediated by lower dietary cysteine intake. The anti-obesity effect of chronic dietary protein restriction is largely mediated by lower dietary cysteine intake.
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Affiliation(s)
- David J Matye
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States
| | - Huaiwen Wang
- Laboratory for Molecular Biology and Cytometry Research, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
| | - Yifeng Wang
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States
| | - Lei Xiong
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
| | - Tiangang Li
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
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Zhang C, Zhang Q, Zhang X, Du S, Zhang Y, Wang X, Liu Y, Fang B, Chen J, Liu R, Hao Y, Li Y, Wang P, Zhao L, Feng H, Zhu L, Chen L, Chen S, Wang F, Jiang Z, Ji Y, Xiao R, Wang R, He J. Effects of synbiotics surpass probiotics alone in improving type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled trial. Clin Nutr 2025; 44:248-258. [PMID: 39719724 DOI: 10.1016/j.clnu.2024.11.042] [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: 07/03/2024] [Revised: 11/22/2024] [Accepted: 11/28/2024] [Indexed: 12/26/2024]
Abstract
BACKGROUND AND AIMS Combining probiotics and prebiotics in synbiotics may present a synergistic approach to improve type 2 diabetes mellitus (T2DM); however, further evidence is required to establish the comparative efficacy of synbiotics versus probiotics. This study aimed to evaluate the effects of Bifidobacterium animalis subsp. lactis MN-Gup (MN-Gup) and a synbiotic mixture of MN-Gup and galactooligosaccharide (MN-Gup-GOS) on glycemic control in T2DM patients and explore possible mechanisms. METHODS This randomized, double-blind, placebo-controlled clinical trial assigned 120 T2DM patients, to receive MN-Gup, MN-Gup-GOS, or placebo intervention for 12 weeks. The primary outcome was fasting blood glucose (FBG), with secondary outcomes including hemoglobin A1C (HbA1C), insulin, homeostatic model assessment of insulin resistance (HOMA-IR), inflammatory indicators, oxidative stress indicators, gastrointestinal hormones, gut microbiota, and bile acids (BAs). RESULTS The median age of the 120 participants was 59 years (interquartile range: 55-62 years), with 40 being men. Compared to baseline, all three groups exhibited significant reductions in FBG. Additionally, the MN-Gup-GOS group demonstrated significant decreases in HbA1c, serum insulin, and HOMA-IR after intervention, whereas no such reductions were observed in the placebo and MN-Gup groups. Regarding the between-group comparisons, the MN-Gup-GOS intervention showed a significantly greater reduction in FBG compared to the placebo (least squares mean difference [95 % CI], -0.69 [-1.29, -0.10] mmol/L, P = 0.022) and MN-Gup (-0.59 [-1.17, -0.01], P = 0.047) group, but not for other indicators of glucose metabolism. Additionally, MN-Gup and MN-Gup-GOS intervention, especially the latter, significantly modified inflammation, oxidative stress, gut microbiota, serum BAs, and GLP-1 levels. Correlation analysis showed significant associations between changes in certain gut microbiota (Bifidobacterium) and BAs (deoxycholic acid and lithocholic acid) with glycemic indicators. CONCLUSIONS The auxiliary effect of synbiotics MN-Gup-GOS on reducing FBG levels surpassed that of MN-Gup probiotics alone in T2DM patients, potentially attributed to the enhanced modulation of gut microbiota, BAs, and GLP-1 secretion. TRIAL REGISTRATION This study was registered on the website of www.chictr.org.cn, number ChiCTR2100052187.
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Affiliation(s)
- Chao Zhang
- Department of Nutrition and Health, Key Laboratory of Functional Dairy, Co-constructed by Ministry of Education and Beijing Government, China Agricultural University, Beijing 100193, China
| | - Qi Zhang
- Department of Nutrition and Health, Key Laboratory of Functional Dairy, Co-constructed by Ministry of Education and Beijing Government, China Agricultural University, Beijing 100193, China
| | - Xiaoxu Zhang
- Department of Nutrition and Health, Key Laboratory of Functional Dairy, Co-constructed by Ministry of Education and Beijing Government, China Agricultural University, Beijing 100193, China
| | - Shuang Du
- Mengniu Hi-Tech Dairy Product Beijing Co., Ltd., Beijing 101100, China
| | - Yong Zhang
- Department of Nutrition, The first medical Center of PLA General Hospital, Beijing 100039, China
| | - Xifan Wang
- Department of Obstetrics and Gynecology, Columbia University, New York 10032, USA
| | - Yinghua Liu
- Department of Nutrition, The first medical Center of PLA General Hospital, Beijing 100039, China
| | - Bing Fang
- Department of Nutrition and Health, Key Laboratory of Functional Dairy, Co-constructed by Ministry of Education and Beijing Government, China Agricultural University, Beijing 100193, China
| | - Juan Chen
- Research Center for Probiotics, China Agricultural University, Beijing 100193, China
| | - Rong Liu
- Department of Nutrition and Health, Key Laboratory of Functional Dairy, Co-constructed by Ministry of Education and Beijing Government, China Agricultural University, Beijing 100193, China
| | - Yanling Hao
- Research Center for Probiotics, China Agricultural University, Beijing 100193, China
| | - Yixuan Li
- Department of Nutrition and Health, Key Laboratory of Functional Dairy, Co-constructed by Ministry of Education and Beijing Government, China Agricultural University, Beijing 100193, China
| | - Pengjie Wang
- Department of Nutrition and Health, Key Laboratory of Functional Dairy, Co-constructed by Ministry of Education and Beijing Government, China Agricultural University, Beijing 100193, China
| | - Liang Zhao
- Research Center for Probiotics, China Agricultural University, Beijing 100193, China
| | - Haihong Feng
- Research Center for Probiotics, China Agricultural University, Beijing 100193, China; Hebei Engineering Research Center of Animal Product, Langfang 065200, China
| | - Longjiao Zhu
- Department of Nutrition and Health, Key Laboratory of Functional Dairy, Co-constructed by Ministry of Education and Beijing Government, China Agricultural University, Beijing 100193, China
| | - Lishui Chen
- Food Laboratory of Zhongyuan, Luohe 462300, China
| | - Shuxing Chen
- School of Food and Bioengineering, Henan University of Science and Technology, Luoyang 471003, China
| | - Fuqing Wang
- Tibet Tianhong Science and Technology Co., Ltd., Xizang 850000, China
| | - Zhengqiang Jiang
- Key Laboratory of Food Bioengineering (China National Light Industry), College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Yuting Ji
- Center for Mitochondrial Genetics and Health, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou 511458, China; School of Life Sciences, Fudan University, Shanghai 200433, China
| | - Ran Xiao
- Mengniu Hi-Tech Dairy Product Beijing Co., Ltd., Beijing 101100, China.
| | - Ran Wang
- Research Center for Probiotics, China Agricultural University, Beijing 100193, China.
| | - Jingjing He
- Department of Nutrition and Health, Key Laboratory of Functional Dairy, Co-constructed by Ministry of Education and Beijing Government, China Agricultural University, Beijing 100193, China.
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Li T, Chiang JYL. Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development. Pharmacol Rev 2024; 76:1221-1253. [PMID: 38977324 PMCID: PMC11549937 DOI: 10.1124/pharmrev.124.000978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/26/2024] [Accepted: 06/28/2024] [Indexed: 07/10/2024] Open
Abstract
Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders. SIGNIFICANCE STATEMENT: Bile acids facilitate biliary cholesterol solubilization and dietary lipid absorption, regulate host metabolism and immunity, and modulate gut microbiome. Targeting bile acid metabolism and signaling holds promise for treating metabolic and inflammatory diseases.
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Affiliation(s)
- Tiangang Li
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
| | - John Y L Chiang
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
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Nemeth DV, Iannelli L, Gangitano E, D’Andrea V, Bellini MI. Energy Metabolism and Metformin: Effects on Ischemia-Reperfusion Injury in Kidney Transplantation. Biomedicines 2024; 12:1534. [PMID: 39062107 PMCID: PMC11275143 DOI: 10.3390/biomedicines12071534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 07/03/2024] [Accepted: 07/09/2024] [Indexed: 07/28/2024] Open
Abstract
Metformin (MTF) is the only biguanide included in the World Health Organization's list of essential medicines; representing a widespread drug in the management of diabetes mellitus. With its accessibility and affordability being one of its biggest assets, it has become the target of interest for many trying to find alternative treatments for varied pathologies. Over time, an increasing body of evidence has shown additional roles of MTF, with unexpected interactions of benefit in other diseases. Metformin (MTF) holds significant promise in mitigating ischemia-reperfusion injury (IRI), particularly in the realm of organ transplantation. As acceptance criteria for organ transplants expand, IRI during the preservation phase remain a major concern within the transplant community, prompting a keen interest in MTF's effects. Emerging evidence suggests that administering MTF during reperfusion may activate the reperfusion injury salvage kinase (RISK) pathway. This pathway is pivotal in alleviating IRI in transplant recipients, potentially leading to improved outcomes such as reduced rates of organ rejection. This review aims to contextualize MTF historically, explore its current uses, pharmacokinetics, and pharmacodynamics, and link these aspects to the pathophysiology of IRI to illuminate its potential future role in transplantation. A comprehensive survey of the current literature highlights MTF's potential to recondition and protect against IRI by attenuating free radical damage, activating AMP-activated protein kinase to preserve cellular energy and promote repair, as well as directly reducing inflammation and enhancing microcirculation.
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Affiliation(s)
- Denise V. Nemeth
- School of Osteopathic Medicine, University of the Incarnate Word, San Antonio, TX 78235, USA
| | - Leonardo Iannelli
- Department of Surgery, Sapienza University of Rome, 00161 Rome, Italy
| | - Elena Gangitano
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Vito D’Andrea
- Department of Surgery, Sapienza University of Rome, 00161 Rome, Italy
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Li XJ, Fang C, Zhao RH, Zou L, Miao H, Zhao YY. Bile acid metabolism in health and ageing-related diseases. Biochem Pharmacol 2024; 225:116313. [PMID: 38788963 DOI: 10.1016/j.bcp.2024.116313] [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: 02/18/2024] [Revised: 05/18/2024] [Accepted: 05/21/2024] [Indexed: 05/26/2024]
Abstract
Bile acids (BAs) have surpassed their traditional roles as lipid solubilizers and regulators of BA homeostasis to emerge as important signalling molecules. Recent research has revealed a connection between microbial dysbiosis and metabolism disruption of BAs, which in turn impacts ageing-related diseases. The human BAs pool is primarily composed of primary BAs and their conjugates, with a smaller proportion consisting of secondary BAs. These different BAs exert complex effects on health and ageing-related diseases through several key nuclear receptors, such as farnesoid X receptor and Takeda G protein-coupled receptor 5. However, the underlying molecular mechanisms of these effects are still debated. Therefore, the modulation of signalling pathways by regulating synthesis and composition of BAs represents an interesting and novel direction for potential therapies of ageing-related diseases. This review provides an overview of synthesis and transportion of BAs in the healthy body, emphasizing its dependence on microbial community metabolic capacity. Additionally, the review also explores how ageing and ageing-related diseases affect metabolism and composition of BAs. Understanding BA metabolism network and the impact of their nuclear receptors, such as farnesoid X receptor and G protein-coupled receptor 5 agonists, paves the way for developing therapeutic agents for targeting BA metabolism in various ageing-related diseases, such as metabolic disorder, hepatic injury, cardiovascular disease, renal damage and neurodegenerative disease.
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Affiliation(s)
- Xiao-Jun Li
- School of Pharmacy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China; Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, No.13, Shi Liu Gang Road, Haizhu District, Guangzhou, Guangdong 510315, China
| | - Chu Fang
- School of Pharmacy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China
| | - Rui-Hua Zhao
- School of Pharmacy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China
| | - Liang Zou
- School of Food and Bioengineering, Chengdu University, No. 2025 Chengluo Avenue, Chengdu, Sichuan 610106, China
| | - Hua Miao
- School of Pharmacy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China.
| | - Ying-Yong Zhao
- School of Pharmacy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China; National Key Laboratory of Kidney Diseases, First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853, China.
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Holst JJ, Madsbad S, Bojsen-Møller KN, Dirksen C, Svane M. New Lessons from the gut: Studies of the role of gut peptides in weight loss and diabetes resolution after gastric bypass and sleeve gastrectomy. Peptides 2024; 176:171199. [PMID: 38552903 DOI: 10.1016/j.peptides.2024.171199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 03/18/2024] [Accepted: 03/22/2024] [Indexed: 04/05/2024]
Abstract
It has been known since 2005 that the secretion of several gut hormones changes radically after gastric bypass operations and, although more moderately, after sleeve gastrectomy but not after gastric banding. It has therefore been speculated that increased secretion of particularly GLP-1 and Peptide YY (PYY), which both inhibit appetite and food intake, may be involved in the weight loss effects of surgery and for improvements in glucose tolerance. Experiments involving inhibition of hormone secretion with somatostatin, blockade of their actions with antagonists, or blockade of hormone formation/activation support this notion. However, differences between results of bypass and sleeve operations indicate that distinct mechanisms may also be involved. Although the reductions in ghrelin secretion after sleeve gastrectomy would seem to provide an obvious explanation, experiments with restoration of ghrelin levels pointed towards effects on insulin secretion and glucose tolerance rather than on food intake. It seems clear that changes in GLP-1 secretion are important for insulin secretion after bypass and appear to be responsible for postbariatric hypoglycemia in glucose-tolerant individuals; however, with time the improvements in insulin sensitivity, which in turn are secondary to the weight loss, may be more important. Changes in bile acid metabolism do not seem to be of particular importance in humans.
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Affiliation(s)
- Jens Juul Holst
- The NovoNordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Denmark.
| | - Sten Madsbad
- Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Denmark
| | | | - Carsten Dirksen
- Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Denmark
| | - Maria Svane
- Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Denmark
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10
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Jin W, Zheng M, Chen Y, Xiong H. Update on the development of TGR5 agonists for human diseases. Eur J Med Chem 2024; 271:116462. [PMID: 38691888 DOI: 10.1016/j.ejmech.2024.116462] [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: 03/05/2024] [Revised: 04/20/2024] [Accepted: 04/27/2024] [Indexed: 05/03/2024]
Abstract
The G protein-coupled bile acid receptor 1 (GPBAR1) or TGR5 is widely distributed across organs, including the small intestine, stomach, liver, spleen, and gallbladder. Many studies have established strong correlations between TGR5 and glucose homeostasis, energy metabolism, immune-inflammatory responses, and gastrointestinal functions. These results indicate that TGR5 has a significant impact on the progression of tumor development and metabolic disorders such as diabetes mellitus and obesity. Targeting TGR5 represents an encouraging therapeutic approach for treating associated human ailments. Notably, the GLP-1 receptor has shown exceptional efficacy in clinical settings for diabetes management and weight loss promotion. Currently, numerous TGR5 agonists have been identified through natural product-based approaches and virtual screening methods, with some successfully progressing to clinical trials. This review summarizes the intricate relationships between TGR5 and various diseases emphasizing recent advancements in research on TGR5 agonists, including their structural characteristics, design tactics, and biological activities. We anticipate that this meticulous review could facilitate the expedited discovery and optimization of novel TGR5 agonists.
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Affiliation(s)
- Wangrui Jin
- Institute for Advanced Study, and College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, 518060, China; Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Mingyue Zheng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yihua Chen
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan, 650500, China; Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China.
| | - Hai Xiong
- Institute for Advanced Study, and College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, 518060, China.
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11
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Nerild HH, Brønden A, Haddouchi AE, Ellegaard AM, Hartmann B, Rehfeld JF, Holst JJ, Sonne DP, Vilsbøll T, Knop FK. Elucidating the glucose-lowering effect of the bile acid sequestrant sevelamer. Diabetes Obes Metab 2024; 26:1252-1263. [PMID: 38151760 DOI: 10.1111/dom.15421] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/28/2023] [Accepted: 11/30/2023] [Indexed: 12/29/2023]
Abstract
AIM Bile acid sequestrants are cholesterol-lowering drugs, which also improve glycaemic control in people with type 2 diabetes. The mechanism behind the glucose-lowering effect is unknown but has been proposed to be mediated by increased glucagon-like peptide-1 (GLP-1) secretion. Here, we investigated the glucose-lowering effects of sevelamer including any contribution from GLP-1 in people with type 2 diabetes. MATERIALS AND METHODS In a randomized, double-blind, placebo-controlled, crossover study, 15 people with type 2 diabetes on metformin monotherapy underwent two 17-day treatment periods with the bile acid sequestrant sevelamer and placebo, respectively, in a randomized order and with an interposed wash-out period of minimum 6 weeks. On days 15 and 17 of each treatment period, participants underwent experimental days with 4-h liquid meal tests and application of concomitant infusion of exendin(9-39)NH2 or saline. RESULTS Compared with placebo, sevelamer improved insulin sensitivity (assessed by homeostatic model assessment of insulin resistance) and beta-cell sensitivity to glucose and lowered fasting and postprandial plasma glucose concentrations. In both treatment periods, exendin(9-39)NH2 increased postprandial glucose excursions compared with saline but without absolute or relative difference between the two treatment periods. In contrast, exendin(9-39)NH2 abolished the sevelamer-induced improvement in beta-cell glucose sensitivity. CONCLUSIONS The bile acid sequestrant sevelamer improved insulin sensitivity and beta-cell sensitivity to glucose, but using the GLP-1 receptor antagonist exendin(9-39)NH2 we were not able to detect a GLP-1-mediated glucose-lowering effect of sevelamer in individuals with type 2 diabetes. Nevertheless, the sevelamer-induced improvement of beta-cell sensitivity to glucose was shown to be GLP-1-dependent.
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Affiliation(s)
- Henriette H Nerild
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
| | - Andreas Brønden
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
- Department of Clinical Pharmacology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark
| | - Abdullah E Haddouchi
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
| | - Anne-Marie Ellegaard
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens F Rehfeld
- Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - David P Sonne
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
- Department of Clinical Pharmacology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
- the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
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12
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Lange AH, Pedersen MG, Ellegaard AM, Nerild HH, Brønden A, Sonne DP, Knop FK. The bile-gut axis and metabolic consequences of cholecystectomy. Eur J Endocrinol 2024; 190:R1-R9. [PMID: 38551177 DOI: 10.1093/ejendo/lvae034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 02/23/2024] [Accepted: 03/14/2024] [Indexed: 04/09/2024]
Abstract
Cholelithiasis and cholecystitis affect individuals of all ages and are often treated by surgical removal of the gallbladder (cholecystectomy), which is considered a safe, low-risk procedure. Nevertheless, recent findings show that bile and its regulated storage and excretion may have important metabolic effects and that cholecystectomy is associated with several metabolic diseases postoperatively. Bile acids have long been known as emulsifiers essential to the assimilation of lipids and absorption of lipid-soluble vitamins, but more recently, they have also been reported to act as metabolic signaling agents. The nuclear receptor, farnesoid X receptor (FXR), and the G protein-coupled membrane receptor, Takeda G protein-coupled receptor 5 (TGR5), are specific to bile acids. Through activation of these receptors, bile acids control numerous metabolic functions. Cholecystectomy affects the storage and excretion of bile acids, which in turn may influence the activation of FXR and TGR5 and their effects on metabolism including processes leading to metabolic conditions such as metabolic dysfunction-associated steatotic liver disease and metabolic syndrome. Here, with the aim of elucidating mechanisms behind cholecystectomy-associated dysmetabolism, we review studies potentially linking cholecystectomy and bile acid-mediated metabolic effects and discuss possible pathophysiological mechanisms behind cholecystectomy-associated dysmetabolism.
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Affiliation(s)
- Andreas H Lange
- Center for Clinical Metabolic Research, Copenhagen University Hospital-Herlev and Gentofte, DK-2900 Hellerup, Denmark
| | - Miriam G Pedersen
- Center for Clinical Metabolic Research, Copenhagen University Hospital-Herlev and Gentofte, DK-2900 Hellerup, Denmark
| | - Anne-Marie Ellegaard
- Center for Clinical Metabolic Research, Copenhagen University Hospital-Herlev and Gentofte, DK-2900 Hellerup, Denmark
| | - Henriette H Nerild
- Center for Clinical Metabolic Research, Copenhagen University Hospital-Herlev and Gentofte, DK-2900 Hellerup, Denmark
| | - Andreas Brønden
- Center for Clinical Metabolic Research, Copenhagen University Hospital-Herlev and Gentofte, DK-2900 Hellerup, Denmark
- Department of Clinical Pharmacology, Copenhagen University Hospital-Bispebjerg and Frederiksberg, DK-2400 Copenhagen, Denmark
| | - David P Sonne
- Center for Clinical Metabolic Research, Copenhagen University Hospital-Herlev and Gentofte, DK-2900 Hellerup, Denmark
- Department of Clinical Pharmacology, Copenhagen University Hospital-Bispebjerg and Frederiksberg, DK-2400 Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Copenhagen University Hospital-Herlev and Gentofte, DK-2900 Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, DK-2730 Herlev, Denmark
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13
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Gether IM, Bahne E, Nerild HH, Rehfeld JF, Hartmann B, Holst JJ, Vilsbøll T, Sonne DP, Knop FK. Colesevelam has no acute effect on postprandial GLP-1 levels but abolishes gallbladder refilling. Eur J Endocrinol 2024; 190:314-326. [PMID: 38551029 DOI: 10.1093/ejendo/lvae033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 03/04/2024] [Accepted: 03/14/2024] [Indexed: 04/18/2024]
Abstract
OBJECTIVE Colesevelam, a bile acid sequestrant approved for the treatment of hypercholesterolaemia, improves glycaemic control in type 2 diabetes. We hypothesised that single-dose colesevelam increases postprandial GLP-1 secretion, thus, reducing postprandial glucose excursions in individuals with type 2 diabetes. Further, we explored the effects of single-dose colesevelam on ultrasonography-assessed postprandial gallbladder motility, paracetamol absorption (proxy for gastric emptying), and circulating factors known to affect gallbladder motility. METHODS In a randomised, double-blind, placebo-controlled crossover study, 12 individuals with type 2 diabetes (mean ± SD: age 61 ± 8.8 years; body mass index 29.8 ± 3.0 kg/m2) were subjected to 4 mixed meal tests on separate days; 2 with orally administered colesevelam (3.75 g) and 2 with placebo, with intravenous infusion of the GLP-1 receptor antagonist exendin(9-39)NH2 or saline. RESULTS Single-dose colesevelam had no effect on postprandial concentrations of glucose (P = .786), C-peptide (P = .440), or GLP-1 (P = .729), and exendin(9-39)NH2 administration revealed no GLP-1-mediated effects of colesevelam. Colesevelam did not affect gallbladder emptying but abolished gallbladder refilling (P = .001), increased postprandial cholecystokinin (CCK) secretion (P = .010), and decreased postprandial serum concentrations of fibroblast growth factor 19 (FGF19) (P = .035) and bile acids (P = .043). CONCLUSION Single-dose colesevelam had no effect on postprandial GLP-1 responses or glucose tolerance but disrupted postprandial gallbladder refilling by increasing CCK secretion and reducing circulating concentrations of FGF19 and bile acids. These findings leave the antidiabetic actions of colesevelam unresolved but provide mechanistic insights into its effect on gallbladder motility.
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Affiliation(s)
- Ida M Gether
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
| | - Emilie Bahne
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
| | - Henriette H Nerild
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
| | - Jens F Rehfeld
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, DK-2730 Herlev, Denmark
| | - David P Sonne
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, DK-2730 Herlev, Denmark
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14
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Soileau LG, Nguyen A, Senthil A, Boullion JA, Talbot NC, Ahmadzadeh S, Shekoohi S, Kaye AD, Varrassi G. Bromocriptine and Colesevelam Hydrochloride: Novel Therapies for Type II Diabetes Mellitus. Cureus 2023; 15:e50138. [PMID: 38192911 PMCID: PMC10771968 DOI: 10.7759/cureus.50138] [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: 11/01/2023] [Accepted: 12/07/2023] [Indexed: 01/10/2024] Open
Abstract
The increasing prevalence of type II diabetes mellitus (T2DM) is a worldwide healthcare concern. Over the years, our understanding of T2DM has grown considerably in uncovering the pathophysiology of the disease and, in turn, understanding how improved treatment methods can be used to slow disease progression. Some long-term complications that are responsible for most T2DM mortalities include cardiovascular disease, neurological decline, and renal failure. In treating T2DM, it is important that not only glycemic control be obtained but also control of associated complications. Bromocriptine and colesevelam hydrochloride have both been approved by the Food and Drug Administration (FDA) to treat T2DM but are not readily used in practice. These medications are known to treat glycemic dysregulation via unconventional mechanisms, which might contribute to their potential to provide protection against common diabetic complications such as cardiovascular disease. In order to ensure that these overlooked medications become more readily used, it is vital that more research be performed to further elucidate their efficacy in a clinical setting. Future studies should continue to provide clinicians a better understanding of the role these medications have on the treatment of T2DM such as their ability to be used in combination with other commonly used T2DM medications or as monotherapies.
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Affiliation(s)
- Lenise G Soileau
- School of Medicine, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Angela Nguyen
- School of Medicine, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Aarthi Senthil
- School of Medicine, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Jolie A Boullion
- School of Medicine, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Norris C Talbot
- School of Medicine, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Shahab Ahmadzadeh
- Department of Anesthesiology, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Sahar Shekoohi
- Department of Anesthesiology, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Alan D Kaye
- Department of Anesthesiology, Louisiana State University Health Sciences Center, Shreveport, USA
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15
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Majait S, Meessen ECE, Vaz FM, Kemper EM, van Nierop S, Olde Damink SW, Schaap FG, Romijn JA, Nieuwdorp M, Verrips A, Knop FK, Soeters MR. Characterization of Postprandial Bile Acid Profiles and Glucose Metabolism in Cerebrotendinous Xanthomatosis. Nutrients 2023; 15:4625. [PMID: 37960277 PMCID: PMC10648145 DOI: 10.3390/nu15214625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 10/17/2023] [Accepted: 10/27/2023] [Indexed: 11/15/2023] Open
Abstract
Cerebrotendinous xanthomatosis (CTX) is a rare inherited disease characterized by sterol 27-hydroxylase (CYP27A1) deficiency and, thus, a lack of bile acid synthesis with a marked accumulation of 7α-hydroxylated bile acid precursors. In addition to their renowned lipid-emulgating role, bile acids have been shown to stimulate secretion of the glucose-lowering and satiety-promoting gut hormone glucagon-like peptide 1 (GLP-1). In this paper, we examined postprandial bile acid, glucose, insulin, GLP-1 and fibroblast growth factor 19 (FGF19) plasma profiles in patients with CTX and matched healthy controls. Seven patients and seven age, gender and body mass index matched controls were included and subjected to a 4 h mixed meal test with regular blood sampling. CTX patients withdrew from chenodeoxycholic acid (CDCA) and statin therapy three weeks prior to the test. Postprandial levels of total bile acids were significantly lower in CTX patients and consisted of residual CDCA with low amounts of ursodeoxycholic acid (UDCA). The postprandial plasma glucose peak concentration occurred later in CTX patients compared to controls, and patients' insulin levels remained elevated for a longer time. Postprandial GLP-1 levels were slightly higher in CTX subjects whereas postprandial FGF19 levels were lower in CTX subjects. This novel characterization of CTX patients reveals very low circulating bile acid levels and FGF19 levels, aberrant postprandial glucose and insulin profiles, and elevated postprandial GLP-1 responses.
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Affiliation(s)
- Soumia Majait
- Department of Pharmacy and Clinical Pharmacology, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Emma C. E. Meessen
- Department of Endocrinology and Metabolism, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (E.C.E.M.); (S.v.N.)
| | - Frederic Maxime Vaz
- Department of Clinical Chemistry and Pediatrics, Amsterdam UMC Location University of Amsterdam, Laboratory Genetic Metabolic Diseases, Emma Children’s Hospital, 1105 AZ Amsterdam, The Netherlands;
- Inborn Errors of Metabolism, Amsterdam Gastroenterology Endocrinology Metabolism, 1105 AZ Amsterdam, The Netherlands
- Core Facility Metabolomics, Amsterdam UMC location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - E. Marleen Kemper
- Department of Experimental Vascular Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands;
| | - Samuel van Nierop
- Department of Endocrinology and Metabolism, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (E.C.E.M.); (S.v.N.)
| | - Steven W. Olde Damink
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, 6229 ER Maastricht, The Netherlands; (S.W.O.D.); (F.G.S.)
- Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, 52074 Aachen, Germany
| | - Frank G. Schaap
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, 6229 ER Maastricht, The Netherlands; (S.W.O.D.); (F.G.S.)
- Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, 52074 Aachen, Germany
| | - Johannes A. Romijn
- Department of Internal Medicine, Amsterdam UMC Location University of Amsterdam, 1012 WX Amsterdam, The Netherlands;
| | - Max Nieuwdorp
- Department of Vascular Medicine, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Aad Verrips
- Department of Neurology, Canisius Wilhelmina Hospital, 6532 SZ Nijmegen, The Netherlands;
| | - Filip Krag Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark;
- Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 1353 Copenhagen, Denmark
| | - Maarten R. Soeters
- Department of Endocrinology and Metabolism, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (E.C.E.M.); (S.v.N.)
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16
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Petakh P, Kamyshna I, Kamyshnyi A. Unveiling the potential pleiotropic effects of metformin in treating COVID-19: a comprehensive review. Front Mol Biosci 2023; 10:1260633. [PMID: 37881440 PMCID: PMC10595158 DOI: 10.3389/fmolb.2023.1260633] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 09/28/2023] [Indexed: 10/27/2023] Open
Abstract
This review article explores the potential of metformin, a medication commonly used for type 2 diabetes, as an antiviral and anti-inflammatory agent in the context of coronavirus disease 2019 (COVID-19). Metformin has demonstrated inhibitory effects on the growth of SARS-CoV-2 in cell culture models and has shown promising results in reducing viral load and achieving undetectable viral levels in clinical trials. Additionally, metformin exhibits anti-inflammatory properties by reducing the production of pro-inflammatory cytokines and modulating immune cell function, which may help prevent cytokine storms associated with severe COVID-19. The drug's ability to regulate the balance between pro-inflammatory Th17 cells and anti-inflammatory Treg cells suggests its potential in mitigating inflammation and restoring T cell functionality. Furthermore, metformin's modulation of the gut microbiota, particularly changes in bacterial taxa and the production of short-chain fatty acids, may contribute to its therapeutic effects. The interplay between metformin, bile acids, the gut microbiome, glucagon-like peptide-1 secretion, and glycemic control has implications for the management of diabetes and potential interventions in COVID-19. By refreshing the current evidence, this review highlights the potential of metformin as a therapeutic option in the management of COVID-19, while also exploring its effects on the gut microbiome and immunometabolism.
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Affiliation(s)
- Pavlo Petakh
- Department of Biochemistry and Pharmacology, Uzhhorod National University, Uzhhorod, Ukraine
- Department of Microbiology, Virology, and Immunology, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
| | - Iryna Kamyshna
- Department of Medical Rehabilitation, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
| | - Aleksandr Kamyshnyi
- Department of Microbiology, Virology, and Immunology, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
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17
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Li H, Zhang R, Hu Y, Li J, Yang Y, Wu D, Gu X, Zhang F, Zhou H, Yang C. Axitinib attenuates the progression of liver fibrosis by restoring mitochondrial function. Int Immunopharmacol 2023; 122:110555. [PMID: 37399607 DOI: 10.1016/j.intimp.2023.110555] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/21/2023] [Accepted: 06/21/2023] [Indexed: 07/05/2023]
Abstract
Liver fibrosis can progress to cirrhosis and hepatocellular carcinoma, which may eventually lead to liver failure and even death. No direct anti-fibrosis drugs are available at present. Axitinib is a new generation of potent multitarget tyrosine kinase receptor inhibitors, but its role in liver fibrosis remains unclear. In this study, a CCl4-induced hepatic fibrosis mouse model and a TGF-β1-induced hepatic stellate cell model were used to explore the effect and mechanism of axitinib on hepatic fibrosis. Results confirmed that axitinib could alleviate the pathological damage of liver tissue induced by CCl4 and inhibit the production of glutamic-oxalacetic transaminase and glutamic-pyruvic transaminase. It also inhibited collagen and hydroxyproline deposition and the protein expression of Col-1 and α-SMA in CCl4-induced liver fibrosis. In addition, axitinib inhibited the expression of CTGF and α-SMA in TGF-β1-induced hepatic stellate cells. Further studies showed that axitinib inhibited mitochondrial damage and reduced oxidative stress and NLRP3 maturation. The use of rotenone and antimycin A confirmed that axitinib could restore the activity of mitochondrial complexes I and III, thereby inhibiting the maturation of NLRP3. In summary, axitinib inhibits the activation of HSCs by enhancing the activity of mitochondrial complexes I and III, thereby alleviating the progression of liver fibrosis. This study reveals the strong potential of axitinib in the treatment of liver fibrosis.
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Affiliation(s)
- Hailong Li
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China
| | - Ruotong Zhang
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China; High-throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin 300350, China
| | - Yayue Hu
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China; High-throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin 300350, China
| | - Jinhe Li
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China; High-throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin 300350, China
| | - Ying Yang
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China
| | - Dan Wu
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China
| | - Xiaoting Gu
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China
| | - Fubo Zhang
- Organ Transplantation Center, Tianjin First Central Hospital, No. 24 Fukang Road, Nankai District, Tianjin 300192, China.
| | - Honggang Zhou
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China; High-throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin 300350, China.
| | - Cheng Yang
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China; High-throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin 300350, China.
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18
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Peng J, Fan M, Huang KX, Huang LA, Wang Y, Yin R, Zhao H, Xu S, Li H, Agua A, Xie J, Horne DA, Kandeel F, Huang W, Li J. Design, Synthesis, Computational and Biological Evaluation of Novel Structure Fragments Based on Lithocholic Acid (LCA). Molecules 2023; 28:5332. [PMID: 37513205 PMCID: PMC10383687 DOI: 10.3390/molecules28145332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 06/30/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023] Open
Abstract
The regulation of bile acid pathways has become a particularly promising therapeutic strategy for a variety of metabolic disorders, cancers, and diseases. However, the hydrophobicity of bile acids has been an obstacle to clinical efficacy due to off-target effects from rapid drug absorption. In this report, we explored a novel strategy to design new structure fragments based on lithocholic acid (LCA) with improved hydrophilicity by introducing a polar "oxygen atom" into the side chain of LCA, then (i) either retaining the carboxylic acid group or replacing the carboxylic acid group with (ii) a diol group or (iii) a vinyl group. These novel fragments were evaluated using luciferase-based reporter assays and the MTS assay. Compared to LCA, the result revealed that the two lead compounds 1a-1b were well tolerated in vitro, maintaining similar potency and efficacy to LCA. The MTS assay results indicated that cell viability was not affected by dose dependence (under 25 µM). Additionally, computational model analysis demonstrated that compounds 1a-1b formed more extensive hydrogen bond networks with Takeda G protein-coupled receptor 5 (TGR5) than LCA. This strategy displayed a potential approach to explore the development of novel endogenous bile acids fragments. Further evaluation on the biological activities of the two lead compounds is ongoing.
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Affiliation(s)
- Jiangling Peng
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Mingjie Fan
- Department of Diabetes Complications & Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Kelly X Huang
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Lina A Huang
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Yangmeng Wang
- Department of Diabetes Complications & Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Runkai Yin
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Hanyi Zhao
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Senlin Xu
- Department of Diabetes Complications & Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Hongzhi Li
- Department of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Alon Agua
- Department of Diabetes Complications & Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Jun Xie
- Department of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - David A Horne
- Department of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Fouad Kandeel
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Wendong Huang
- Department of Diabetes Complications & Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Junfeng Li
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
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19
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Sah DK, Arjunan A, Park SY, Jung YD. Bile acids and microbes in metabolic disease. World J Gastroenterol 2022; 28:6846-6866. [PMID: 36632317 PMCID: PMC9827586 DOI: 10.3748/wjg.v28.i48.6846] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/01/2022] [Accepted: 12/05/2022] [Indexed: 12/26/2022] Open
Abstract
Bile acids (BAs) serve as physiological detergents that enable the intestinal absorption and transportation of nutrients, lipids and vitamins. BAs are primarily produced by humans to catabolize cholesterol and play crucial roles in gut metabolism, microbiota habitat regulation and cell signaling. BA-activated nuclear receptors regulate the enterohepatic circulation of BAs which play a role in energy, lipid, glucose, and drug metabolism. The gut microbiota plays an essential role in the biotransformation of BAs and regulates BAs composition and metabolism. Therefore, altered gut microbial and BAs activity can affect human metabolism and thus result in the alteration of metabolic pathways and the occurrence of metabolic diseases/syndromes, such as diabetes mellitus, obesity/hypercholesterolemia, and cardiovascular diseases. BAs and their metabolites are used to treat altered gut microbiota and metabolic diseases. This review explores the increasing body of evidence that links alterations of gut microbial activity and BAs with the pathogenesis of metabolic diseases. Moreover, we summarize existing research on gut microbes and BAs in relation to intracellular pathways pertinent to metabolic disorders. Finally, we discuss how therapeutic interventions using BAs can facilitate microbiome functioning and ease metabolic diseases.
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Affiliation(s)
- Dhiraj Kumar Sah
- Department of Biochemistry, Chonnam National University, Gwangju 501190, South Korea
| | - Archana Arjunan
- Department of Biochemistry, Chonnam National University, Gwangju 501190, South Korea
| | - Sun Young Park
- Department of Internal Medicine, Chonnam National University, Gwangju 501190, South Korea
| | - Young Do Jung
- Department of Biochemistry, Chonnam National University, Gwangju 501190, South Korea
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20
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Cook JR, Kohan AB, Haeusler RA. An Updated Perspective on the Dual-Track Model of Enterocyte Fat Metabolism. J Lipid Res 2022; 63:100278. [PMID: 36100090 PMCID: PMC9593242 DOI: 10.1016/j.jlr.2022.100278] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 08/08/2022] [Accepted: 08/31/2022] [Indexed: 02/04/2023] Open
Abstract
The small intestinal epithelium has classically been envisioned as a conduit for nutrient absorption, but appreciation is growing for a larger and more dynamic role for enterocytes in lipid metabolism. Considerable gaps remain in our knowledge of this physiology, but it appears that the enterocyte's structural polarization dictates its behavior in fat partitioning, treating fat differently based on its absorption across the apical versus the basolateral membrane. In this review, we synthesize existing data and thought on this dual-track model of enterocyte fat metabolism through the lens of human integrative physiology. The apical track includes the canonical pathway of dietary lipid absorption across the apical brush-border membrane, leading to packaging and secretion of those lipids as chylomicrons. However, this track also reserves a portion of dietary lipid within cytoplasmic lipid droplets for later uses, including the "second-meal effect," which remains poorly understood. At the same time, the enterocyte takes up circulating fats across the basolateral membrane by mechanisms that may include receptor-mediated import of triglyceride-rich lipoproteins or their remnants, local hydrolysis and internalization of free fatty acids, or enterocyte de novo lipogenesis using basolaterally absorbed substrates. The ultimate destinations of basolateral-track fat may include fatty acid oxidation, structural lipid synthesis, storage in cytoplasmic lipid droplets, or ultimate resecretion, although the regulation and purposes of this basolateral track remain mysterious. We propose that the enterocyte integrates lipid flux along both of these tracks in order to calibrate its overall program of lipid metabolism.
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Affiliation(s)
- Joshua R. Cook
- Naomi Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, NY, USA,Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Alison B. Kohan
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Rebecca A. Haeusler
- Naomi Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, NY, USA,Department of Pathology and Cell Biology; Columbia University College of Physicians and Surgeons, New York, NY, USA,For correspondence: Rebecca A. Haeusler
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21
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Cai J, Rimal B, Jiang C, Chiang JYL, Patterson AD. Bile acid metabolism and signaling, the microbiota, and metabolic disease. Pharmacol Ther 2022; 237:108238. [PMID: 35792223 DOI: 10.1016/j.pharmthera.2022.108238] [Citation(s) in RCA: 169] [Impact Index Per Article: 56.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/13/2022] [Accepted: 06/27/2022] [Indexed: 11/24/2022]
Abstract
The diversity, composition, and function of the bacterial community inhabiting the human gastrointestinal tract contributes to host health through its role in producing energy or signaling molecules that regulate metabolic and immunologic functions. Bile acids are potent metabolic and immune signaling molecules synthesized from cholesterol in the liver and then transported to the intestine where they can undergo metabolism by gut bacteria. The combination of host- and microbiota-derived enzymatic activities contribute to the composition of the bile acid pool and thus there can be great diversity in bile acid composition that depends in part on the differences in the gut bacteria species. Bile acids can profoundly impact host metabolic and immunological functions by activating different bile acid receptors to regulate signaling pathways that control a broad range of complex symbiotic metabolic networks, including glucose, lipid, steroid and xenobiotic metabolism, and modulation of energy homeostasis. Disruption of bile acid signaling due to perturbation of the gut microbiota or dysregulation of the gut microbiota-host interaction is associated with the pathogenesis and progression of metabolic disorders. The metabolic and immunological roles of bile acids in human health have led to novel therapeutic approaches to manipulate the bile acid pool size, composition, and function by targeting one or multiple components of the microbiota-bile acid-bile acid receptor axis.
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Affiliation(s)
- Jingwei Cai
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Bipin Rimal
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Changtao Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, PR China
| | - John Y L Chiang
- Department of Integrative Medical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Andrew D Patterson
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA.
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22
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Esan O, Viljoen A, Wierzbicki AS. Colesevelam - a bile acid sequestrant for treating hypercholesterolemia and improving hyperglycemia. Expert Opin Pharmacother 2022; 23:1363-1370. [PMID: 35968655 DOI: 10.1080/14656566.2022.2112945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Low density Lipoprotein cholesterol)LDL-C) levels show a clear relationship with cardiovascular disease (CVD). Statins are first line agents to reduce LDL-C and CVD risk. However, combination lipid-lowering therapy is often required to achieve large reductions in LDL-C. AREA COVERED Colesevelam HCl is a bile acid sequestrant (BAS), which reduces LDL-C by 16-22% in monotherapy and adds a further 12-14% reduction in LDL-C when combined with other lipid-lowering drugs. Like statins, colesevelam reduces C-reactive protein levels by 16% in monotherapy and additional 6% when added to statins. Colesevelam also reduced HbA1c by 4mmol/mol (0.5%) when used alone and added to other hypoglycaemic drugs in studies of patients with diabetes . EXPERT OPINION Bile acid sequestrants reduce LDL-C and HbA1c and have some CVD outcome evidence. The uses of these agents are limited in patients with gastrointestinal disease or high triglycerides due to adverse effects on gut function and raising triglycerides and they interfere with the absorption of lipid-soluble drugs. Colesevelam has a higher bile acid binding capacity, and fewer adverse effects than other BAS. Colesevelam may be useful as a third line agent for treatment of hypercholesterolemia with some additional specific benefits on glycemic control.
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Affiliation(s)
- Oluwayemisi Esan
- Metabolic Medicine/Chemical Pathology, Guy's & St Thomas Hospitals, London SE1 7EH, UK
| | - Adie Viljoen
- Metabolic Medicine/Chemical Pathology, East & North Hertfordshire Hospitals, Lister Hospital, Stevenage, Hertfordshire SG1 4AB, UK
| | - Anthony S Wierzbicki
- Metabolic Medicine/Chemical Pathology, Guy's & St Thomas Hospitals, London SE1 7EH, UK
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23
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Cheng H, Liu J, Zhang D, Tan Y, Feng W, Peng C. Gut microbiota, bile acids, and nature compounds. Phytother Res 2022; 36:3102-3119. [PMID: 35701855 DOI: 10.1002/ptr.7517] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 05/09/2022] [Accepted: 05/17/2022] [Indexed: 11/09/2022]
Abstract
Natural compounds (NPs) have historically made a major contribution to pharmacotherapy in various diseases and drug discovery. In the past decades, studies on gut microbiota have shown that the efficacy of NPs can be affected by the interactions between gut microbiota and NPs. On one hand, gut microbiota can metabolize NPs. On the other hand, NPs can influence the metabolism and composition of gut microbiota. Among gut microbiota metabolites, bile acids (BAs) have attracted widespread attention due to their effects on the body homeostasis and the development of diseases. Studies have also confirmed that NPs can regulate the metabolism of BAs and ultimately regulate the physiological function of the body and disease progresses. In this review, we comprehensively summarize the interactions among NPs, gut microbiota, and BAs. In addition, we also discuss the role of microbial BAs metabolism in understanding the toxicity and efficacy of NPs. Furthermore, we present personal insights into the future research directions of NPs and BAs.
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Affiliation(s)
- Hao Cheng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Juan Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Dandan Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuzhu Tan
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,The Ministry of Education Key Laboratory of Standardization of Chinese Herbal Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wuwen Feng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,The Ministry of Education Key Laboratory of Standardization of Chinese Herbal Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,The Ministry of Education Key Laboratory of Standardization of Chinese Herbal Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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24
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Hao Y, Zhou P, Zhu YJ, Zou S, Zhao Q, Yu J, Hu Y, Li J. Gut Microbiota Dysbiosis and Altered Bile Acid Catabolism Lead to Metabolic Disorder in Psoriasis Mice. Front Microbiol 2022; 13:853566. [PMID: 35495722 PMCID: PMC9048827 DOI: 10.3389/fmicb.2022.853566] [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: 01/12/2022] [Accepted: 03/15/2022] [Indexed: 11/13/2022] Open
Abstract
Patients with psoriasis tend to have significant comorbidities, such as hyperlipemia, diabetes mellitus, and obesity, which belong to metabolic disorders. The specific mechanism through which psoriasis increases the metabolic disorder risk is uncertain. In this study, we demonstrated that the dysbiotic gut microbiota of 6-month-old psoriasis-like model mice (K14-VEGF-A-transgenic) exacerbated psoriasis disease and induced metabolic disorder when transferred into 2-month-old mice. By 16S rRNA gene sequencing, we confirmed that the Parabacteroides distasonis decreased with age in K14-VEGF mice, and P. distasonis also decreased in the transferred mice. Metabolomic screening identified an altered bile acid profile, including a decrease in chenodeoxycholic acid (CDCA) in the feces of transferred mice. Additionally, CDCA supplements prevented metabolic disorders in K14-VEGF-A-transgenic mice. Consequently, we found that aberrant bile acid metabolism may contribute to metabolic disorder in K14-VEGF-A-transgenic mice, indicating the possibility to prevent and treat the metabolic disorder in psoriasis mice by targeting gut microbial metabolites.
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Affiliation(s)
- Yan Hao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Pei Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Ya-juan Zhu
- Department of Biotherapy and Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Song Zou
- Department of Cardiology West China Hospital, Sichuan University, Chengdu, China
| | - Qixiang Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Jiadong Yu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Yawen Hu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Jiong Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
- *Correspondence: Jiong Li
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25
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Kårhus ML, Sonne DP, Thomasen M, Ellegaard AM, Holst JJ, Rehfeld JF, Chávez-Talavera O, Tailleux A, Staels B, Nielsen DS, Krych L, Dragsted LO, Vilsbøll T, Brønden A, Knop FK. Enterohepatic, Gluco-metabolic, and Gut Microbial Characterization of Individuals With Bile Acid Malabsorption. GASTRO HEP ADVANCES 2022; 1:299-312. [PMID: 39131668 PMCID: PMC11307667 DOI: 10.1016/j.gastha.2021.12.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 12/14/2021] [Indexed: 08/13/2024]
Abstract
Background and Aims Bile acid malabsorption (BAM) is a debilitating disease characterized by loose stools and high stool frequency. The pathophysiology of BAM is not well-understood. We investigated postprandial enterohepatic and gluco-metabolic physiology, as well as gut microbiome composition and fecal bile acid content in patients with BAM. Methods Twelve participants with selenium-75 homocholic acid taurine test-verified BAM and 12 healthy controls, individually matched on sex, age, and body mass index, were included. Each participant underwent 2 mixed meal tests (with and without administration of the bile acid sequestrant colesevelam) with blood sampling and evaluation of gallbladder motility; bile acid content and microbiota composition were evaluated in fecal specimens. Results Patients with BAM were characterized by increased bile acid synthesis as assessed by circulating 7-alpha-hydroxy-4-cholesten-3-one, fecal bile acid content, and postprandial concentrations of glucose, insulin, C-peptide, and glucagon. The McAuley index of insulin sensitivity was lower in patients with BAM than that in healthy controls. In patients with BAM, colesevelam co-administered with the meal reduced postprandial concentrations of bile acids and fibroblast growth factor 19 and increased 7-alpha-hydroxy-4-cholesten-3-one concentrations but did not affect postprandial glucagon-like peptide 1 responses or other gluco-metabolic parameters. Patients with BAM were characterized by a gut microbiome with low relative abundance of bifidobacteria and high relative abundance of Blautia, Streptococcus, Ruminococcus gnavus, and Akkermansia muciniphila. Conclusion Patients with BAM are characterized by an overproduction of bile acids, greater fecal bile acid content, and a gluco-metabolic profile indicative of a dysmetabolic prediabetic-like state, with changes in their gut microbiome composition potentially linking their enterohepatic pathophysiology and their dysmetabolic phenotype. ClinicalTrials.gov number NCT03009916.
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Affiliation(s)
- Martin L. Kårhus
- Center for Clinical Metabolic Research, Copenhagen University Hospital – Herlev and Gentofte, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - David P. Sonne
- Center for Clinical Metabolic Research, Copenhagen University Hospital – Herlev and Gentofte, Hellerup, Denmark
- Department of Clinical Pharmacology, Copenhagen University Hospital – Bispebjerg and Frederiksberg, Copenhagen, Denmark
| | - Martin Thomasen
- Center for Clinical Metabolic Research, Copenhagen University Hospital – Herlev and Gentofte, Hellerup, Denmark
| | - Anne-Marie Ellegaard
- Center for Clinical Metabolic Research, Copenhagen University Hospital – Herlev and Gentofte, Hellerup, 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
| | - Jens F. Rehfeld
- Department of Clinical Biochemistry, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
| | - Oscar Chávez-Talavera
- University of Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Anne Tailleux
- University of Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Bart Staels
- University of Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Dennis S. Nielsen
- Department of Food Science, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Lukasz Krych
- Department of Food Science, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Lars O. Dragsted
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Frederiksberg, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Copenhagen University Hospital – Herlev and Gentofte, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Andreas Brønden
- Center for Clinical Metabolic Research, Copenhagen University Hospital – Herlev and Gentofte, Hellerup, Denmark
- Department of Clinical Pharmacology, Copenhagen University Hospital – Bispebjerg and Frederiksberg, Copenhagen, Denmark
| | - Filip K. Knop
- Center for Clinical Metabolic Research, Copenhagen University Hospital – Herlev and Gentofte, Hellerup, Denmark
- Department of Clinical Medicine, 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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26
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van de Wiel SM, Porteiro B, Belt SC, Vogels EW, Bolt I, Vermeulen JL, de Waart DR, Verheij J, Muncan V, Oude Elferink RP, van de Graaf SF. Differential and organ-specific functions of organic solute transporter alpha and beta in experimental cholestasis. JHEP Rep 2022; 4:100463. [PMID: 35462858 PMCID: PMC9019253 DOI: 10.1016/j.jhepr.2022.100463] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 02/15/2022] [Accepted: 02/17/2022] [Indexed: 02/07/2023] Open
Abstract
Background & Aims Organic solute transporter (OST) subunits OSTα and OSTβ facilitate bile acid efflux from the enterocyte into the portal circulation. Patients with deficiency of OSTα or OSTβ display considerable variation in the level of bile acid malabsorption, chronic diarrhea, and signs of cholestasis. Herein, we generated and characterized a mouse model of OSTβ deficiency. Methods Ostβ-/- mice were generated using CRISR/Cas9 and compared to wild-type and Ostα-/- mice. OSTβ was re-expressed in livers of Ostβ-/- mice using adeno-associated virus serotype 8 vectors. Cholestasis was induced in both models by bile duct ligation (BDL) or 3.5-diethoxycarbonyl-1.4-dihydrocollidine (DDC) feeding. Results Similar to Ostα-/- mice, Ostβ-/- mice exhibited elongated small intestines with blunted villi and increased crypt depth. Increased expression levels of ileal Fgf15, and decreased Asbt expression in Ostβ-/- mice indicate the accumulation of bile acids in the enterocyte. In contrast to Ostα-/- mice, induction of cholestasis in Ostβ-/- mice by BDL or DDC diet led to lower survival rates and severe body weight loss, but an improved liver phenotype. Restoration of hepatic Ostβ expression via adeno-associated virus-mediated overexpression did not rescue the phenotype of Ostβ-/- mice. Conclusions OSTβ is pivotal for bile acid transport in the ileum and its deficiency leads to an intestinal phenotype similar to Ostα-/- mice, but it exerts distinct effects on survival and the liver phenotype, independent of its expression in the liver. Our findings provide insights into the variable clinical presentation of patients with OSTα and OSTβ deficiencies. Lay summary Organic solute transporter (OST) subunits OSTα and OSTβ together facilitate the efflux of conjugated bile acids into the portal circulation. Ostα knockout mice have longer and thicker small intestines and are largely protected against experimental cholestatic liver injury. Herein, we generated and characterized Ostβ knockout mice for the first time. Ostα and Ostβ knockout mice shared a similar phenotype under normal conditions. However, in cholestasis, Ostβ knockout mice had a worsened overall phenotype which indicates a separate and specific role of OSTβ, possibly as an interacting partner of other intestinal proteins.
This manuscript describes the first mouse model of OSTβ deficiency. Ostβ-/- mice are viable and fertile, but show increased length and weight of the small intestine, blunted villi and deeper crypts. Ostβ deficiency leads to an altered microbiome compared to both wild-type and Ostα-/- mice. Cholestasis led to lower survival and worse body weight loss, but an improved liver phenotype, in Ostβ-/- mice compared to Ostα-/- mice.
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Affiliation(s)
- Sandra M.W. van de Wiel
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Begoña Porteiro
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
- CIMUS, Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain
| | - Saskia C. Belt
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Esther W.M. Vogels
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Isabelle Bolt
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Jacqueline L.M. Vermeulen
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - D. Rudi de Waart
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Joanne Verheij
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
- Department of Pathology, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Vanesa Muncan
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Ronald P.J. Oude Elferink
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Stan F.J. van de Graaf
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, the Netherlands
- Corresponding author. Address: Meibergdreef 69-71, 1105 BK Amsterdam, the Netherlands; Tel.: 020-5668832, fax: 020-5669190
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Keely SJ, Urso A, Ilyaskin AV, Korbmacher C, Bunnett NW, Poole DP, Carbone SE. Contributions of bile acids to gastrointestinal physiology as receptor agonists and modifiers of ion channels. Am J Physiol Gastrointest Liver Physiol 2022; 322:G201-G222. [PMID: 34755536 PMCID: PMC8782647 DOI: 10.1152/ajpgi.00125.2021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 10/28/2021] [Accepted: 11/08/2021] [Indexed: 02/03/2023]
Abstract
Bile acids (BAs) are known to be important regulators of intestinal motility and epithelial fluid and electrolyte transport. Over the past two decades, significant advances in identifying and characterizing the receptors, transporters, and ion channels targeted by BAs have led to exciting new insights into the molecular mechanisms involved in these processes. Our appreciation of BAs, their receptors, and BA-modulated ion channels as potential targets for the development of new approaches to treat intestinal motility and transport disorders is increasing. In the current review, we aim to summarize recent advances in our knowledge of the different BA receptors and BA-modulated ion channels present in the gastrointestinal system. We discuss how they regulate motility and epithelial transport, their roles in pathogenesis, and their therapeutic potential in a range of gastrointestinal diseases.
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Affiliation(s)
- Stephen J Keely
- Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland
| | - Andreacarola Urso
- Department of Surgery, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York
- Department of Pharmacology, Columbia University, New York, New York
| | - Alexandr V Ilyaskin
- Institute of Cellular and Molecular Physiology, Friedrich-Alexander University Erlangen-Nürnberg, Bavaria, Germany
| | - Christoph Korbmacher
- Institute of Cellular and Molecular Physiology, Friedrich-Alexander University Erlangen-Nürnberg, Bavaria, Germany
| | - Nigel W Bunnett
- Department of Molecular Pathobiology, Neuroscience Institute, New York University, New York, New York
- Department of Neuroscience and Physiology, Neuroscience Institute, New York University, New York, New York
| | - Daniel P Poole
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
- Australian Research Council, Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Simona E Carbone
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
- Australian Research Council, Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
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McMurdie PJ, Stoeva MK, Justice N, Nemchek M, Sieber CMK, Tyagi S, Gines J, Skennerton CT, Souza M, Kolterman O, Eid J. Increased circulating butyrate and ursodeoxycholate during probiotic intervention in humans with type 2 diabetes. BMC Microbiol 2022; 22:19. [PMID: 34996347 PMCID: PMC8742391 DOI: 10.1186/s12866-021-02415-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 12/07/2021] [Indexed: 02/07/2023] Open
Abstract
Background An increasing body of evidence implicates the resident gut microbiota as playing a critical role in type 2 diabetes (T2D) pathogenesis. We previously reported significant improvement in postprandial glucose control in human participants with T2D following 12-week administration of a 5-strain novel probiotic formulation (‘WBF-011’) in a double-blind, randomized, placebo controlled setting (NCT03893422). While the clinical endpoints were encouraging, additional exploratory measurements were needed in order to link the motivating mechanistic hypothesis - increased short-chain fatty acids - with markers of disease. Results Here we report targeted and untargeted metabolomic measurements on fasting plasma (n = 104) collected at baseline and end of intervention. Butyrate and ursodeoxycholate increased among participants randomized to WBF-011, along with compelling trends between butyrate and glycated haemoglobin (HbA1c). In vitro monoculture experiments demonstrated that the formulation’s C. butyricum strain efficiently synthesizes ursodeoxycholate from the primary bile acid chenodeoxycholate during butyrogenic growth. Untargeted metabolomics also revealed coordinated decreases in intermediates of fatty acid oxidation and bilirubin, potential secondary signatures for metabolic improvement. Finally, improvement in HbA1c was limited almost entirely to participants not using sulfonylurea drugs. We show that these drugs can inhibit growth of formulation strains in vitro. Conclusion To our knowledge, this is the first description of an increase in circulating butyrate or ursodeoxycholate following a probiotic intervention in humans with T2D, adding support for the possibility of a targeted microbiome-based approach to assist in the management of T2D. The efficient synthesis of UDCA by C. butyricum is also likely of interest to investigators of its use as a probiotic in other disease settings. The potential for inhibitory interaction between sulfonylurea drugs and gut microbiota should be considered carefully in the design of future studies. Supplementary Information The online version contains supplementary material available at 10.1186/s12866-021-02415-8.
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Affiliation(s)
- Paul J McMurdie
- Pendulum Therapeutics, Inc, 933 20th Street, San Francisco, CA, 94107, USA.
| | - Magdalena K Stoeva
- Pendulum Therapeutics, Inc, 933 20th Street, San Francisco, CA, 94107, USA
| | - Nicholas Justice
- Pendulum Therapeutics, Inc, 933 20th Street, San Francisco, CA, 94107, USA
| | - Madeleine Nemchek
- Pendulum Therapeutics, Inc, 933 20th Street, San Francisco, CA, 94107, USA
| | | | - Surabhi Tyagi
- Pendulum Therapeutics, Inc, 933 20th Street, San Francisco, CA, 94107, USA
| | - Jessica Gines
- Pendulum Therapeutics, Inc, 933 20th Street, San Francisco, CA, 94107, USA
| | | | - Michael Souza
- Pendulum Therapeutics, Inc, 933 20th Street, San Francisco, CA, 94107, USA
| | - Orville Kolterman
- Pendulum Therapeutics, Inc, 933 20th Street, San Francisco, CA, 94107, USA
| | - John Eid
- Pendulum Therapeutics, Inc, 933 20th Street, San Francisco, CA, 94107, USA
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Miedzybrodzka EL, Gribble FM, Reimann F. Targeting the Enteroendocrine System for Treatment of Obesity. Handb Exp Pharmacol 2022; 274:487-513. [PMID: 35419620 DOI: 10.1007/164_2022_583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Mimetics of the anorexigenic gut hormone glucagon-like peptide 1 (GLP-1) were originally developed as insulinotropic anti-diabetic drugs but also evoke significant weight loss, leading to their recent approval as obesity therapeutics. Co-activation of receptors for GLP-1 and other gut hormones which reduce food intake - peptide YY (PYY3-36), cholecystokinin (CCK) and glucose-dependent insulinotropic peptide (GIP) - is now being explored clinically to enhance efficacy. An alternative approach involves pharmacologically stimulating endogenous secretion of these hormones from enteroendocrine cells (EECs) to recapitulate the metabolic consequences of bariatric surgery, where highly elevated postprandial levels of GLP-1 and PYY3-36 are thought to contribute to improved glycaemia and weight loss.
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Affiliation(s)
- Emily L Miedzybrodzka
- Wellcome Trust - MRC Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
| | - Fiona M Gribble
- Wellcome Trust - MRC Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
| | - Frank Reimann
- Wellcome Trust - MRC Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
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30
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Zhang S, Zhou J, Wu W, Zhu Y, Liu X. The Role of Bile Acids in Cardiovascular Diseases: from Mechanisms to Clinical Implications. Aging Dis 2022; 14:261-282. [PMID: 37008052 PMCID: PMC10017164 DOI: 10.14336/ad.2022.0817] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 08/17/2022] [Indexed: 11/18/2022] Open
Abstract
Bile acids (BAs), key regulators in the metabolic network, are not only involved in lipid digestion and absorption but also serve as potential therapeutic targets for metabolic disorders. Studies have shown that cardiac dysfunction is associated with abnormal BA metabolic pathways. As ligands for several nuclear receptors and membrane receptors, BAs systematically regulate the homeostasis of metabolism and participate in cardiovascular diseases (CVDs), such as myocardial infarction, diabetic cardiomyopathy, atherosclerosis, arrhythmia, and heart failure. However, the molecular mechanism by which BAs trigger CVDs remains controversial. Therefore, the regulation of BA signal transduction by modulating the synthesis and composition of BAs is an interesting and novel direction for potential therapies for CVDs. Here, we mainly summarized the metabolism of BAs and their role in cardiomyocytes and noncardiomyocytes in CVDs. Moreover, we comprehensively discussed the clinical prospects of BAs in CVDs and analyzed the clinical diagnostic and application value of BAs. The latest development prospects of BAs in the field of new drug development are also prospected. We aimed to elucidate the underlying mechanism of BAs treatment in CVDs, and the relationship between BAs and CVDs may provide new avenues for the prevention and treatment of these diseases.
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Affiliation(s)
- Shuwen Zhang
- Laboratory of Cardiovascular Diseases, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China.
| | - Junteng Zhou
- Laboratory of Cardiovascular Diseases, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China.
- Health Management Center, West China Hospital, Sichuan University, Chengdu, China.
| | - Wenchao Wu
- Laboratory of Cardiovascular Diseases, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China.
| | - Ye Zhu
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China.
- Correspondence should be addressed to: Prof. Xiaojing Liu (), and Prof. Ye Zhu (), West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiaojing Liu
- Laboratory of Cardiovascular Diseases, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China.
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China.
- Correspondence should be addressed to: Prof. Xiaojing Liu (), and Prof. Ye Zhu (), West China Hospital, Sichuan University, Chengdu, Sichuan, China
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31
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Orozco-Aguilar J, Simon F, Cabello-Verrugio C. Redox-Dependent Effects in the Physiopathological Role of Bile Acids. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:4847941. [PMID: 34527174 PMCID: PMC8437588 DOI: 10.1155/2021/4847941] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 08/17/2021] [Indexed: 12/17/2022]
Abstract
Bile acids (BA) are recognized by their role in nutrient absorption. However, there is growing evidence that BA also have endocrine and metabolic functions. Besides, the steroidal-derived structure gives BA a toxic potential over the biological membrane. Thus, cholestatic disorders, characterized by elevated BA on the liver and serum, are a significant cause of liver transplant and extrahepatic complications, such as skeletal muscle, central nervous system (CNS), heart, and placenta. Further, the BA have an essential role in cellular damage, mediating processes such as membrane disruption, mitochondrial dysfunction, and the generation of reactive oxygen species (ROS) and oxidative stress. The purpose of this review is to describe the BA and their role on hepatic and extrahepatic complications in cholestatic diseases, focusing on the association between BA and the generation of oxidative stress that mediates tissue damage.
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Affiliation(s)
- Josué Orozco-Aguilar
- Laboratory of Muscle Pathology, Fragility, and Aging, Department of Biological Sciences, Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370146, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago 8370146, Chile
- Center for the Development of Nanoscience and Nanotechnology (CEDENNA), Universidad de Santiago de Chile, Santiago 8350709, Chile
| | - Felipe Simon
- Millennium Institute on Immunology and Immunotherapy, Santiago 8370146, Chile
- Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Universidad de Chile, Santiago 8370146, Chile
- Laboratory of Integrative Physiopathology, Department of Biological Sciences, Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370146, Chile
| | - Claudio Cabello-Verrugio
- Laboratory of Muscle Pathology, Fragility, and Aging, Department of Biological Sciences, Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370146, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago 8370146, Chile
- Center for the Development of Nanoscience and Nanotechnology (CEDENNA), Universidad de Santiago de Chile, Santiago 8350709, Chile
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32
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McGlone ER, Malallah K, Cuenco J, Wewer Albrechtsen NJ, Holst JJ, Vincent RP, Ling C, Khan OA, Verma S, Ahmed AR, Walters JRF, Khoo B, Bloom SR, Tan TMM. Differential effects of bile acids on the postprandial secretion of gut hormones: a randomized crossover study. Am J Physiol Endocrinol Metab 2021; 320:E671-E679. [PMID: 33459181 DOI: 10.1152/ajpendo.00580.2020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Bile acids (BA) regulate postprandial metabolism directly and indirectly by affecting the secretion of gut hormones like glucagon-like peptide-1 (GLP-1). The postprandial effects of BA on the secretion of other metabolically active hormones are not well understood. The objective of this study was to investigate the effects of oral ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) on postprandial secretion of GLP-1, oxyntomodulin (OXM), peptide YY (PYY), glucose-dependent insulinotropic peptide (GIP), glucagon, and ghrelin. Twelve healthy volunteers underwent a mixed meal test 60 min after ingestion of UDCA (12-16 mg/kg), CDCA (13-16 mg/kg), or no BA in a randomized crossover study. Glucose, insulin, GLP-1, OXM, PYY, GIP, glucagon, ghrelin, and fibroblast growth factor 19 were measured prior to BA administration at -60 and 0 min (just prior to mixed meal) and 15, 30, 60, 120, 180, and 240 min after the meal. UDCA and CDCA provoked differential gut hormone responses; UDCA did not have any significant effects, but CDCA provoked significant increases in GLP-1 and OXM and a profound reduction in GIP. CDCA increased fasting GLP-1 and OXM secretion in parallel with an increase in insulin. On the other hand, CDCA reduced postprandial secretion of GIP, with an associated reduction in postprandial insulin secretion. Exogenous CDCA can exert multiple salutary effects on the secretion of gut hormones; if these effects are confirmed in obesity and type 2 diabetes, CDCA may be a potential therapy for these conditions.NEW & NOTEWORTHY Oral CDCA and UDCA have different effects on gut and pancreatic hormone secretion. A single dose of CDCA increased fasting secretion of the hormones GLP-1 and OXM with an accompanying increase in insulin secretion. CDCA also reduced postprandial GIP secretion, which was associated with reduced insulin. In contrast, UDCA did not change gut hormone secretion fasting or postprandially. Oral CDCA could be beneficial to patients with obesity and diabetes.
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Affiliation(s)
- Emma Rose McGlone
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Khalefah Malallah
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Joyceline Cuenco
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Nicolai J Wewer Albrechtsen
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- NNF Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences and the NNF Center for Basic Metabolic Research, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences and the NNF Center for Basic Metabolic Research, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
| | - Royce P Vincent
- Department of Clinical Biochemistry, King's College Hospital NHS Foundation Trust, London, United Kingdom
| | - Charlotte Ling
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Omar A Khan
- Department of Surgery, St. George's University Hospitals NHS Trust, London, United Kingdom
| | - Surabhi Verma
- Leadiant Biosciences, Amberley House, Windsor, Berkshire, United Kingdom
| | - Ahmed R Ahmed
- Department of Surgery and Cancer, Imperial College Healthcare NHS Trust, London, United Kingdom
| | - Julian R F Walters
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Bernard Khoo
- Endocrinology, UCL Division of Medicine, Royal Free Hospital, London, United Kingdom
| | - Stephen R Bloom
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Tricia M M Tan
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
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33
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Bell DSH, Goncalves E. Diabetogenic effects of cardioprotective drugs. Diabetes Obes Metab 2021; 23:877-885. [PMID: 33319474 DOI: 10.1111/dom.14295] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 11/22/2020] [Accepted: 12/07/2020] [Indexed: 01/11/2023]
Abstract
Drugs that protect against cardiovascular events in the patient with diabetes may also positively or negatively affect glycaemic control in the patient with established diabetes and may induce the development of diabetes in the predisposed patient. Mainly through increasing insulin resistance, beta-blockers, statins and high-dose diuretics have the potential to worsen glycaemic control. Dihydropyridine calcium channel blockers, low-dose diuretics, vasodilating beta-blockers, alpha-blockers and pitavastatin have little or no effect on glycaemic control. Blockers of the renin-angiotensin-aldosterone system, colesevelam, ranolazine and verapamil, through slowing breakdown of bradykinin, vasodilation, increasing cholecystokinin levels, blocking sodium channels and decreasing beta cell apoptosis, may improve glycaemic control and avoid the development of diabetes.
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Xie C, Huang W, Young RL, Jones KL, Horowitz M, Rayner CK, Wu T. Role of Bile Acids in the Regulation of Food Intake, and Their Dysregulation in Metabolic Disease. Nutrients 2021; 13:1104. [PMID: 33800566 PMCID: PMC8066182 DOI: 10.3390/nu13041104] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/23/2021] [Accepted: 03/25/2021] [Indexed: 02/07/2023] Open
Abstract
Bile acids are cholesterol-derived metabolites with a well-established role in the digestion and absorption of dietary fat. More recently, the discovery of bile acids as natural ligands for the nuclear farnesoid X receptor (FXR) and membrane Takeda G-protein-coupled receptor 5 (TGR5), and the recognition of the effects of FXR and TGR5 signaling have led to a paradigm shift in knowledge regarding bile acid physiology and metabolic health. Bile acids are now recognized as signaling molecules that orchestrate blood glucose, lipid and energy metabolism. Changes in FXR and/or TGR5 signaling modulates the secretion of gastrointestinal hormones including glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), hepatic gluconeogenesis, glycogen synthesis, energy expenditure, and the composition of the gut microbiome. These effects may contribute to the metabolic benefits of bile acid sequestrants, metformin, and bariatric surgery. This review focuses on the role of bile acids in energy intake and body weight, particularly their effects on gastrointestinal hormone secretion, the changes in obesity and T2D, and their potential relevance to the management of metabolic disorders.
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Affiliation(s)
- Cong Xie
- Adelaide Medical School, Center of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5005, Australia; (C.X.); (W.H.); (R.L.Y.); (K.L.J.); (M.H.); (C.K.R.)
| | - Weikun Huang
- Adelaide Medical School, Center of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5005, Australia; (C.X.); (W.H.); (R.L.Y.); (K.L.J.); (M.H.); (C.K.R.)
- The ARC Center of Excellence for Nanoscale BioPhotonics, Institute for Photonics and Advanced Sensing, School of Physical Sciences, The University of Adelaide, Adelaide 5005, Australia
| | - Richard L. Young
- Adelaide Medical School, Center of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5005, Australia; (C.X.); (W.H.); (R.L.Y.); (K.L.J.); (M.H.); (C.K.R.)
- Nutrition, Diabetes & Gut Health, Lifelong Health Theme South Australian Health & Medical Research Institute, Adelaide 5005, Australia
| | - Karen L. Jones
- Adelaide Medical School, Center of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5005, Australia; (C.X.); (W.H.); (R.L.Y.); (K.L.J.); (M.H.); (C.K.R.)
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide 5005, Australia
| | - Michael Horowitz
- Adelaide Medical School, Center of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5005, Australia; (C.X.); (W.H.); (R.L.Y.); (K.L.J.); (M.H.); (C.K.R.)
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide 5005, Australia
| | - Christopher K. Rayner
- Adelaide Medical School, Center of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5005, Australia; (C.X.); (W.H.); (R.L.Y.); (K.L.J.); (M.H.); (C.K.R.)
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide 5005, Australia
| | - Tongzhi Wu
- Adelaide Medical School, Center of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5005, Australia; (C.X.); (W.H.); (R.L.Y.); (K.L.J.); (M.H.); (C.K.R.)
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide 5005, Australia
- Institute of Diabetes, School of Medicine, Southeast University, Nanjing 210009, China
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35
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Lu J, Wang S, Li M, Gao Z, Xu Y, Zhao X, Hu C, Zhang Y, Liu R, Hu R, Shi L, Zheng R, Du R, Su Q, Wang J, Chen Y, Yu X, Yan L, Wang T, Zhao Z, Wang X, Li Q, Qin G, Wan Q, Chen G, Xu M, Dai M, Zhang D, Tang X, Wang G, Shen F, Luo Z, Qin Y, Chen L, Huo Y, Li Q, Ye Z, Zhang Y, Liu C, Wang Y, Wu S, Yang T, Deng H, Li D, Lai S, Mu Y, Chen L, Zhao J, Xu G, Ning G, Bi Y, Wang W. Association of Serum Bile Acids Profile and Pathway Dysregulation With the Risk of Developing Diabetes Among Normoglycemic Chinese Adults: Findings From the 4C Study. Diabetes Care 2021; 44:499-510. [PMID: 33355246 DOI: 10.2337/dc20-0884] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Accepted: 10/29/2020] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Comprehensive assessment of serum bile acids (BAs) aberrations before diabetes onset remains inconclusive. We examined the association of serum BA profile and coregulation with the risk of developing type 2 diabetes mellitus (T2DM) among normoglycemic Chinese adults. RESEARCH DESIGN AND METHODS We tested 23 serum BA species in subjects with incident diabetes (n = 1,707) and control subjects (n = 1,707) matched by propensity score (including age, sex, BMI, and fasting glucose) from the China Cardiometabolic Disease and Cancer Cohort (4C) Study, which was composed of 54,807 normoglycemic Chinese adults with a median follow-up of 3.03 years. Multivariable-adjusted odds ratios (ORs) for associations of BAs with T2DM were estimated using conditional logistic regression. RESULTS In multivariable-adjusted logistic regression analysis, per SD increment of unconjugated primary and secondary BAs were inversely associated with incident diabetes, with an OR (95% CI) of 0.89 (0.83-0.96) for cholic acid, 0.90 (0.84-0.97) for chenodeoxycholic acid, and 0.90 (0.83-0.96) for deoxycholic acid (P < 0.05 and false discovery rate <0.05). On the other hand, conjugated primary BAs (glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, and sulfated glycochenodeoxycholic acid) and secondary BA (tauroursodeoxycholic acid) were positively related with incident diabetes, with ORs ranging from 1.11 to 1.19 (95% CIs ranging between 1.05 and 1.28). In a fully adjusted model additionally adjusted for liver enzymes, HDL cholesterol, diet, 2-h postload glucose, HOMA-insulin resistance, and waist circumference, the risk estimates were similar. Differential correlation network analysis revealed that perturbations in intraclass (i.e., primary and secondary) and interclass (i.e., unconjugated and conjugated) BA coregulation preexisted before diabetes onset. CONCLUSIONS These findings reveal novel changes in BAs exist before incident T2DM and support a potential role of BA metabolism in the pathogenesis of diabetes.
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Affiliation(s)
- Jieli Lu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China .,Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Shuangyuan Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China .,Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Mian Li
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China .,Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Zhengnan Gao
- Dalian Municipal Central Hospital, Dalian, China
| | - Yu Xu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Xinjie Zhao
- Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Chunyan Hu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Yi Zhang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Ruixin Liu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Ruying Hu
- Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China
| | - Lixin Shi
- Affiliated Hospital of Guiyang Medical College, Guiyang, China
| | - Ruizhi Zheng
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Rui Du
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Qing Su
- Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jiqiu Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China .,Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Yuhong Chen
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Xuefeng Yu
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Li Yan
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Tiange Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China .,Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Zhiyun Zhao
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Xiaolin Wang
- Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Qi Li
- Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Guijun Qin
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qin Wan
- The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Gang Chen
- Fujian Provincial Hospital, Fujian Medical University, Fuzhou, China
| | - Min Xu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Meng Dai
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Di Zhang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Xulei Tang
- The First Hospital of Lanzhou University, Lanzhou, China
| | - Guixia Wang
- The First Hospital of Jilin University, Changchun, China
| | - Feixia Shen
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zuojie Luo
- The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yingfen Qin
- The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Li Chen
- Qilu Hospital of Shandong University, Jinan, China
| | - Yanan Huo
- Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, China
| | - Qiang Li
- The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhen Ye
- Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China
| | - Yinfei Zhang
- Central Hospital of Shanghai Jiading District, Shanghai, China
| | - Chao Liu
- Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing, China
| | - Youmin Wang
- The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Shengli Wu
- Karamay Municipal People's Hospital, Xinjiang, China
| | - Tao Yang
- The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Huacong Deng
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Donghui Li
- Department of Gastrointestinal Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX
| | - Shenghan Lai
- Johns Hopkins University School of Medicine, Baltimore, MD
| | - Yiming Mu
- Chinese People's Liberation Army General Hospital, Beijing, China
| | - Lulu Chen
- Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiajun Zhao
- Shandong Provincial Hospital affiliated to Shandong University, Jinan, China
| | - Guowang Xu
- Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Guang Ning
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Yufang Bi
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
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Jonsson I, Bojsen-Møller KN, Kristiansen VB, Veedfald S, Wewer Albrechtsen NJ, Clausen TR, Kuhre RE, Rehfeld JF, Holst JJ, Madsbad S, Svane MS. Effects of Manipulating Circulating Bile Acid Concentrations on Postprandial GLP-1 Secretion and Glucose Metabolism After Roux-en-Y Gastric Bypass. Front Endocrinol (Lausanne) 2021; 12:681116. [PMID: 34084153 PMCID: PMC8166580 DOI: 10.3389/fendo.2021.681116] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 04/16/2021] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Altered bile acid (BA) turnover has been suggested to be involved in the improved glucose regulation after Roux-en-Y gastric bypass (RYGB), possibly via stimulation of GLP-1 secretion. We investigated the role of exogenous as well as endogenous BAs for GLP-1 secretion after RYGB by administering chenodeoxycholic acid (CDCA) and the BA sequestrant colesevelam (COL) both in the presence and the absence of a meal stimulus. METHODS Two single-blinded randomized cross-over studies were performed. In study 1, eight RYGB operated participants ingested 200 ml water with 1) CDCA 1.25 g or 2) CDCA 1.25 g + colesevelam 3.75 g on separate days. In study 2, twelve RYGB participants ingested on separate days a mixed meal with addition of 1) CDCA 1.25 g, 2) COL 3.75 g or 3) COL 3.75 g × 2, or 4) no additions. RESULTS In study 1, oral intake of CDCA increased circulating BAs, GLP-1, C-peptide, glucagon, and neurotensin. Addition of colesevelam reduced all responses. In study 2, addition of CDCA enhanced meal-induced increases in plasma GLP-1, glucagon and FGF-19 and lowered plasma glucose and C-peptide concentrations, while adding colesevelam lowered circulating BAs but did not affect meal-induced changes in plasma glucose or measured gastrointestinal hormones. CONCLUSION In RYGB-operated persons, exogenous CDCA enhanced meal-stimulated GLP-1 and glucagon secretion but not insulin secretion, while the BA sequestrant colesevelam decreased CDCA-stimulated GLP-1 secretion but did not affect meal-stimulated GLP-1, C-peptide or glucagon secretion, or glucose tolerance. These findings suggest a limited role for endogenous bile acids in the acute regulation of postprandial gut hormone secretion or glucose metabolism after RYGB.
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Affiliation(s)
- Isabella Jonsson
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark
| | - Kirstine N. Bojsen-Møller
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Simon Veedfald
- Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nicolai J. Wewer Albrechtsen
- Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Biochemistry Rigshospitalet, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
| | | | - Rune E. Kuhre
- Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Research and Development, Novo Nordisk A/S, Måløv, Denmark
| | - Jens F. Rehfeld
- Department of Clinical Biochemistry Rigshospitalet, Copenhagen, Denmark
| | - Jens J. Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sten Madsbad
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- *Correspondence: Sten Madsbad, ; Maria S. Svane,
| | - Maria S. Svane
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Surgical Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark
- *Correspondence: Sten Madsbad, ; Maria S. Svane,
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37
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Portincasa P, Di Ciaula A, Garruti G, Vacca M, De Angelis M, Wang DQH. Bile Acids and GPBAR-1: Dynamic Interaction Involving Genes, Environment and Gut Microbiome. Nutrients 2020; 12:3709. [PMID: 33266235 PMCID: PMC7760347 DOI: 10.3390/nu12123709] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 11/25/2020] [Accepted: 11/26/2020] [Indexed: 02/06/2023] Open
Abstract
Bile acids (BA) are amphiphilic molecules synthesized in the liver from cholesterol. BA undergo continuous enterohepatic recycling through intestinal biotransformation by gut microbiome and reabsorption into the portal tract for uptake by hepatocytes. BA are detergent molecules aiding the digestion and absorption of dietary fat and fat-soluble vitamins, but also act as important signaling molecules via the nuclear receptor, farnesoid X receptor (FXR), and the membrane-associated G protein-coupled bile acid receptor 1 (GPBAR-1) in the distal intestine, liver and extra hepatic tissues. The hydrophilic-hydrophobic balance of the BA pool is finely regulated to prevent BA overload and liver injury. By contrast, hydrophilic BA can be hepatoprotective. The ultimate effects of BA-mediated activation of GPBAR-1 is poorly understood, but this receptor may play a role in protecting the remnant liver and in maintaining biliary homeostasis. In addition, GPBAR-1 acts on pathways involved in inflammation, biliary epithelial barrier permeability, BA pool hydrophobicity, and sinusoidal blood flow. Recent evidence suggests that environmental factors influence GPBAR-1 gene expression. Thus, targeting GPBAR-1 might improve liver protection, facilitating beneficial metabolic effects through primary prevention measures. Here, we discuss the complex pathways linked to BA effects, signaling properties of the GPBAR-1, mechanisms of liver damage, gene-environment interactions, and therapeutic aspects.
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Affiliation(s)
- Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy;
| | - Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy;
| | - Gabriella Garruti
- Section of Endocrinology, Department of Emergency and Organ Transplantations, University of Bari “Aldo Moro” Medical School, Piazza G. Cesare 11, 70124 Bari, Italy;
| | - Mirco Vacca
- Dipartimento di Scienze del Suolo, Della Pianta e Degli Alimenti, Università degli Studi di Bari Aldo Moro, 70124 Bari, Italy; (M.V.); (M.D.A.)
| | - Maria De Angelis
- Dipartimento di Scienze del Suolo, Della Pianta e Degli Alimenti, Università degli Studi di Bari Aldo Moro, 70124 Bari, Italy; (M.V.); (M.D.A.)
| | - David Q.-H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA;
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38
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Zagoskin P, Erlykina E. Bile Acids as a New Type of Steroid Hormones Regulating Nonspecific Energy Expenditure of the Body (Review). Sovrem Tekhnologii Med 2020; 12:114-127. [PMID: 34796012 PMCID: PMC8596256 DOI: 10.17691/stm2020.12.5.13] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Indexed: 12/12/2022] Open
Abstract
The review is devoted to the systematization, classification, and generalization of the results of modern scientific research on the role of bile acids as a new class of steroid hormones. The paper presents the evidence for bile acid participation in the regulation of the body energy metabolism, body weight control, as well as the pathogenesis of obesity, diabetes mellitus, insulin resistance, and cardiovascular diseases. Particular attention is paid to the role of bile acids in the control of nonspecific energy expenditure of the body. The applied aspects of using the novel data about the membrane and intracellular receptors responsible for the development of hormonal regulatory effects of bile acids are analyzed. According to the authors, the modern data on the role of bile acids in the regulation of body functions allow a deeper understanding of the pathogenesis of body weight disorders and associated cardiovascular diseases. The review demonstrates promising directions in the search for specific methods of prevention and correction of these pathological conditions.
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Affiliation(s)
- P.P. Zagoskin
- Associate Professor, Department of Biochemistry named after G.Ya. Gorodisskaya; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
| | - E.I. Erlykina
- Professor, Head of the Department of Biochemistry named after G.Ya. Gorodisskaya Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
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39
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Wu Y, Zhou A, Tang L, Lei Y, Tang B, Zhang L. Bile Acids: Key Regulators and Novel Treatment Targets for Type 2 Diabetes. J Diabetes Res 2020; 2020:6138438. [PMID: 32733968 PMCID: PMC7383344 DOI: 10.1155/2020/6138438] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 06/29/2020] [Accepted: 07/04/2020] [Indexed: 02/08/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM), characterized by insulin resistance and unclear pathogenesis, is a serious menace to human health. Bile acids are the end products of cholesterol catabolism and play an important role in maintaining cholesterol homeostasis. Furthermore, increasing studies suggest that bile acids may regulate glucose tolerance, insulin sensitivity, and energy metabolism, suggesting that bile acids may represent a potential therapeutic target for T2DM. This study summarizes the metabolism of bile acids and, more importantly, changes in their concentrations, constitution, and receptors in diabetes. Furthermore, we provide an overview of the mechanisms underlying the role of bile acids in glucose and lipid metabolism, as well as the occurrence and development of T2DM. Bile acid-targeted therapy may represent a valid approach for T2DM treatment.
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Affiliation(s)
- Yingjie Wu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510030, China
| | - An Zhou
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Li Tang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Yuanyuan Lei
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Bo Tang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Linjing Zhang
- Department of Nuclear Medicine, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
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40
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Li B, Hu Y, Wang G, Liu L. The effect of exenatide on fasting bile acids in newly diagnosed type 2 diabetes mellitus patients, a pilot study. BMC Pharmacol Toxicol 2020; 21:44. [PMID: 32539783 PMCID: PMC7296654 DOI: 10.1186/s40360-020-00422-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Accepted: 05/26/2020] [Indexed: 11/10/2022] Open
Abstract
Background Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) demonstrated good glycemic efficacy in patients with type 2 diabetes mellitus (T2DM) recent years, whereas studies on GLP-1 RAs’ biliary effects were limited. Therefore, we aimed to assess the effect of exenatide on bile acids (BAs) and investigate the role of BAs in the glycemic control effect of exenatide. Methods Thirty-eight newly diagnosed T2DM participants without glucose-lowering drugs intake were recruited. Plasma total bile acids in fasting state (FTBAs) and other parameters were tested at baseline. Then exenatide were applied to the T2DM participants for 12 weeks. FTBAs and glycemic parameters were measured again after exenatide treatment, and correlation analysis between changes of FTBAs and glycemic parameters were conducted to investigate the role of BAs in the glycemic control effect of exenatide. Results The baseline FTBAs level of T2DM patients had no significance (3.84 ± 2.06 vs. 3.87 ± 2.89, P = 0.954) compared with healthy subjects. After 12-week exenatide treatment for the T2DM patients, FTBAs were decreased from 3.84 ± 2.06 μmol/L to 3.06 ± 1.27 μmol/L (P < 0.01). The correlation analysis showed that changes of FTBAs was positively correlated with changes of FPG (r = 0.355, P < 0.05). Conclusions Our results demonstrated a decreased FTBAs level after exenatide treatment for 12 weeks, without the interference of metformin and other glucose-lowering drugs. The reduction of FTBAs might not exert a positive role in the glycemic control effect of exenatide. Trial registration Trial registration number: NCT04303819. Registered in March 11, 2020 - Retrospectively registered.
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Affiliation(s)
- Boyu Li
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongtinan Road, Chaoyang District, Beijing, 100020, China
| | - Yanjin Hu
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongtinan Road, Chaoyang District, Beijing, 100020, China
| | - Guang Wang
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongtinan Road, Chaoyang District, Beijing, 100020, China.
| | - Lihong Liu
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongtinan Road, Chaoyang District, Beijing, 100020, China.
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41
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Sansome DJ, Xie C, Veedfald S, Horowitz M, Rayner CK, Wu T. Mechanism of glucose-lowering by metformin in type 2 diabetes: Role of bile acids. Diabetes Obes Metab 2020; 22:141-148. [PMID: 31468642 DOI: 10.1111/dom.13869] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 08/07/2019] [Accepted: 08/28/2019] [Indexed: 02/05/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is an increasingly prevalent chronic condition, characterized by abnormally elevated blood glucose concentrations and, as a consequence, increased risk of micro- and macrovascular complications. Metformin is usually the first-line glucose-lowering medication in T2DM; however, despite being used for more than 60 years, the mechanism underlying the glucose-lowering action of metformin remains incompletely understood. Although metformin reduces hepatic glucose production, there is persuasive evidence that the gastrointestinal tract is crucial in mediating this effect, particularly via secretion of the incretin hormone glucagon-like peptide 1 (GLP-1). It is now well recognized that bile acids, in addition to their established function in fat digestion and absorption, are important regulators of glucose metabolism. Exposure of the small and large intestine to bile acids induces GLP-1 secretion, modulates the composition of the gut microbiota, and reduces postprandial blood glucose excursions in humans with and without T2DM. Metformin reduces intestinal bile acid resorption substantially, such that intraluminal bile acids may, at least in part, account for its glucose-lowering effect. The present review focuses on the conceptual shift in our understanding as to how metformin lowers blood glucose in T2DM, with a particular emphasis on the role of intestinal bile acids.
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Affiliation(s)
- Daniel J Sansome
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, South Australia, Australia
| | - Cong Xie
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, South Australia, Australia
| | - Simon Veedfald
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, South Australia, Australia
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Michael Horowitz
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, South Australia, Australia
| | - Christopher K Rayner
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, South Australia, Australia
| | - Tongzhi Wu
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, South Australia, Australia
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
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42
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Delgado GE, Krämer BK, Scharnagl H, Fauler G, Stojakovic T, März W, Kleber ME, Lammert A. Bile Acids in Patients with Uncontrolled Type 2 Diabetes Mellitus - The Effect of Two Days of Oatmeal Treatment. Exp Clin Endocrinol Diabetes 2020; 128:624-630. [PMID: 31896155 DOI: 10.1055/a-1069-7330] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Beta-glucans are effective in binding bile acids (BA) thereby lowering cholesterol concentration. This might contribute to the beneficial effects of the consumption of β-glucan-rich foods like oatmeal on glucose homeostasis. OBJECTIVE We measured BA serum concentrations in patients with uncontrolled type 2 diabetes (T2DM) to investigate the effect of two days of oatmeal treatment on BA concentration as compared to a conventional T2DM-adapted diet. METHODS The OatMeal And Insulin Resistance study was performed as a randomized, open label crossover dietary intervention study with consecutive inclusion of 15 patients in an inpatient clinical setting. Bile acids were measured by high-resolution mass spectrometry. For statistical analysis, the differences in the concentration of serum BA and laboratory parameters between the fifth day and the third day of each inpatient stay were calculated and the effect compared between both phases by using the Wilcoxon test. RESULTS Whereas there was a mean decrease in total BA following oatmeal treatment (-0.82±1.14 µmol/l), there was no decrease following the control treatment. Glycocholic acid was lower after oatmeal treatment but higher following control treatment (-0.09±0.17 vs. 0.05±0.11 µmol/l). The reduction in total BA was directly correlated with a decrease in proinsulin during the oatmeal phase. Decreases in blood lipids or apolipoproteins were mostly greater after oatmeal treatment, but these differences were not statistically significant. CONCLUSION Two days of oatmeal diet led to significant reductions in total BA as compared to a diabetes-adapted control diet. The magnitude of BA reduction was directly correlated with a decrease in proinsulin.
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Affiliation(s)
- Graciela E Delgado
- Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Bernhard K Krämer
- Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Hubert Scharnagl
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Günther Fauler
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Tatjana Stojakovic
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, University Hospital Graz, Graz, Austria
| | - Winfried März
- Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.,Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany
| | - Marcus Edi Kleber
- Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Alexander Lammert
- Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Praxis für Diabetes, Stoffwechsel-und Nierenerkrankungen, Grünstadt, Germany
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43
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Martinussen C, Dirksen C, Bojsen-Møller KN, Svane MS, Carlsson ER, Hartmann B, Clausen TR, Veedfald S, Kristiansen VB, Rehfeld JF, Hansen HS, Holst JJ, Madsbad S. Intestinal sensing and handling of dietary lipids in gastric bypass-operated patients and matched controls. Am J Clin Nutr 2020; 111:28-41. [PMID: 31742316 DOI: 10.1093/ajcn/nqz272] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 10/09/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Altered meal-related gut hormone secretion seems important for weight loss and diabetes remission after Roux-en-Y gastric bypass (RYGB). Elucidating the responsible meal components and receptors could aid discovery of new treatments of obesity and diabetes. Enteroendocrine cells respond to digestion products of dietary triacylglycerol, especially long-chain fatty acids (LCFAs) and 2-oleoyl-glycerol (2-OG), but not medium-chain fatty acids (MCFAs). OBJECTIVE We examined the impact of olive oil (20 mL) and its derivates, LCFAs and 2-OG, on enteroendocrine secretions [glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), peptide YY (PYY), and neurotensin (NT)] and on glucose, lipid, and bile acid metabolism in RYGB-operated and unoperated individuals. METHODS In an exploratory randomized crossover design, 10 RYGB-operated patients and 10 matched controls ingested 3 equimolar triacylglycerol formulations on separate days: olive oil (digested to 2-OG + LCFAs), C8-dietary oil (2-OG + MCFAs), and tricaprylin (MCFAs; negative control). Hormone responses were calculated as area under the curve (AUC). RESULTS Independent of group status, olive oil had greater effects than C8-dietary oil on AUCs of plasma GLP-1 (+32%; 95% CI: 23%, 43%; P < 0.01), CCK (+53%, P < 0.01), and NT (+71%, P < 0.01), whereas the effect on GIP differed between groups (+90% in controls, P < 0.01; +24% in RYGB, P = 0.10). Independent of group status, C8-dietary oil had greater effects than tricaprylin on AUCs of plasma CCK (+40%, P < 0.01) and NT (+32%, P < 0.01), but not GLP-1 (+5%; 95% CI: -2.9%, 13%; P = 0.22), whereas the effect on GIP again differed between groups (+78% in controls, P < 0.01; +39% in RYGB, P = 0.01). Distal (GLP-1/PYY/NT), but not proximal (CCK/GIP), enteroendocrine responses were generally greater in RYGB patients than in controls. CONCLUSIONS The combination of LCFAs plus 2-OG was substantially more effective than 2-OG plus MCFAs in stimulating enteroendocrine secretion in RYGB-operated and matched control individuals. Distal lipid-induced gut hormone release was greater after RYGB.This trial was registered at clinicaltrials.gov as NCT03223389.
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Affiliation(s)
- Christoffer Martinussen
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark.,Danish Diabetes Academy, Odense University Hospital, Odense, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Carsten Dirksen
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kirstine N Bojsen-Møller
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Maria S Svane
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Elin R Carlsson
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark.,Department of Clinical Biochemistry, Hvidovre Hospital, Hvidovre, Denmark
| | - Bolette Hartmann
- Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Simon Veedfald
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Viggo B Kristiansen
- Department of Surgical Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark
| | - Jens F Rehfeld
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
| | - Harald S Hansen
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sten Madsbad
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
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Brønden A, Knop FK. Gluco-Metabolic Effects of Pharmacotherapy-Induced Modulation of Bile Acid Physiology. J Clin Endocrinol Metab 2020; 105:5601203. [PMID: 31630179 DOI: 10.1210/clinem/dgz025] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 08/04/2019] [Accepted: 10/04/2019] [Indexed: 02/08/2023]
Abstract
CONTEXT The discovery and characterization of the bile acid specific receptors farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) have facilitated a wealth of research focusing on the link between bile acid physiology and glucose metabolism. Modulation of FXR and TGR5 activation have been demonstrated to affect the secretion of glucagon-like peptide 1, insulin, and glucagon as well as energy expenditure and gut microbiota composition, with potential beneficial effects on glucose metabolism. EVIDENCE ACQUISITION A search strategy based on literature searches in on PubMed with various combinations of the key words FXR, TGR5, agonist, apical sodium-dependent bile acid transporter (ASBT), bile acid sequestrant, metformin, and glucose metabolism has been applied to obtain material for the present review. Furthermore, manual searches including scanning of reference lists in relevant papers and conference proceedings have been performed. EVIDENCE SYNTHESIS This review provides an outline of the link between bile acid and glucose metabolism, with a special focus on the gluco-metabolic impact of treatment modalities with modulating effects on bile acid physiology; including FXR agonists, TGR5 agonists, ASBT inhibitors, bile acid sequestrants, and metformin. CONCLUSIONS Any potential beneficial gluco-metabolic effects of FXR agonists remain to be established, whereas the clinical relevance of TGR5-based treatment modalities seems limited because of substantial safety concerns of TGR5 agonists observed in animal models. The glucose-lowering effects of ASBT inhibitors, bile acid sequestrants, and metformin are at least partly mediated by modulation of bile acid circulation, which might allow an optimization of these bile acid-modulating treatment modalities. (J Clin Endocrinol Metab XX: 00-00, 2019).
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Affiliation(s)
- Andreas Brønden
- Center for Clinical M etabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
| | - Filip K Knop
- Center for Clinical M etabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark
- Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark
- Steno Diabetes Copenhagen, DK-2820 Gentofte, Denmark
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45
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Ahmad TR, Haeusler RA. Bile acids in glucose metabolism and insulin signalling - mechanisms and research needs. Nat Rev Endocrinol 2019; 15:701-712. [PMID: 31616073 PMCID: PMC6918475 DOI: 10.1038/s41574-019-0266-7] [Citation(s) in RCA: 209] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/11/2019] [Indexed: 12/12/2022]
Abstract
Of all the novel glucoregulatory molecules discovered in the past 20 years, bile acids (BAs) are notable for the fact that they were hiding in plain sight. BAs were well known for their requirement in dietary lipid absorption and biliary cholesterol secretion, due to their micelle-forming properties. However, it was not until 1999 that BAs were discovered to be endogenous ligands for the nuclear receptor FXR. Since that time, BAs have been shown to act through multiple receptors (PXR, VDR, TGR5 and S1PR2), as well as to have receptor-independent mechanisms (membrane dynamics, allosteric modulation of N-acyl phosphatidylethanolamine phospholipase D). We now also have an appreciation of the range of physiological, pathophysiological and therapeutic conditions in which endogenous BAs are altered, raising the possibility that BAs contribute to the effects of these conditions on glycaemia. In this Review, we highlight the mechanisms by which BAs regulate glucose homeostasis and the settings in which endogenous BAs are altered, and provide suggestions for future research.
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Affiliation(s)
- Tiara R Ahmad
- Naomi Berrie Diabetes Center, Columbia University Medical Center, New York, NY, USA
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Rebecca A Haeusler
- Naomi Berrie Diabetes Center, Columbia University Medical Center, New York, NY, USA.
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
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Osonoi T, Tamasawa A, Osonoi Y, Ofuchi K, Katoh M, Saito M. Canagliflozin Increases Postprandial Total Glucagon-Like Peptide 1 Levels in the Absence of α-Glucosidase Inhibitor Therapy in Patients with Type 2 Diabetes: A Single-Arm, Non-randomized, Open-Label Study. Diabetes Ther 2019; 10:2045-2059. [PMID: 31506889 PMCID: PMC6848431 DOI: 10.1007/s13300-019-00689-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION To investigate canagliflozin-induced changes in postprandial total glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels in patients with type 2 diabetes mellitus (T2DM). METHODS Forty-five patients with T2DM who had inadequate glycemic control (glycated hemoglobin ≥ 6.5%) with diet and exercise alone (n = 15, drug naïve) and in combination with either a stable dose of the α-glucosidase inhibitor acarbose (n = 15) or metformin (n = 15) received canagliflozin, a sodium-glucose cotransporter 2 inhibitor, at 100 mg once daily for 12 weeks. The primary endpoint was the change from baseline to week 12 in postprandial glucose and plasma levels of total GLP-1 and GIP during a meal tolerance test (MTT). RESULTS Canagliflozin significantly reduced postprandial blood glucose (mean difference - 40.2 mg/mL at 60 min) and increased postprandial total GLP-1 (mean difference 1.8 pg/mL at 60 min) during an MTT. A transient reduction in the postprandial GIP level at only 30 min (mean difference - 80.3 pg/mL) during an MTT was observed. No changes in postprandial GLP-1 or GIP levels were seen after canagliflozin treatment as an add-on to acarbose in patients with T2DM. Acarbose treatment significantly decreased postprandial total GIP levels (P < 0.05) and tended to increase postprandial total GLP-1 levels (P = 0.07) compared to the other two treatments prior to canagliflozin. CONCLUSION Canagliflozin 100 mg increased postprandial total GLP-1 levels in the absence of acarbose, suggesting that it may upregulate GLP-1 secretion through delayed glucose absorption in the upper intestine, as with the α-glucosidase inhibitor. TRIAL REGISTRATION University Hospital Medical Information Network, UMIN000018345. FUNDING Mitsubishi Tanabe Pharma Corporation.
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Affiliation(s)
- Takeshi Osonoi
- Naka Kinen Clinic, 745-5 Nakadai, Naka, Ibaraki, 311-0113, Japan
| | - Atsuko Tamasawa
- Naka Kinen Clinic, 745-5 Nakadai, Naka, Ibaraki, 311-0113, Japan
| | - Yusuke Osonoi
- Naka Kinen Clinic, 745-5 Nakadai, Naka, Ibaraki, 311-0113, Japan
| | - Kensuke Ofuchi
- Naka Kinen Clinic, 745-5 Nakadai, Naka, Ibaraki, 311-0113, Japan
| | - Makoto Katoh
- Naka Kinen Clinic, 745-5 Nakadai, Naka, Ibaraki, 311-0113, Japan.
| | - Miyoko Saito
- Naka Kinen Clinic, 745-5 Nakadai, Naka, Ibaraki, 311-0113, Japan
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47
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Martin AM, Sun EW, Keating DJ. Mechanisms controlling hormone secretion in human gut and its relevance to metabolism. J Endocrinol 2019; 244:R1-R15. [PMID: 31751295 PMCID: PMC6892457 DOI: 10.1530/joe-19-0399] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Accepted: 11/18/2019] [Indexed: 12/16/2022]
Abstract
The homoeostatic regulation of metabolism is highly complex and involves multiple inputs from both the nervous and endocrine systems. The gut is the largest endocrine organ in our body and synthesises and secretes over 20 different hormones from enteroendocrine cells that are dispersed throughout the gut epithelium. These hormones include GLP-1, PYY, GIP, serotonin, and CCK, each of whom play pivotal roles in maintaining energy balance and glucose homeostasis. Some are now the basis of several clinically used glucose-lowering and weight loss therapies. The environment in which these enteroendocrine cells exist is also complex, as they are exposed to numerous physiological inputs including ingested nutrients, circulating factors and metabolites produced from neighbouring gut microbiome. In this review, we examine the diverse means by which gut-derived hormones carry out their metabolic functions through their interactions with different metabolically important organs including the liver, pancreas, adipose tissue and brain. Furthermore, we discuss how nutrients and microbial metabolites affect gut hormone secretion and the mechanisms underlying these interactions.
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Affiliation(s)
- Alyce M Martin
- College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | - Emily W Sun
- College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | - Damien J Keating
- College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
- Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
- Correspondence should be addressed to D J Keating:
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Foretz M, Guigas B, Viollet B. Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Nat Rev Endocrinol 2019; 15:569-589. [PMID: 31439934 DOI: 10.1038/s41574-019-0242-2] [Citation(s) in RCA: 396] [Impact Index Per Article: 66.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/11/2019] [Indexed: 02/07/2023]
Abstract
Despite its position as the first-line drug for treatment of type 2 diabetes mellitus, the mechanisms underlying the plasma glucose level-lowering effects of metformin (1,1-dimethylbiguanide) still remain incompletely understood. Metformin is thought to exert its primary antidiabetic action through the suppression of hepatic glucose production. In addition, the discovery that metformin inhibits the mitochondrial respiratory chain complex 1 has placed energy metabolism and activation of AMP-activated protein kinase (AMPK) at the centre of its proposed mechanism of action. However, the role of AMPK has been challenged and might only account for indirect changes in hepatic insulin sensitivity. Various mechanisms involving alterations in cellular energy charge, AMP-mediated inhibition of adenylate cyclase or fructose-1,6-bisphosphatase 1 and modulation of the cellular redox state through direct inhibition of mitochondrial glycerol-3-phosphate dehydrogenase have been proposed for the acute inhibition of gluconeogenesis by metformin. Emerging evidence suggests that metformin could improve obesity-induced meta-inflammation via direct and indirect effects on tissue-resident immune cells in metabolic organs (that is, adipose tissue, the gastrointestinal tract and the liver). Furthermore, the gastrointestinal tract also has a major role in metformin action through modulation of glucose-lowering hormone glucagon-like peptide 1 and the intestinal bile acid pool and alterations in gut microbiota composition.
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Affiliation(s)
- Marc Foretz
- INSERM, U1016, Institut Cochin, Paris, France
- CNRS, UMR8104, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Bruno Guigas
- Department of Parasitology, Leiden University Medical Centre, Leiden, Netherlands
| | - Benoit Viollet
- INSERM, U1016, Institut Cochin, Paris, France.
- CNRS, UMR8104, Paris, France.
- Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
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Song M, Ye J, Zhang F, Su H, Yang X, He H, Liu F, Zhu X, Wang L, Gao P, Shu G, Jiang Q, Wang S. Chenodeoxycholic Acid (CDCA) Protects against the Lipopolysaccharide-Induced Impairment of the Intestinal Epithelial Barrier Function via the FXR-MLCK Pathway. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2019; 67:8868-8874. [PMID: 31319027 DOI: 10.1021/acs.jafc.9b03173] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Chenodeoxycholic acid (CDCA), a primary bile acid, has been demonstrated to play important roles as a signaling molecule in various physiology functions. However, the role of CDCA in regulating intestinal barrier function remains largely unknown. This study aimed to investigate the effects of CDCA on the lipopolysaccharide (LPS)-impaired intestinal epithelial barrier function and explore the underlying mechanisms. In IPEC-J2 cells, CDCA reversed the LPS-induced increase in transepithelial electrical resistance and decrease in tight junction protein expression. In addition, we found that farnesoid X receptor (FXR) but not Takeda G-protein receptor 5 was responsible for the CDCA-improved epithelial barrier function impaired by LPS. Furthermore, CDCA blocked LPS-induced activation of the myosin light chain kinase (MLCK) pathway in a FXR-dependent manner and elicited similar effects to MLCK inhibition. In mice, CDCA supplementation restored LPS-induced elevation of intestinal permeability and MLCK expression and reduction of tight junction protein expression, thus alleviating LPS-induced intestinal barrier impairment. In conclusion, CDCA protected against the LPS-induced impairment of the intestinal epithelial barrier function via the FXR-MLCK pathway.
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50
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Chenodeoxycholic Acid Ameliorates AlCl 3-Induced Alzheimer's Disease Neurotoxicity and Cognitive Deterioration via Enhanced Insulin Signaling in Rats. Molecules 2019; 24:molecules24101992. [PMID: 31137621 PMCID: PMC6571973 DOI: 10.3390/molecules24101992] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 05/22/2019] [Accepted: 05/22/2019] [Indexed: 12/20/2022] Open
Abstract
Insulin resistance is a major risk factor for Alzheimer’s disease (AD). Chenodeoxycholic acid (CDCA) and synthetic Farnesoid X receptor (FXR) ligands have shown promising outcomes in ameliorating insulin resistance associated with various medical conditions. This study aimed to investigate whether CDCA treatment has any potential in AD management through improving insulin signaling. Adult male Wistar rats were randomly allocated into three groups and treated for six consecutive weeks; control (vehicle), AD-model (AlCl3 50 mg/kg/day i.p) and CDCA-treated group (AlCl3 + CDCA 90 mg/kg/day p.o from day 15). CDCA improved cognition as assessed by Morris Water Maze and Y-maze tests and preserved normal histological features. Moreover, CDCA lowered hippocampal beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and amyloid-beta 42 (Aβ42). Although no significant difference was observed in hippocampal insulin level, CDCA reduced insulin receptor substrate-1 phosphorylation at serine-307 (pSer307-IRS1), while increased protein kinase B (Akt) activation, glucose transporter type 4 (GLUT4), peroxisome proliferator-activated receptor gamma (PPARγ) and glucagon-like peptide-1 (GLP-1). Additionally, CDCA activated cAMP response element-binding protein (CREB) and enhanced brain-derived neurotrophic factor (BDNF). Ultimately, CDCA was able to improve insulin sensitivity in the hippocampi of AlCl3-treated rats, which highlights its potential in AD management.
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