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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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2
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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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Abstract
Diabetes represents one of the most significant, and rapidly escalating, global healthcare crises we face today. Diabetes already affects one-tenth of the world's adults-more than 537 million people, numbers that have tripled since 2000 and are estimated to reach 643 million by 2030. Type 2 diabetes (T2D), the most prevalent form, is a complex disease with numerous contributing factors, including genetics, epigenetics, diet, lifestyle, medication use, and socioeconomic factors. In addition, the gut microbiome has emerged as a significant potential contributing factor in T2D development and progression. Gut microbes and their metabolites strongly influence host metabolism and immune function, and are now known to contribute to vitamin biosynthesis, gut hormone production, satiety, maintenance of gut barrier integrity, and protection against pathogens, as well as digestion and nutrient absorption. In turn, gut microbes are influenced by diet and lifestyle factors such as alcohol and medication use, including antibiotic use and the consumption of probiotics and prebiotics. Here we review current evidence regarding changes in microbial populations in T2D and the mechanisms by which gut microbes influence glucose metabolism and insulin resistance, including inflammation, gut permeability, and bile acid production. We also explore the interrelationships between gut microbes and different T2D medications and other interventions, including prebiotics, probiotics, and bariatric surgery. Lastly, we explore the particular role of the small bowel in digestion and metabolism and the importance of studying small bowel microbes directly in our search to find metabolically relevant biomarkers and therapeutic targets for T2D.
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Affiliation(s)
- Gillian M Barlow
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, Los Angeles, CA, USA
| | - Ruchi Mathur
- Correspondence: Ruchi Mathur, MD, FRCPC, Director, Clinical Diabetes, Cedars-Sinai, 700 N San Vicente, Ste G271, West Hollywood, CA 90069, USA.
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4
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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: 11] [Impact Index Per Article: 2.8] [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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5
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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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6
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Ticho AL, Malhotra P, Dudeja PK, Gill RK, Alrefai WA. Intestinal Absorption of Bile Acids in Health and Disease. Compr Physiol 2019; 10:21-56. [PMID: 31853951 PMCID: PMC7171925 DOI: 10.1002/cphy.c190007] [Citation(s) in RCA: 140] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The intestinal reclamation of bile acids is crucial for the maintenance of their enterohepatic circulation. The majority of bile acids are actively absorbed via specific transport proteins that are highly expressed in the distal ileum. The uptake of bile acids by intestinal epithelial cells modulates the activation of cytosolic and membrane receptors such as the farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (GPBAR1), which has a profound effect on hepatic synthesis of bile acids as well as glucose and lipid metabolism. Extensive research has focused on delineating the processes of bile acid absorption and determining the contribution of dysregulated ileal signaling in the development of intestinal and hepatic disorders. For example, a decrease in the levels of the bile acid-induced ileal hormone FGF15/19 is implicated in bile acid-induced diarrhea (BAD). Conversely, the increase in bile acid absorption with subsequent overload of bile acids could be involved in the pathophysiology of liver and metabolic disorders such as fatty liver diseases and type 2 diabetes mellitus. This review article will attempt to provide a comprehensive overview of the mechanisms involved in the intestinal handling of bile acids, the pathological implications of disrupted intestinal bile acid homeostasis, and the potential therapeutic targets for the treatment of bile acid-related disorders. Published 2020. Compr Physiol 10:21-56, 2020.
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Affiliation(s)
- Alexander L. Ticho
- Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Pooja Malhotra
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Pradeep K. Dudeja
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
- jesse Brown VA Medical Center, Chicago, Illinois, USA
| | - Ravinder K. Gill
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Waddah A. Alrefai
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
- jesse Brown VA Medical Center, Chicago, Illinois, USA
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7
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Valencia-Rodríguez A, Aquino-Matus J, Vera-Barajas A, Qi X, Méndez-Sánchez N. New therapeutic options for bile acid malabsorption diarrhea. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:695. [PMID: 31930096 PMCID: PMC6944536 DOI: 10.21037/atm.2019.09.112] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 09/16/2019] [Indexed: 02/05/2023]
Affiliation(s)
| | - Jorge Aquino-Matus
- Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico
| | | | - Xingshun Qi
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, China
| | - Nahum Méndez-Sánchez
- Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
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8
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Brønden A, Mikkelsen K, Sonne DP, Hansen M, Våben C, Gabe MN, Rosenkilde M, Tremaroli V, Wu H, Bäckhed F, Rehfeld JF, Holst JJ, Vilsbøll T, Knop FK. Glucose-lowering effects and mechanisms of the bile acid-sequestering resin sevelamer. Diabetes Obes Metab 2018; 20:1623-1631. [PMID: 29493868 DOI: 10.1111/dom.13272] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 02/19/2018] [Accepted: 02/23/2018] [Indexed: 12/18/2022]
Abstract
AIMS Sevelamer, a non-absorbable amine-based resin used for treatment of hyperphosphataemia, has been demonstrated to have a marked bile acid-binding potential alongside beneficial effects on lipid and glucose metabolism. The aim of this study was to investigate the glucose-lowering effect and mechanism(s) of sevelamer in patients with type 2 diabetes. MATERIALS AND METHODS In this double-blinded randomized controlled trial, we randomized 30 patients with type 2 diabetes to sevelamer (n = 20) or placebo (n = 10). Participants were subjected to standardized 4-hour liquid meal tests at baseline and after 7 days of treatment. The main outcome measure was plasma glucagon-like peptide-1 excursions as measured by area under the curve. In addition, blood was sampled for measurements of glucose, lipids, glucose-dependent insulinotropic polypeptide, C-peptide, glucagon, fibroblast growth factor-19, cholecystokinin and bile acids. Assessments of gastric emptying, resting energy expenditure and gut microbiota composition were performed. RESULTS Sevelamer elicited a significant placebo-corrected reduction in plasma glucose with concomitant reduced fibroblast growth factor-19 concentrations, increased de novo synthesis of bile acids, a shift towards a more hydrophilic bile acid pool and increased lipogenesis. No glucagon-like peptide-1-mediated effects on insulin, glucagon or gastric emptying were evident, which points to a limited contribution of this incretin hormone to the glucose-lowering effect of sevelamer. Furthermore, no sevelamer-mediated effects on gut microbiota composition or resting energy expenditure were observed. CONCLUSIONS Sevelamer reduced plasma glucose concentrations in patients with type 2 diabetes by mechanisms that seemed to involve decreased intestinal and hepatic bile acid-mediated farnesoid X receptor activation.
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Affiliation(s)
- Andreas Brønden
- Steno Diabetes Center Copenhagen, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Kristian Mikkelsen
- Steno Diabetes Center Copenhagen, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - David P Sonne
- Steno Diabetes Center Copenhagen, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Morten Hansen
- Steno Diabetes Center Copenhagen, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Christoffer Våben
- Steno Diabetes Center Copenhagen, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Maria N Gabe
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mette Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Valentina Tremaroli
- The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Hao Wu
- The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Fredrik Bäckhed
- The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
- 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, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Steno Diabetes Center Copenhagen, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Steno Diabetes Center Copenhagen, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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9
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Brønden A, Albér A, Rohde U, Gasbjerg LS, Rehfeld JF, Holst JJ, Vilsbøll T, Knop FK. The bile acid-sequestering resin sevelamer eliminates the acute GLP-1 stimulatory effect of endogenously released bile acids in patients with type 2 diabetes. Diabetes Obes Metab 2018; 20:362-369. [PMID: 28786523 DOI: 10.1111/dom.13080] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 08/01/2017] [Accepted: 08/02/2017] [Indexed: 12/27/2022]
Abstract
AIMS Discovery of the specific bile acid receptors farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) in enteroendocrine L cells has prompted research focusing on the impact of bile acids on glucagon-like peptide-1 (GLP-1) secretion and glucose metabolism. The aim of the present study was to assess the GLP-1 secretory and gluco-metabolic effects of endogenously released bile, with and without concomitant administration of the bile acid-sequestering resin, sevelamer, in patients with type 2 diabetes. MATERIALS AND METHODS We performed a randomized, placebo-controlled, double-blinded cross-over study including 15 metformin-treated patients with type 2 diabetes. During 4 experimental study days, either sevelamer 3200 mg or placebo in combination with intravenous infusion of cholecystokinin (CCK) (0.4 pmol sulfated CCK-8/kg/min) or saline was administered in randomized order. The primary endpoint was plasma GLP-1 excursions as measured by incremental area under the curve. Secondary endpoints included plasma responses of glucose, triglycerides, insulin, CCK, fibroblast growth factor-19 and 7α-hydroxy-4-cholesten-3-one (C4). In addition, gallbladder dynamics, gastric emptying, resting energy expenditure, appetite and ad libitum food intake were assessed. RESULTS CCK-mediated gallbladder emptying was demonstrated to elicit a significant induction of GLP-1 secretion compared to saline, whereas concomitant single-dose administration of the bile acid sequestrant sevelamer was shown to eliminate the acute bile acid-induced increase in plasma GLP-1 excursions. CONCLUSIONS Single-dose administration of sevelamer eliminated bile acid-mediated GLP-1 secretion in patients with type 2 diabetes, which could be explained by reduced bile acid stimulation of the basolaterally localized TGR5 on enteroendocrine L cells.
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Affiliation(s)
- Andreas Brønden
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Anders Albér
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Ulrich Rohde
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Laerke S Gasbjerg
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens F Rehfeld
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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10
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Mazidi M, de Caravatto PPP, Speakman JR, Cohen RV. Mechanisms of Action of Surgical Interventions on Weight-Related Diseases: the Potential Role of Bile Acids. Obes Surg 2017; 27:826-836. [PMID: 28091894 DOI: 10.1007/s11695-017-2549-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Surgical interventions for weight-related diseases (SWRD) may have substantial and sustainable effect on weight reduction, also leading to a higher remission rate of type 2 diabetes (T2D) mellitus than any other medical treatment or lifestyle intervention. The resolution of T2D after Roux-en-Y gastric bypass (RYGB) typically occurs too quickly to be accounted for by weight loss alone, suggesting that these operations have a direct impact on glucose homeostasis. The mechanisms underlying these beneficial effects however remain unclear. Recent research suggests that changes in the concentrations of plasma bile acids might contribute to these metabolic changes after surgery. In this review, we aimed to outline the potential role of bile acids in SWRD. We systematically reviewed MEDLINE, SCOPUS, and Web of Science for articles reporting the effect of SWRD on outcomes published between 1969 and 2016. We found that changes in circulating bile acids after surgery may play a major role through activation of the farnesoid X receptor A (FXRA), the fibroblast growth factor 19 (FGF19), and the G protein-coupled bile acid receptor (TGR5). Bile acid concentration increased significantly after RYGB. Some studies suggest that a transitory decrease occurs at 1 week post-surgery, followed by a gradual increase. Most studies have shown the increase to be proportionate by all bile acid subtypes. Bile acids can regulate glucose metabolism through the expression of TGR5 receptor in L cells, resulting in a release of glucagon-like peptide 1 (GLP-1). It may also induce the synthesis and secretion of FGF19 in ileal cells, thereby improving insulin sensitivity and regulating glucose metabolism. All the present SWRD are involved with changes in food stimulation to the stomach. This implies that discovering and developing the antagonists to TGR5 and FXRA may effectively control metabolic syndrome and the elucidation of the mechanisms underlying the physiological effects related to weight loss and T2D remission after surgery may help to identify new drug targets.
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Affiliation(s)
- Mohsen Mazidi
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Chaoyang, Beijing, China.,University of the Chinese Academy of Sciences, Huairou, Beijing, China
| | - Pedro Paulo P de Caravatto
- The Center for Obesity and Diabetes, Oswaldo Cruz German Hospital, Rua Cincinato Braga, 37 5o. andar, São Paulo, São Paulo, Brazil
| | - John R Speakman
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Chaoyang, Beijing, China.,Institute of Biological and Environmental Science, University of Aberdeen, Aberdeen, Scotland, UK
| | - Ricardo V Cohen
- The Center for Obesity and Diabetes, Oswaldo Cruz German Hospital, Rua Cincinato Braga, 37 5o. andar, São Paulo, São Paulo, Brazil.
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11
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Tian J, Huang S, Sun S, Ding L, Zhang E, Huang W. Bile acid signaling and bariatric surgery. LIVER RESEARCH 2017; 1:208-213. [PMID: 30034914 PMCID: PMC6051716 DOI: 10.1016/j.livres.2017.12.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The rapid worldwide rise in obesity rates over the past few decades imposes an urgent need to develop effective strategies for treating obesity and associated metabolic complications. Bariatric surgical procedures, such as Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), currently provide the most effective treatment for obesity and type 2 diabetes (T2D), as well as for non-alcoholic steatohepatitis (NASH). However, the underlying mechanisms of the beneficial effects of bariatric surgery remain elusive. Recent studies have identified bile acids as potential signaling molecules involved in the beneficial effects of bariatric surgery. This review focuses on the most recent studies on the roles of bile acids and bile acid receptors Farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 5 (TGR5) in bariatric surgery. We also discuss the possibility of modulating bile acid signaling as a pharmacological therapeutic approach to treating obesity and its associated metabolic complications.
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Affiliation(s)
- Jingyan Tian
- National Clinical Research Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Silvia Huang
- Eugene Robert Summer Program, City of Hope, Duarte, CA, USA
| | - Siming Sun
- Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Lili Ding
- Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA, USA
- Shanghai Key Laboratory of Compound Chinese Medicines and the Ministry of Education (MOE) Key Laboratory of Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Eryun Zhang
- Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA, USA
- Shanghai Key Laboratory of Compound Chinese Medicines and the Ministry of Education (MOE) Key Laboratory of Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wendong Huang
- Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, Duarte, CA, USA
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12
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Sjöberg BG, Straniero S, Angelin B, Rudling M. Cholestyramine treatment of healthy humans rapidly induces transient hypertriglyceridemia when treatment is initiated. Am J Physiol Endocrinol Metab 2017; 313:E167-E174. [PMID: 28487440 DOI: 10.1152/ajpendo.00416.2016] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 03/29/2017] [Accepted: 05/04/2017] [Indexed: 01/11/2023]
Abstract
Bile acid (BA) production in mice is regulated by hepatic farnesoid X receptors and by intestinal fibroblast growth factor (FGF)-15 (in humans, FGF-19), a suppressor of BA synthesis that also reduces serum triglycerides and glucose. Cholestyramine treatment reduces FGF-19 and induces BA synthesis, whereas plasma triglycerides may increase from unclear reasons. We explored whether FGF-19 may suppress BA synthesis and plasma triglycerides in humans by modulation of FGF-19 levels through long-term cholestyramine treatment at increasing doses. In a second acute experiment, metabolic responses from 1 day of cholestyramine treatment were monitored. Long-term treatment reduced serum FGF-19 by >90%; BA synthesis increased up to 17-fold, whereas serum BAs, triglycerides, glucose, and insulin were stable. After long-term treatment, serum BAs and FGF-19 displayed rebound increases above baseline levels, and BA and cholesterol syntheses normalized after 1 wk without rebound reductions. Acute cholestyramine treatment decreased FGF-19 by 95% overnight and serum BAs by 60%, while BA synthesis increased fourfold and triglycerides doubled. The results support that FGF-19 represses BA synthesis but not serum triglycerides. However, after cessation of both long-term and 1-day cholestyramine treatment, circulating FGF-19 levels were normalized within 2 days, whereas BA synthesis remained significantly induced in both situations, indicating that also other mechanisms than the FGF-19 pathway are responsible for stimulation of BA synthesis elicited by cholestyramine. Several of the responses during cholestyramine treatment persisted at least 6 days after treatment, highlighting the importance of removing such treatment well before evaluating dynamics of the enterohepatic circulation in humans.
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Affiliation(s)
- Beatrice G Sjöberg
- Metabolism Unit C2:94 and KI/AZ Integrated CardioMetabolic Center, Department of Medicine, and Center for Innovative Medicine, Department of Biosciences and Nutrition, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Sara Straniero
- Metabolism Unit C2:94 and KI/AZ Integrated CardioMetabolic Center, Department of Medicine, and Center for Innovative Medicine, Department of Biosciences and Nutrition, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Bo Angelin
- Metabolism Unit C2:94 and KI/AZ Integrated CardioMetabolic Center, Department of Medicine, and Center for Innovative Medicine, Department of Biosciences and Nutrition, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Mats Rudling
- Metabolism Unit C2:94 and KI/AZ Integrated CardioMetabolic Center, Department of Medicine, and Center for Innovative Medicine, Department of Biosciences and Nutrition, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
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13
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The effects of bile acid sequestrants on lipid profile and blood glucose concentrations: A systematic review and meta-analysis of randomized controlled trials. Int J Cardiol 2017; 227:850-857. [DOI: 10.1016/j.ijcard.2016.10.011] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 08/10/2016] [Accepted: 10/04/2016] [Indexed: 12/11/2022]
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14
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Taoka H, Yokoyama Y, Morimoto K, Kitamura N, Tanigaki T, Takashina Y, Tsubota K, Watanabe M. Role of bile acids in the regulation of the metabolic pathways. World J Diabetes 2016; 7:260-270. [PMID: 27433295 PMCID: PMC4937164 DOI: 10.4239/wjd.v7.i13.260] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 11/24/2015] [Accepted: 05/27/2016] [Indexed: 02/05/2023] Open
Abstract
Recent studies have revealed that bile acids (BAs) are not only facilitators of dietary lipid absorption but also important signaling molecules exerting multiple physiological functions. Some major signaling pathways involving the nuclear BAs receptor farnesoid X receptor and the G protein-coupled BAs receptor TGR5/M-BAR have been identified to be the targets of BAs. BAs regulate their own homeostasis via signaling pathways. BAs also affect diverse metabolic pathways including glucose metabolism, lipid metabolism and energy expenditure. This paper suggests the mechanism of controlling metabolism via BA signaling and demonstrates that BA signaling is an attractive therapeutic target of the metabolic syndrome.
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15
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Colesevelam as an Add-On Treatment for Control of Dyslipidemia and Hyperglycemia in Type 2 Diabetes. Can J Diabetes 2016; 40:112-4. [DOI: 10.1016/j.jcjd.2015.07.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 07/28/2015] [Accepted: 07/29/2015] [Indexed: 01/06/2023]
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Abstract
Bile acids (BA), long believed to only have lipid-digestive functions, have emerged as novel metabolic modulators. They have important endocrine effects through multiple cytoplasmic as well as nuclear receptors in various organs and tissues. BA affect multiple functions to control energy homeostasis, as well as glucose and lipid metabolism, predominantly by activating the nuclear farnesoid X receptor and the cytoplasmic G protein-coupled BA receptor TGR5 in a variety of tissues. However, BA also are aimed at many other cellular targets in a wide array of organs and cell compartments. Their role in the pathogenesis of diabetes, obesity and other 'diseases of civilization' becomes even more clear. They also interact with the gut microbiome, with important clinical implications, further extending the complexity of their biological functions. Therefore, it is not surprising that BA metabolism is substantially modulated by bariatric surgery, a phenomenon contributing favorably to the therapeutic effects of these surgical procedures. Based on these data, several therapeutic approaches to ameliorate obesity and diabetes have been proposed to affect the cellular targets of BA.
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Affiliation(s)
- Libor Vítek
- Fourth Department of Internal MedicineFirst Faculty of Medicine, Charles University, Na Bojišti 3, Prague 2 12000, Czech RepublicInstitute of Medical Biochemistry and Laboratory DiagnosticsFirst Faculty of Medicine, Charles University, Prague, Czech RepublicInstitute of EndocrinologyCharles University, Prague, Czech Republic Fourth Department of Internal MedicineFirst Faculty of Medicine, Charles University, Na Bojišti 3, Prague 2 12000, Czech RepublicInstitute of Medical Biochemistry and Laboratory DiagnosticsFirst Faculty of Medicine, Charles University, Prague, Czech RepublicInstitute of EndocrinologyCharles University, Prague, Czech Republic
| | - Martin Haluzík
- Fourth Department of Internal MedicineFirst Faculty of Medicine, Charles University, Na Bojišti 3, Prague 2 12000, Czech RepublicInstitute of Medical Biochemistry and Laboratory DiagnosticsFirst Faculty of Medicine, Charles University, Prague, Czech RepublicInstitute of EndocrinologyCharles University, Prague, Czech Republic Fourth Department of Internal MedicineFirst Faculty of Medicine, Charles University, Na Bojišti 3, Prague 2 12000, Czech RepublicInstitute of Medical Biochemistry and Laboratory DiagnosticsFirst Faculty of Medicine, Charles University, Prague, Czech RepublicInstitute of EndocrinologyCharles University, Prague, Czech Republic
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17
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Morimoto K, Watanabe M, Sugizaki T, Irie JI, Itoh H. Intestinal Bile Acid Composition Modulates Prohormone Convertase 1/3 (PC1/3) Expression and Consequent GLP-1 Production in Male Mice. Endocrinology 2016; 157:1071-81. [PMID: 26789236 DOI: 10.1210/en.2015-1551] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Besides an established medication for hypercholesterolemia, bile acid binding resins (BABRs) present antidiabetic effects. Although the mechanisms underlying these effects are still enigmatic, glucagon-like peptide-1 (GLP-1) appears to be involved. In addition to a few reported mechanisms, we propose prohormone convertase 1/3 (PC1/3), an essential enzyme of GLP-1 production, as a potent molecule in the GLP-1 release induced by BABRs. In our study, the BABR colestimide leads to a bile acid-specific G protein-coupled receptor TGR5-dependent induction of PC1/3 gene expression. Here, we focused on the alteration of intestinal bile acid composition and consequent increase of total TGR5 agonistic activity to explain the TGR5 activation. Furthermore, we demonstrate that nuclear factor of activated T cells mediates the TGR5-triggered PC1/3 gene expression. Altogether, our data indicate that the TGR5-dependent intestinal PC1/3 gene expression supports the BABR-stimulated GLP-1 release. We also propose a combination of BABR and dipeptidyl peptidase-4 inhibitor in the context of GLP-1-based antidiabetic therapy.
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Affiliation(s)
- Kohkichi Morimoto
- Department of Internal Medicine (K.M., T.S., J.-i.I., H.I.), School of Medicine, Keio University, Tokyo 160-8582, Japan; and Graduate School of Media and Governance (M.W.), Faculty of Environment and Information Studies, Keio University, Kanagawa 252-0882, Japan
| | - Mitsuhiro Watanabe
- Department of Internal Medicine (K.M., T.S., J.-i.I., H.I.), School of Medicine, Keio University, Tokyo 160-8582, Japan; and Graduate School of Media and Governance (M.W.), Faculty of Environment and Information Studies, Keio University, Kanagawa 252-0882, Japan
| | - Taichi Sugizaki
- Department of Internal Medicine (K.M., T.S., J.-i.I., H.I.), School of Medicine, Keio University, Tokyo 160-8582, Japan; and Graduate School of Media and Governance (M.W.), Faculty of Environment and Information Studies, Keio University, Kanagawa 252-0882, Japan
| | - Jun-ichiro Irie
- Department of Internal Medicine (K.M., T.S., J.-i.I., H.I.), School of Medicine, Keio University, Tokyo 160-8582, Japan; and Graduate School of Media and Governance (M.W.), Faculty of Environment and Information Studies, Keio University, Kanagawa 252-0882, Japan
| | - Hiroshi Itoh
- Department of Internal Medicine (K.M., T.S., J.-i.I., H.I.), School of Medicine, Keio University, Tokyo 160-8582, Japan; and Graduate School of Media and Governance (M.W.), Faculty of Environment and Information Studies, Keio University, Kanagawa 252-0882, Japan
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18
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Abstract
The influence of alpha and beta cells, through glucagon and insulin, on energy metabolism is well known. The insulin:glucagon ratio (IGR) is a frequently discussed entity in the medical literature. However, in recent years, focus has shifted to other pathways and markers of health and disease. This communication revisits the insulin:glucagon bipolar axis and describes the significance of the IGR. It reviews the effects of various glucose-lowering drugs on this ratio, and hypothesizes that the ratio can be used to predict the appropriate choice of drugs for managing diabetes. Drugs which increase the IGR may be beneficial in insulinopenic conditions, while those which decrease IGR may be of help in the setting of hyperinsulinemia or insulin resistance.
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Affiliation(s)
- Sanjay Kalra
- Department of Endocrinology, Bharti Hospital, Karnal, India.
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19
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Abstract
The armamentarium for the treatment of dyslipidemia today comprises six different modes of action with overall around 24 different drugs. The treatment of lipid disorders was revolutionized with the introduction of statins which have become the most important therapeutic option available today to reduce and prevent atherosclerosis and its detrimental consequences like cardiovascular diseases and stroke. With and optimized reduction of elevated LDL levels with statins, the risk for cardiovascular diseases (CVD) can be reduced by 30%, indicating a residual remaining risk of 70% for the development and progression of CVD notifying still a high medical need for more effective antilipidemic drugs. Consequently, the search for novel lipid-modifying drugs is still one of the most active areas in research and development in the pharmaceutical industry. Major focus lies on approaches to LDL-lowering drugs superior to statins with regard to efficacy, safety, and patient compliance and on approaches modifying plasma levels and functionality of HDL particles based on the clinically validated inverse relationship between high-plasma HDL levels and the risk for CVD. The available drugs today for the treatment of dyslipidemia are small organic molecules or nonabsorbable polymers for binding of bile acids to be applied orally. Besides small molecules for novel targets, biological drugs such as monoclonal antibodies, antisense or gene-silencing oligonucleotides, peptidomimetics, reconstituted synthetic HDL particles and therapeutic proteins are novel approaches in clinical development are which have to be applied by injection or infusion. The promising clinical results of several novel drug candidates, particularly for LDL cholesterol lowering with monoclonal antibodies raised against PCSK9, may indicate more than a decade after the statins, the entrance of new breakthrough therapies to treat lipid disorders.
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Affiliation(s)
- Werner Kramer
- Institute of Biochemistry, Biocenter, Goethe-Universität Frankfurt, Max-von-Laue-Str. 9, Frankfurt, Germany.
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20
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Lee SS, Yoo JH, So YS. Effect of the low- versus high-intensity exercise training on endoplasmic reticulum stress and GLP-1 in adolescents with type 2 diabetes mellitus. J Phys Ther Sci 2015; 27:3063-8. [PMID: 26644644 PMCID: PMC4668135 DOI: 10.1589/jpts.27.3063] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 07/06/2015] [Indexed: 12/17/2022] Open
Abstract
[Purpose] The primary objective of this study was to investigate the effect of low-intensity exercise training compare with high-intensity exercise training on endoplasmic reticulum stress and glucagon-like peptide-1 in adolescents with type 2 diabetes mellitus. [Subjects and Methods] The low-intensity exercise training group performed aerobic exercise training at an intensity of ≤ 45% of the heart rate reserve. The high-intensity interval exercise training group performed interval exercise training at an intensity of ≥ 80% of the heart rate reserve. The exercise-related energy consumption was determined for both groups on a per-week basis (1,200 kcal/week). [Results] Both groups showed improvement in the glucose-regulated protein 78 and dipeptidyl peptidase-4, but the size of the between-group effect was not statistically significant. The high-intensity interval exercise training group showed a significant reduction in percentage body fat. The C-peptide level increased after the 12-weeks programs and was significantly different, between the groups. Fasting glucose, insulin resistance in the fasting state according to homeostasis model assessment, and leptin decreased after the 12-weeks exercise program and were significantly different between the groups, and glucagon-like peptide-1 increased after the 12-week exercise programs and was significantly different between the groups. [Conclusion] In conclusion high-intensity interval exercise training, as defined in this study, may lead to improvements in body composition, glycemic control, endoplasmic reticulum stress, and the glucagon-like peptide-1 in adolescents with type 2 diabetes mellitus.
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Affiliation(s)
- Sung Soo Lee
- Department of Coaching, Dong-A University, Republic of
Korea
| | - Jae Ho Yoo
- Department of Pediatric, College of Medicine, Dong-A
University Medical Center, Repulic of Korea
| | - Yong Seok So
- Department of Physical Education, Dong-A University, Repulic of Korea
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21
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Brønden A, Hansen M, Sonne DP, Rohde U, Vilsbøll T, Knop FK. Sevelamer in a diabetologist's perspective: a phosphate-binding resin with glucose-lowering potential. Diabetes Obes Metab 2015; 17:116-20. [PMID: 25041567 DOI: 10.1111/dom.12355] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Revised: 06/30/2014] [Accepted: 07/03/2014] [Indexed: 01/11/2023]
Abstract
Sevelamer is a calcium-free and metal-free phosphate-binding oral drug used in the management of hyperphosphataemia in chronic kidney disease. Preclinical and clinical trials have shown glucose and lipid-lowering effects of sevelamer, thereby giving rise to a potential role of the drug in the treatment of patients with type 2 diabetes. These 'novel' effects are most probably derived from the bile acid-binding properties of sevelamer. The proposed potential is supported by the approval of the bile acid sequestrant colesevelam in the United States for the treatment of type 2 diabetes and hypercholesterolaemia. This article offers a brief review on the effects of sevelamer and a perspective on the potential mechanisms behind the glucose-lowering effect of the drug.
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Affiliation(s)
- A Brønden
- Department of Medicine, Centre for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; The Danish Diabetes Academy, Odense, Denmark
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22
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23
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Ullmer C, Alvarez Sanchez R, Sprecher U, Raab S, Mattei P, Dehmlow H, Sewing S, Iglesias A, Beauchamp J, Conde-Knape K. Systemic bile acid sensing by G protein-coupled bile acid receptor 1 (GPBAR1) promotes PYY and GLP-1 release. Br J Pharmacol 2014; 169:671-84. [PMID: 23488746 DOI: 10.1111/bph.12158] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Revised: 01/18/2013] [Accepted: 02/07/2013] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND AND PURPOSE Nutrient sensing in the gut is believed to be accomplished through activation of GPCRs expressed on enteroendocrine cells. In particular, L-cells located predominantly in distal regions of the gut secrete glucagon-like peptide 1 (GLP-1) and peptide tyrosine-tyrosine (PYY) upon stimulation by nutrients and bile acids (BA). The study was designed to address the mechanism of hormone secretion in L-cells stimulated by the BA receptor G protein-coupled bile acid receptor 1 (GPBAR1). EXPERIMENTAL APPROACH A novel, selective, orally bioavailable, and potent GPBAR1 agonist, RO5527239, was synthesized in order to investigate L-cell secretion in vitro and in vivo in mice and monkey. In analogy to BA, RO5527239 was conjugated with taurine to reduce p.o. bioavailability yet retaining its potency. Using RO5527239 and tauro-RO5527239, the acute secretion effects on L-cells were addressed via different routes of administration. KEY RESULTS GPBAR1 signalling triggers the co-secretion of PYY and GLP-1, and leads to improved glucose tolerance. The strong correlation of plasma drug exposure and plasma PYY levels suggests activation of GPBAR1 from systemically accessible compartments. In contrast to the orally bioavailable agonist RO5527239, we show that tauro-RO5527239 triggers PYY release only when applied intravenously. Compared to mice, a slower and more sustained PYY secretion was observed in monkeys. CONCLUSION AND IMPLICATIONS Selective GPBAR1 activation elicits a strong secretagogue effect on L-cells, which primarily requires systemic exposure. We suggest that GPBAR1 is a key player in the intestinal proximal-distal loop that mediates the early phase of nutrient-evoked L-cell secretion effects.
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Affiliation(s)
- C Ullmer
- DTA CV & Metabolic Diseases, DTA CV and Metabolic Diseases, Pharma Research and Early Development, F. Hoffmann-La Roche AG, Basel, Switzerland.
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24
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Sugimoto K. [New prospect of bile acid sequestrants as a novel therapy for metabolic disorders - research strategy utilizing clinical data]. Nihon Yakurigaku Zasshi 2014; 144:64-8. [PMID: 25109518 DOI: 10.1254/fpj.144.64] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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25
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Sonne DP, Hansen M, Knop FK. Bile acid sequestrants in type 2 diabetes: potential effects on GLP1 secretion. Eur J Endocrinol 2014; 171:R47-65. [PMID: 24760535 DOI: 10.1530/eje-14-0154] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Bile acid sequestrants have been used for decades for the treatment of hypercholesterolaemia. Sequestering of bile acids in the intestinal lumen interrupts enterohepatic recirculation of bile acids, which initiate feedback mechanisms on the conversion of cholesterol into bile acids in the liver, thereby lowering cholesterol concentrations in the circulation. In the early 1990s, it was observed that bile acid sequestrants improved glycaemic control in patients with type 2 diabetes. Subsequently, several studies confirmed the finding and recently - despite elusive mechanisms of action - bile acid sequestrants have been approved in the USA for the treatment of type 2 diabetes. Nowadays, bile acids are no longer labelled as simple detergents necessary for lipid digestion and absorption, but are increasingly recognised as metabolic regulators. They are potent hormones, work as signalling molecules on nuclear receptors and G protein-coupled receptors and trigger a myriad of signalling pathways in many target organs. The most described and well-known receptors activated by bile acids are the farnesoid X receptor (nuclear receptor) and the G protein-coupled cell membrane receptor TGR5. Besides controlling bile acid metabolism, these receptors are implicated in lipid, glucose and energy metabolism. Interestingly, activation of TGR5 on enteroendocrine L cells has been suggested to affect secretion of incretin hormones, particularly glucagon-like peptide 1 (GLP1 (GCG)). This review discusses the role of bile acid sequestrants in the treatment of type 2 diabetes, the possible mechanism of action and the role of bile acid-induced secretion of GLP1 via activation of TGR5.
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Affiliation(s)
- David P Sonne
- Diabetes Research DivisionDepartment of Medicine, Gentofte Hospital, Niels Andersens Vej 65, DK-2900 Hellerup, Denmark
| | - Morten Hansen
- Diabetes Research DivisionDepartment of Medicine, Gentofte Hospital, Niels Andersens Vej 65, DK-2900 Hellerup, Denmark
| | - Filip K Knop
- Diabetes Research DivisionDepartment of Medicine, Gentofte Hospital, Niels Andersens Vej 65, DK-2900 Hellerup, Denmark
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26
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Bile acids, obesity, and the metabolic syndrome. Best Pract Res Clin Gastroenterol 2014; 28:573-83. [PMID: 25194176 PMCID: PMC4159616 DOI: 10.1016/j.bpg.2014.07.004] [Citation(s) in RCA: 140] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 06/30/2014] [Accepted: 07/05/2014] [Indexed: 01/31/2023]
Abstract
Bile acids are increasingly recognized as key regulators of systemic metabolism. While bile acids have long been known to play important and direct roles in nutrient absorption, bile acids also serve as signalling molecules. Bile acid interactions with the nuclear hormone receptor farnesoid X receptor (FXR) and the membrane receptor G-protein-coupled bile acid receptor 5 (TGR5) can regulate incretin hormone and fibroblast growth factor 19 (FGF19) secretion, cholesterol metabolism, and systemic energy expenditure. Bile acid levels and distribution are altered in type 2 diabetes and increased following bariatric procedures, in parallel with reduced body weight and improved insulin sensitivity and glycaemic control. Thus, modulation of bile acid levels and signalling, using bile acid binding resins, TGR5 agonists, and FXR agonists, may serve as a potent therapeutic approach for the treatment of obesity, type 2 diabetes, and other components of the metabolic syndrome in humans.
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27
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Bays HE. Lowering low-density lipoprotein cholesterol levels in patients with type 2 diabetes mellitus. Int J Gen Med 2014; 7:355-64. [PMID: 25045281 PMCID: PMC4094576 DOI: 10.2147/ijgm.s65148] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia, insulin resistance, and/or progressive loss of β-cell function. T2DM patients are at increased risk of micro- and macrovascular disease, and are often considered as representing an atherosclerotic coronary heart disease (CHD) risk equivalent. Interventions directed at glucose and lipid level control in T2DM patients may reduce micro- and macrovascular disease. The optimal T2DM agent is one that lowers glucose levels with limited risk for hypoglycemia, and with no clinical trial evidence of worsening CHD risk. Lipid-altering drugs should preferably reduce low-density lipoprotein cholesterol and apolipoprotein B (apo B) and have evidence that the mechanism of action reduces CHD risk. Statins reduce low-density lipoprotein cholesterol and apo B and have evidence of improving CHD outcomes, and are thus first-line therapy for the treatment of hypercholesterolemia. In patients who do not achieve optimal lipid levels with statin therapy, or who are intolerant to statin therapy, add-on therapy or alternative therapies may be indicated. Additional available agents to treat hypercholesterolemic patients with T2DM include bile acid sequestrants, fibrates, niacin, and ezetimibe. This review discusses the use of these alternative agents to treat hypercholesterolemia in patients with T2DM, either as monotherapy or in combination with statin therapy.
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Affiliation(s)
- Harold E Bays
- Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY, USA
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28
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Lipid-lowering Therapies, Glucose Control and Incident Diabetes: Evidence, Mechanisms and Clinical Implications. Cardiovasc Drugs Ther 2014; 28:361-77. [DOI: 10.1007/s10557-014-6534-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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29
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Prawitt J, Caron S, Staels B. Glucose-lowering effects of intestinal bile acid sequestration through enhancement of splanchnic glucose utilization. Trends Endocrinol Metab 2014; 25:235-44. [PMID: 24731596 DOI: 10.1016/j.tem.2014.03.007] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 03/17/2014] [Accepted: 03/18/2014] [Indexed: 02/06/2023]
Abstract
Intestinal bile acid (BA) sequestration efficiently lowers plasma glucose concentrations in type 2 diabetes (T2D) patients. Because BAs act as signaling molecules via receptors, including the G protein-coupled receptor TGR5 and the nuclear receptor FXR (farnesoid X receptor), to regulate glucose homeostasis, BA sequestration, which interrupts the entero-hepatic circulation of BAs, constitutes a plausible action mechanism of BA sequestrants. An increase of intestinal L-cell glucagon-like peptide-1 (GLP-1) secretion upon TGR5 activation is the most commonly proposed mechanism, but recent studies also argue for a direct entero-hepatic action to enhance glucose utilization. We discuss here recent findings on the mechanisms of sequestrant-mediated glucose lowering via an increase of splanchnic glucose utilization through entero-hepatic FXR signaling.
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Affiliation(s)
- Janne Prawitt
- European Genomic Institute for Diabetes (EGID), FR 3508, 59000 Lille, France; Université Lille 2, 59000 Lille, France; Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1011, 59000 Lille, France; Institut Pasteur de Lille, 59000 Lille, France
| | - Sandrine Caron
- European Genomic Institute for Diabetes (EGID), FR 3508, 59000 Lille, France; Université Lille 2, 59000 Lille, France; Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1011, 59000 Lille, France; Institut Pasteur de Lille, 59000 Lille, France
| | - Bart Staels
- European Genomic Institute for Diabetes (EGID), FR 3508, 59000 Lille, France; Université Lille 2, 59000 Lille, France; Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1011, 59000 Lille, France; Institut Pasteur de Lille, 59000 Lille, France.
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30
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Abstract
Bile acids are synthesized in the liver from cholesterol and have traditionally been recognized for their role in absorption of lipids and in cholesterol homeostasis. In recent years, however, bile acids have emerged as metabolic signaling molecules that are involved in the regulation of lipid and glucose metabolism, and possibly energy homeostasis, through activation of the bile acid receptors farnesoid X receptor (FXR) and TGR5. Bile acid sequestrants (BASs) constitute a class of drugs that bind bile acids in the intestine to form a nonabsorbable complex resulting in interruption of the enterohepatic circulation. This increases bile acid synthesis and consequently reduces serum low-density lipoprotein cholesterol. Also, BASs improve glycemic control in patients with type 2 diabetes. Despite a growing understanding of the impact of BASs on glucose metabolism, the mechanisms behind their glucose-lowering effect in patients with type 2 diabetes remain unclear. This article offers a review of the mechanisms behind the glucose-lowering effect of BASs, and the efficacy of BASs in the treatment of type 2 diabetes.
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Affiliation(s)
- Morten Hansen
- Diabetes Research Division, Department of Medicine, Gentofte Hospital, University of Copenhagen, Niels Andersens Vej 65, DK-2900, Hellerup, Denmark
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Nwose OM, Jones MR. Atypical mechanism of glucose modulation by colesevelam in patients with type 2 diabetes. CLINICAL MEDICINE INSIGHTS-ENDOCRINOLOGY AND DIABETES 2013; 6:75-9. [PMID: 24348081 PMCID: PMC3864737 DOI: 10.4137/cmed.s12590] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Colesevelam's glucose-lowering mechanism of action is not completely understood. Clinical trials of colesevelam suggest that its mechanism, and often adverse effects, differ from those of other oral antidiabetes drugs. Colesevelam does not affect insulin sensitivity (unlike thiazolidinediones), insulin secretion (unlike sulfonylureas and meglitinides), or early insulin response or glucagon (unlike dipeptidyl peptidase-4 inhibitors). Colesevelam may have some effect on glucose absorption, but likely via a different mechanism than α-glucosidase inhibitors. Colesevelam and metformin have similarities regarding hepatic glucose production, but divergent effects on gluconeogenesis versus glycogenolysis, suggesting differing mechanisms of drug action for improving glycemic control. Colesevelam is thought to be a portal glucagon-like peptide-1 (GLP-1) secretagogue with primarily hepatic effects. Bile acid binding by colesevelam leads to TGR5 activation, increased secretion of GLP-1 or other incretins, and inhibition of hepatic glycogenolysis. Colesevelam's mechanism of action appears to be atypical of other antidiabetes medications, making it a potentially suitable component of many combination regimens in the treatment of type 2 diabetes.
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Affiliation(s)
- Oliseyenum M Nwose
- Executive Medical Director, Therapeutic Area Head, Hypertension, Metabolism and Pain, Daiichi Sankyo, Inc., Parsippany, New Jersey, USA
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Lacroix IME, Li-Chan ECY. Overview of food products and dietary constituents with antidiabetic properties and their putative mechanisms of action: a natural approach to complement pharmacotherapy in the management of diabetes. Mol Nutr Food Res 2013; 58:61-78. [PMID: 23943383 DOI: 10.1002/mnfr.201300223] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Revised: 06/10/2013] [Accepted: 06/13/2013] [Indexed: 01/05/2023]
Abstract
Diabetes is one of the fastest growing chronic, noncommunicable diseases worldwide. Currently, 11 major classes of pharmacotherapy are available for the management of this metabolic disorder. However, the usage of these drugs is often associated with undesirable side effects, including weight gain and hypoglycemia. There is thus a need for new, safe and effective treatment strategies. Diet is known to play a major role in the prevention and management of diabetes. Numerous studies have reported the putative association of the consumption of specific food products, or their constituents, with the incidence of diabetes, and mounting evidence now suggests that some dietary factors can improve glycemic regulation. Foods and dietary constituents, similar to synthetic drugs, have been shown to modulate hormones, enzymes, and organ systems involved in carbohydrate metabolism. The present article reviews the major classes and modes of action of antidiabetic drugs, and examines the evidence on food products and dietary factors with antidiabetic properties as well as their plausible mechanisms of action. The findings suggest potential use of dietary constituents as a complementary approach to pharmacotherapy in the prevention and/or management of diabetes, but further research is necessary to identify the active components and evaluate their efficacy and safety.
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Affiliation(s)
- Isabelle M E Lacroix
- Faculty of Land & Food Systems, Food Nutrition & Health Program, The University of British Columbia, Vancouver, BC, Canada
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Scaldaferri F, Pizzoferrato M, Ponziani FR, Gasbarrini G, Gasbarrini A. Use and indications of cholestyramine and bile acid sequestrants. Intern Emerg Med 2013; 8:205-10. [PMID: 21739227 DOI: 10.1007/s11739-011-0653-0] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2011] [Accepted: 06/19/2011] [Indexed: 01/06/2023]
Abstract
Cholestyramine is a bile acid sequestrant, like colestipol and colesevelam. These molecules are positively charged non-digestible resins that bind to bile acids in the intestine to form an insoluble complex, which is excreted in the feces. They are used mainly for the treatment of primary hypercholesterolemia and hypercholesterolemia associated with mild hypertriglyceridemia, in patients not responding to dietary treatment as well as a second line-treatment for pruritus associated with cholestatic disease, in patients with incomplete biliary obstruction. Several data indicate that modulation of bile acid homeostasis has a good clinical effect in managing diabetes mellitus and the diarrhea from bile acid malabsorption. In this review, we present the "in label" use and indication for these compounds, revisiting the other clinical applications that may benefit from the use of bile acid sequestrants in the near future.
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Sugimoto-Kawabata K, Shimada H, Sakai K, Suzuki K, Kelder T, Pieterman EJ, Cohen LH, Havekes LM, Princen HM, van den Hoek AM. Colestilan decreases weight gain by enhanced NEFA incorporation in biliary lipids and fecal lipid excretion. J Lipid Res 2013; 54:1255-64. [PMID: 23434610 DOI: 10.1194/jlr.m032839] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Bile acid sequestrants (BASs) are cholesterol-lowering drugs that also affect hyperglycemia. The mechanism by which BASs exert these and other metabolic effects beyond cholesterol lowering remains poorly understood. The present study aimed to investigate the effects of a BAS, colestilan, on body weight, energy expenditure, and glucose and lipid metabolism and its mechanisms of action in high-fat-fed hyperlipidemic APOE*3 Leiden (E3L) transgenic mice. Mildly insulin-resistant E3L mice were fed a high-fat diet with or without 1.5% colestilan for 8 weeks. Colestilan treatment decreased body weight, visceral and subcutaneous fat, and plasma cholesterol and triglyceride levels but increased food intake. Blood glucose and plasma insulin levels were decreased, and hyperinsulinemic-euglycemic clamp analysis demonstrated improved insulin sensitivity, particularly in peripheral tissues. In addition, colestilan decreased energy expenditure and physical activity, whereas it increased the respiratory exchange ratio, indicating that colestilan induced carbohydrate catabolism. Moreover, kinetic analysis revealed that colestilan increased [(3)H]NEFA incorporation in biliary cholesterol and phospholipids and increased fecal lipid excretion. Gene expression analysis in liver, fat, and muscle supported the above findings. In summary, colestilan decreases weight gain and improves peripheral insulin sensitivity in high-fat-fed E3L mice by enhanced NEFA incorporation in biliary lipids and increased fecal lipid excretion.
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Affiliation(s)
- Kanami Sugimoto-Kawabata
- Metabolic Diseases, Department I, Pharmacology Research Laboratories 2, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama 335-8505, Japan.
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Incretin secretion stimulated by ursodeoxycholic acid in healthy subjects. SPRINGERPLUS 2013; 2:20. [PMID: 23450079 PMCID: PMC3579475 DOI: 10.1186/2193-1801-2-20] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Accepted: 01/13/2013] [Indexed: 01/12/2023]
Abstract
Bile acids play an important role in post-prandial glucose metabolism by stimulating release of glucagon-like peptide-1 (GLP-1) via the G-protein-coupled receptor TGR5, which is expressed in intestinal L cells. Thus, bile acid sequestrants are expected to stimulate secretion of endogenous GLP-1 through TGR5. We investigated incretin and insulin secretion after a meal with and without ursodeoxycholic acid (UDCA), a widely used therapeutic agent in liver diseases, in 7 non-diabetic Japanese subjects. We found that UDCA intake resulted in higher GLP-1 secretion (area under the curve [AUC] of 0–60 min after meal without UDCA, 450 ± 162 mmol·min/l; with UDCA, 649 ± 232 mmol·min/l, P = 0.046) and lower blood glucose (AUC of 0–60 min without UDCA, 7191 ± 250 mg·min/dl; with UDCA, 6716 ± 189 mg·min/dl, P = 0.001) , although we did not find statistically significant insulin increase by UDCA intake (AUC of 0–60 min without UDCA, 1551 ± 418 μU·min/ml; with UDCA, 1941 ± 246 μU·min/ml, P = 0.065). These results suggest that UDCA increases bile-induced GLP-1 secretion. Ours is the first report showing increased GLP-1 secretion and decreased blood glucose in response to UDCA.
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Abstract
Bile acids (BAs) are not only facilitators participating in the absorption of dietary lipids and soluble vitamins, but are also important signaling molecules exerting versatile biophysiological effects. Three major signaling pathways, including the MAPK pathways, the nuclear hormone receptor farnesoid X receptor a-mediated pathways and the G protein-coupled receptor TGR5/M-BAR-mediated pathways, have been identified to be the targets of BAs. BAs, the biologically many-sided and toxic molecules, regulate the homeostasis of themselves via these signaling pathways. BAs also affect diverse metabolic status including glucose metabolism, lipid metabolism, energy expenditure, immunity and others. BAs and their related signaling mechanisms are attractive therapeutic targets of various diseases such as metabolic syndrome.
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Affiliation(s)
- Kohkichi Morimoto
- a Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
| | - Hiroshi Itoh
- a Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
- b Graduate School of Media and Governance, Faculty of Environment and Information Studies, Keio University, 5322 Endo, Fujisawa, Kanagawa 252-0882, Japan.
| | - Mitsuhiro Watanabe
- a Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
- b Graduate School of Media and Governance, Faculty of Environment and Information Studies, Keio University, 5322 Endo, Fujisawa, Kanagawa 252-0882, Japan.
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Suzuki T, Tsunoda-Kubota M, Aoyama J, Futami-Suda S, Hashimoto M, Igari Y, Watanabe K, Kigawa Y, Nakano H, Oba K. What Characteristics at Baseline Are Associated with the Glucose-lowering Effect of Colestimide in Patients with Type 2 Diabetes and Hypercholesterolemia According to Response to Treatment? J NIPPON MED SCH 2013; 80:211-7. [DOI: 10.1272/jnms.80.211] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
- Tatsuya Suzuki
- Department of Cardiovascular Medicine, Nippon Medical School
| | | | - Junya Aoyama
- Department of Cardiovascular Medicine, Nippon Medical School
| | | | - Masao Hashimoto
- Department of Cardiovascular Medicine, Nippon Medical School
| | - Yoshimasa Igari
- Department of Cardiovascular Medicine, Nippon Medical School
| | | | | | - Hiroshi Nakano
- Department of Cardiovascular Medicine, Nippon Medical School
| | - Kenzo Oba
- Department of Cardiovascular Medicine, Nippon Medical School
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Thulé PM. Mechanisms of current therapies for diabetes mellitus type 2. ADVANCES IN PHYSIOLOGY EDUCATION 2012; 36:275-83. [PMID: 23209008 PMCID: PMC3776431 DOI: 10.1152/advan.00094.2012] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2012] [Accepted: 09/21/2012] [Indexed: 06/12/2023]
Abstract
The array of medications available for the treatment of hyperglycemia has increased rapidly in the previous decade, and recent investigations have clarified novel mechanisms underlying the antihyperglycemic efficacy of these drugs. This article reviews the mechanisms of action for medications currently approved to treat diabetes mellitus in the United States, with the exception of insulin and its analogs. Finally, it attempts to integrate these mechanisms into the schema of pathophysiological factors that combine to produce hyperglycemia in patients with diabetes mellitus.
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Affiliation(s)
- Peter M Thulé
- Emory University School of Medicine, Decatur, Georgia, USA.
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Zema MJ. Colesevelam hydrochloride: evidence for its use in the treatment of hypercholesterolemia and type 2 diabetes mellitus with insights into mechanism of action. CORE EVIDENCE 2012; 7:61-75. [PMID: 22936894 PMCID: PMC3426253 DOI: 10.2147/ce.s26725] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Colesevelam hydrochloride is a molecularly engineered, second-generation bile acid sequestrant demonstrating enhanced specificity for bile acids which has been approved for use as adjunctive therapy to diet and exercise as monotherapy or in combination with a β-hydroxymethylglutaryl-coenzyme A reductase inhibitor for the reduction of elevated low-density lipoprotein cholesterol in patients with primary hypercholesterolemia. It is also the only lipid-lowering agent currently available in the United States which has been approved for use as adjunctive therapy in patients with type 2 diabetes mellitus whose glycemia remains inadequately controlled on therapy with metformin, sulfonylurea, or insulin. With the recent emphasis upon drug safety by the Food and Drug Administration and various consumer agencies, it is fitting that the role of nonsystemic lipid-lowering therapies such as bile acid sequestrants – with nearly 90 years of in-class, clinically safe experience – should be reexamined. This paper presents information on the major pharmacologic effects of colesevelam, including a discussion of recent data derived from both in vitro and in vivo rodent and human studies, which shed light on the putative mechanisms involved.
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Marina AL, Utzschneider KM, Wright LA, Montgomery BK, Marcovina SM, Kahn SE. Colesevelam improves oral but not intravenous glucose tolerance by a mechanism independent of insulin sensitivity and β-cell function. Diabetes Care 2012; 35:1119-25. [PMID: 22446171 PMCID: PMC3329824 DOI: 10.2337/dc11-2050] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To determine the mechanism by which the bile acid sequestrant colesevelam improves glycemic control. RESEARCH DESIGN AND METHODS We performed a frequently sampled intravenous glucose tolerance test (FSIGT) with minimal model analysis and a meal tolerance test (MTT) in 20 subjects with impaired fasting glucose (11 men, 9 women; mean age 60.7 ± 1.9 years, BMI 29.4 ± 0.9 kg/m(2)) in a single-blind study after 2 weeks of placebo treatment and 8 weeks of colesevelam 3.75 g daily. From these tests, insulin sensitivity, β-cell function, and glucose tolerance were determined, along with gastrointestinal peptide levels during the MTT. RESULTS Fasting plasma glucose and HbA(1c) decreased with colesevelam (from 5.9 ± 0.1 to 5.7 ± 0.1 mmol/L, P < 0.05, and from 5.86 ± 0.06 to 5.76 ± 0.06%, P = 0.01, respectively), but fasting insulin did not change. Colesevelam had no effect on any FSIGT measures. In contrast, the MTT incremental area under the curve (iAUC) for both glucose (from 249.3 ± 28.5 to 198.8 ± 23.6 mmol/L · min, P < 0.01) and insulin (from 20,130 [13,542-35,292] to 13,086 [9,804-21,138] pmol/L · min, P < 0.05) decreased with colesevelam. However, the ratio of iAUC insulin to iAUC glucose was not changed. iAUC for cholecystokinin (CCK) increased (from 43.2 [0-130.1] to 127.1 [47.2-295.2] pmol/L · min, P < 0.01), while iAUC for fibroblast growth factor 19 decreased (from 11,185 [1,346-17,661] to 2,093 [673-6,707] pg/mL · min, P < 0.01) with colesevelam. However, iAUC for glucagon, glucose-dependent insulinotropic peptide, and glucagon-like peptide 1 did not change. CONCLUSIONS Colesevelam improves oral but not intravenous glucose tolerance without changing insulin sensitivity, β-cell function, or incretins. This effect may be at least partially explained by the colesevelam-induced increase in CCK.
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Affiliation(s)
- Anna L Marina
- Division of Metabolism, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington, USA
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Porez G, Prawitt J, Gross B, Staels B. Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease. J Lipid Res 2012; 53:1723-37. [PMID: 22550135 DOI: 10.1194/jlr.r024794] [Citation(s) in RCA: 225] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Dyslipidemia is an important risk factor for cardiovascular disease (CVD) and atherosclerosis. When dyslipidemia coincides with other metabolic disorders such as obesity, hypertension, and glucose intolerance, defined as the metabolic syndrome (MS), individuals present an elevated risk to develop type 2 diabetes (T2D) as well as CVD. Because the MS epidemic represents a growing public health problem worldwide, the development of therapies remains a major challenge. Alterations of bile acid pool regulation in T2D have revealed a link between bile acid and metabolic homeostasis. The bile acid receptors farnesoid X receptor (FXR) and TGR5 both regulate lipid, glucose, and energy metabolism, rendering them potential pharmacological targets for MS therapy. This review discusses the mechanisms of metabolic regulation by FXR and TGR5 and the utility relevance of natural and synthetic modulators of FXR and TGR5 activity, including bile acid sequestrants, in the treatment of the MS.
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Holst JJ, McGill MA. Potential new approaches to modifying intestinal GLP-1 secretion in patients with type 2 diabetes mellitus: focus on bile acid sequestrants. Clin Drug Investig 2012; 32:1-14. [PMID: 21958333 DOI: 10.2165/11595370-000000000-00000] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Type 2 diabetes mellitus is associated with a progressive decline in insulin-producing pancreatic β-cells, an increase in hepatic glucose production, and a decrease in insulin sensitivity. The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) stimulate glucose-induced insulin secretion; however, in patients with type 2 diabetes, the incretin system is impaired by loss of the insulinotropic effects of GIP as well as a possible reduction in secretion of GLP-1. Agents that modify GLP-1 secretion may have a role in the management of type 2 diabetes. The currently available incretin-based therapies, GLP-1 receptor agonists (incretin mimetics) and dipeptidyl peptidase-4 (DPP-4) inhibitors (CD26 antigen inhibitors) [incretin enhancers], are safe and effective in the treatment of type 2 diabetes. However, they may be unable to halt the progression of type 2 diabetes, perhaps because they do not increase secretion of endogenous GLP-1. Therapies that directly target intestinal L cells to stimulate secretion of endogenous GLP-1 could possibly prove more effective than treatment with GLP-1 receptor agonists and DPP-4 inhibitors. Potential new approaches to modifying intestinal GLP-1 secretion in patients with type 2 diabetes include G-protein-coupled receptor (GPCR) agonists, α-glucosidase inhibitors, peroxisome proliferator-activated receptor (PPAR) agonists, metformin, bile acid mimetics and bile acid sequestrants. Both the GPCR agonist AR231453 and the novel bile acid mimetic INT-777 have been shown to stimulate GLP-1 release, leading to increased insulin secretion and improved glucose tolerance in mice. Similarly, a study in insulin-resistant rats demonstrated that the bile acid sequestrant colesevelam increased GLP-1 secretion and improved glucose levels and insulin resistance. In addition, the bile acid sequestrant colestimide (colestilan) has been shown to increase GLP-1 secretion and decrease glucose levels in patients with type 2 diabetes; these results suggest that the glucose-lowering effects of bile acid sequestrants may be partly due to their ability to increase endogenous GLP-1 levels. Evidence suggests that GPCR agonists, α-glucosidase inhibitors, PPAR agonists, metformin, bile acid mimetics and bile acid sequestrants may represent a new approach to management of type 2 diabetes via modification of endogenous GLP-1 secretion.
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Affiliation(s)
- Jens Juul Holst
- Department of Biomedical Sciences, The Panum Institute, University of Copenhagen, Blegdamsvej 3, Copenhagen, Denmark.
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Younk LM, Davis SN. Evaluation of colesevelam hydrochloride for the treatment of type 2 diabetes. Expert Opin Drug Metab Toxicol 2012; 8:515-25. [DOI: 10.1517/17425255.2012.672973] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Beysen C, Murphy EJ, Deines K, Chan M, Tsang E, Glass A, Turner SM, Protasio J, Riiff T, Hellerstein MK. Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study. Diabetologia 2012; 55:432-42. [PMID: 22134839 DOI: 10.1007/s00125-011-2382-3] [Citation(s) in RCA: 121] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Accepted: 09/26/2011] [Indexed: 12/28/2022]
Abstract
AIMS/HYPOTHESIS The primary aim of this completed multicentre randomised, parallel, double-blind placebo-controlled study was to elucidate the mechanisms of glucose-lowering with colesevelam and secondarily to investigate its effects on lipid metabolism (hepatic de novo lipogenesis, cholesterol and bile acid synthesis). METHODS Participants with type 2 diabetes (HbA(1c) 6.7-10.0% [50-86 mmol/mol], fasting glucose <16.7 mmol/l, fasting triacylglycerols <3.9 mmol/l and LDL-cholesterol >1.55 mmol/l) treated with diet and exercise, sulfonylurea, metformin or a combination thereof, were randomised by a central coordinator to either 3.75 g/day colesevelam (n = 30) or placebo (n = 30) for 12 weeks at three clinical sites in the USA. The primary measure was the change from baseline in glucose kinetics with colesevelam compared to placebo treatment. Fasting and postprandial glucose, lipid and bile acid pathways were measured at baseline and post-treatment using stable isotope techniques. Plasma glucose, insulin, total glucagon-like peptide-1 (GLP-1), total glucose-dependent insulinotropic polypeptide (GIP), glucagon and fibroblast growth factor-19 (FGF-19) concentrations were measured during the fasting state and following a meal tolerance test. Data was collected by people blinded to treatment. RESULTS Compared with placebo, colesevelam improved HbA(1c) (mean change from baseline of 0.3 [SD 1.1]% for placebo [n = 28] and -0.3 [1.1]% for colesevelam [n = 26]), glucose concentrations, fasting plasma glucose clearance and glycolytic disposal of oral glucose. Colesevelam did not affect gluconeogenesis or appearance rate (absorption) of oral glucose. Fasting endogenous glucose production and glycogenolysis significantly increased with placebo but were unchanged with colesevelam (treatment effect did not reach statistical significance). Compared with placebo, colesevelam increased total GLP-1 and GIP concentrations and improved HOMA-beta cell function while insulin, glucagon and HOMA-insulin resistance were unchanged. Colesevelam increased cholesterol and bile acid synthesis and decreased FGF-19 concentrations. However, no effect was seen on fractional hepatic de novo lipogenesis. CONCLUSIONS/INTERPRETATION Colesevelam, a non-absorbed bile acid sequestrant, increased circulating incretins and improved tissue glucose metabolism in both the fasting and postprandial states in a manner different from other approved oral agents. TRIAL REGISTRATION ClinicalTrials.gov NCT00596427 FUNDING The study was funded by Daiichi Sankyo.
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Affiliation(s)
- C Beysen
- Kinemed, Inc., 5980 Horton Street Suite 470, Emeryville, CA 94608, USA.
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Abstract
PURPOSE OF REVIEW Bile acid sequestrants (BAS) have been used for more than 50 years in the treatment of hypercholesterolemia. The last decade, bile acids are emerging as integrated regulators of metabolism via induction of various signal transduction pathways. Consequently, BAS treatment may exert unexpected side-effects. We discuss a selection of recently published studies that evaluated BAS in several metabolic diseases. RECENT FINDINGS Recently, an increasing body of evidence has shown that BAS in addition to ameliorating hypercholesterolemia are also effective in improving glycemic control in patients with type 2 diabetes, although the mechanism is not completely understood. Furthermore, some reports suggested using these compounds to modulate energy expenditure. Many of these effects have been related to the local effects of BAS in the intestine by directly binding bile acids in the intestine or indirectly by interfering with signaling processes. SUMMARY A substantial effort is being made by researchers to fully define the mechanism by which BAS improve glycemic control in type 2 diabetic patients. A new challenge will be to confirm in clinical trials the recent discoveries coming from animal experiments suggesting a role for bile acids in energy metabolism.
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Affiliation(s)
- Carolien Out
- Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Neda T, Inukai K, Kurihara S, Ono H, Hosaka T, Nakamoto H, Katayama S, Awata T. Hypoglycemic effects of colestimide on type 2 diabetic patients with obesity. Endocr J 2012; 59:239-46. [PMID: 22230809 DOI: 10.1507/endocrj.ej11-0378] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Recent studies have shown colestimide, a bile acid-binding resin, to also exert a glucose-lowering effect via amelioration of insulin resistance. To evaluate the effects of colestimide on glucose metabolism and to elucidate the underlying mechanism, we conducted a 6-month, open-label pilot study on 43 type 2 diabetic patients with obesity (BMI ≥ 25). The subjects were randomized to either treatment with colestimide 4g/day (T group, n=23) or continuation of their current therapy (C group, n=20). In the T group patients, mean HbA1c and fasting glucose improved markedly (from 7.71 ± 0.32% to 6.97 ± 0.20%; from 147.4 ± 7.3mg/dL to 127.0 ± 5.0mg/dL, respectively), while obesity-related parameters, i.e. body weight, waist circumference, and visceral fat and subcutaneous fat as determined by umbilical slice abdominal CT, showed no significant changes. Fractionation analyses of serum bile acids revealed significantly increased cholic acids (CA) and decreased chenodeoxycholic acids (CDCA) in the T group patients. However, no correlation was observed between these changes and ΔHbA1c. According to logistic regression analysis, baseline HbA1c was the only variable predicting the decrease of HbA1c (>0.5%) among sex, age, BMI, total cholesterol, ΔCA and ΔCDCA. The index of insulin resistance, i.e. HOMA-R, did not improve, and the index of β cell function, i.e. HOMA-β, actually increased significantly. These results suggests that, in obese patients with type 2 diabetes, the mechanism underlying improved glycemic control with colestimide treatment involves enhanced β cell activity rather than improved insulin resistance.
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Affiliation(s)
- Tamotsu Neda
- Department of Endocrinology and Diabetes, School of Medicine, Saitama Medical University, Saitama 350-0495, Japan
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Suzuki T, Oba K, Igari Y, Watanabe K, Matsumura N, Futami-Suda S, Ouchi M, Suzuki K, Sekimizu KI, Kigawa Y, Nakano H. Effects of bile-acid-binding resin (colestimide) on blood glucose and visceral fat in Japanese patients with type 2 diabetes mellitus and hypercholesterolemia: an open-label, randomized, case-control, crossover study. J Diabetes Complications 2012; 26:34-9. [PMID: 22240263 DOI: 10.1016/j.jdiacomp.2011.11.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2010] [Revised: 11/26/2011] [Accepted: 11/30/2011] [Indexed: 12/28/2022]
Abstract
OBJECTIVE The objective was to examine the effects of colestimide on blood glucose, visceral fat, adipocytokines, and bile acid conjugate fractions in Japanese patients. METHODS This study was an open-label, randomized, case-control, crossover study of colestimide 3 g/day in 40 Japanese patients with type 2 diabetes mellitus (T2D) and hypercholesterolemia. Patients were assigned to the colestimide group in which pravastatin and colestimide were administered orally and to the statin group in which pravastatin alone was administered orally. The principal outcome measures were serum lipid levels, fasting plasma glucose level in the early morning, hemoglobin A1c (HbA(1c)), visceral fat area (VFA), and serum 1,5-anhydroglucitol (1,5-AG) level. RESULTS Serum low-density lipoprotein cholesterol levels significantly decreased from 113±38 mg/dl at baseline to 90±20 mg/dl (P=.009) at week 12 of colestimide administration. HbA(1c) significantly decreased from 7.4%±0.9% at baseline to 6.9%±0.9% (P=.001) at week 12 of colestimide administration. Serum 1,5-AG levels increased from 9.4±10.1 μg/ml to 12.4±9.5 μg/ml (P=.05) at week 12 of colestimide administration. The statin group showed no significant changes in lipids and 1,5-AG. However, ΔVFA was inversely correlated with Δcholic acid, and multivariate analysis revealed that ΔVFA was a significant explanatory variable. CONCLUSIONS Colestimide holds promise not only for the treatment of hypercholesterolemia but also for the possible improvement of T2D and visceral fat obesity.
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Affiliation(s)
- Tatsuya Suzuki
- Department of Internal Medicine (Divisions of Cardiology, Hepatology, Geriatrics and Integrated Medicine), Nippon Medical School, Tokyo, Japan.
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Hansen M, Sonne DP, Mikkelsen KH, Gluud LL, Vilsbøll T, Knop FK. Effect of bile acid sequestrants on glycaemic control: protocol for a systematic review with meta-analysis of randomised controlled trials. BMJ Open 2012; 2:bmjopen-2012-001803. [PMID: 23148345 PMCID: PMC3533035 DOI: 10.1136/bmjopen-2012-001803] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
INTRODUCTION In addition to the lipid-lowering effect of bile acid sequestrants (BASs), they also lower blood glucose and, therefore, could be beneficial in the treatment of patients with type 2 diabetes mellitus (T2DM). Three oral BASs are approved by the US Food and Drug Administration (FDA) for the treatment of hypercholesterolaemia: colestipol, cholestyramine and colesevelam. The BAS colestimide/colestilan is used in Japan. Colesevelam was recently approved by the FDA for the treatment of T2DM. We plan to provide a systematic review with meta-analysis of the glucose-lowering effect of BASs with the aim to evaluate their potential as glucose-lowering agents in patients with T2DM. METHODS AND ANALYSIS In accordance with the preferred reporting items for systematic reviews and meta-analyses statement, a systematic review with meta-analysis of randomised clinical trials of BASs (vs placebo, oral antidiabetes drugs or insulin), reporting measures of glycaemic control in adult patients with T2DM, will be performed. Change in glycated haemoglobin constitutes the primary endpoint, and secondary endpoints include changes in fasting plasma glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol, triglycerides, body weight and body mass index and adverse events. Electronic searches will be performed in The Cochrane Library, MEDLINE and EMBASE, along with manual searches in the reference lists of relevant papers. The analyses will be performed based on individual patient data and summarised data. The primary meta-analysis will be performed using random effects models owing to expected intertrial heterogeneity. Dichotomous data will be analysed using risk difference and continuous data using weighted mean differences, both with 95% CIs. ETHICS AND DISSEMINATION The study will evaluate the potential of BASs as glucose-lowering agents and possibly contribute to the clinical management of patients with T2DM. RESULTS The study will be disseminated by peer-review publication and conference presentation. PROTOCOL REGISTRATION PROSPERO CRD42012002552.
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Affiliation(s)
- Morten Hansen
- Diabetes Research Division, Department of Internal Medicine, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
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Henry RR, Aroda VR, Mudaliar S, Garvey WT, Chou HS, Jones MR. Effects of colesevelam on glucose absorption and hepatic/peripheral insulin sensitivity in patients with type 2 diabetes mellitus. Diabetes Obes Metab 2012; 14:40-6. [PMID: 21831167 PMCID: PMC4955577 DOI: 10.1111/j.1463-1326.2011.01486.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
AIM Colesevelam lowers glucose and low-density lipoprotein cholesterol levels in patients with type 2 diabetes mellitus. This study examined the mechanisms by which colesevelam might affect glucose control. METHODS In this 12-week, randomized, double-blind, placebo-controlled study, subjects with type 2 diabetes and haemoglobin A(1c) (HbA(1c)) ≥7.5% on either stable diet and exercise or sulphonylurea therapy were randomized to colesevelam 3.75 g/day (n = 16) or placebo (n = 14). Hepatic/peripheral insulin sensitivity was evaluated at baseline and at week 12 by infusion of (3) H-labelled glucose followed by a 2-step hyperinsulinemic-euglycemic clamp. Two 75-g oral glucose tolerance tests (OGTTs) were conducted at baseline, one with and one without co-administration of colesevelam. A final OGTT was conducted at week 12. HbA(1c) and fasting plasma glucose (FPG) levels were evaluated pre- and post-treatment. RESULTS Treatment with colesevelam, compared to placebo, had no significant effects on basal endogenous glucose output, response to insulin or on maximal steady-state glucose disposal rate. At baseline, co-administration of colesevelam with oral glucose reduced total area under the glucose curve (AUC(g)) but not incremental AUC(g). At week 12, neither total AUC(g) nor incremental AUC(g) were changed from pre-treatment values in either group. Post-load insulin levels increased with colesevelam at 30 and 120 min, but these changes in total area under the insulin curve (AUC(i)) and incremental AUC(i) did not differ between groups. Both HbA(1c) and FPG improved with colesevelam, but treatment differences were not significant. CONCLUSIONS Colesevelam does not affect hepatic or peripheral insulin sensitivity and does not directly affect glucose absorption.
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Affiliation(s)
- R R Henry
- Section of Diabetes, Endocrinology and Metabolism, VA San Diego Healthcare System and University of California San Diego, San Diego, CA 92161, USA.
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Influence of platelet lysate on the recovery and metabolic performance of cryopreserved human hepatocytes upon thawing. Transplantation 2011; 91:1340-6. [PMID: 21516066 DOI: 10.1097/tp.0b013e31821aba37] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Storage of human hepatocytes is essential for their use in research and liver cell transplantation. However, cryopreservation and thawing (C/T) procedures have detrimental effects on the viability and functionality compared with fresh cells. The aim of this study was to upgrade the standard C/T methodology to obtain better quality hepatocytes for cell transplantation to improve the overall clinical outcome. METHODS Human hepatocytes isolated from donor livers were cryopreserved in University of Wisconsin solution with 10% dimethyl sulfoxide (standard medium), which was supplemented with 10% or 20% of platelet lysate. Thawing media supplemented with up to 30 mM glucose was also investigated. The effects on cell viability, adhesion proteins (e-cadherin, β-catenin, and β1-integrin) expression, attachment efficiency, apoptotic indicators, Akt signaling, ATP levels, and cytochrome P450 activities have been evaluated. RESULTS The results indicate that the hepatocytes cryopreserved in a medium supplemented with platelet lysate show better recovery than those preserved in the standard medium: higher expression of adhesion molecules, higher attachment efficiency and cell survival; decreased number of apoptotic nuclei and caspase-3 activation; maintenance of ATP levels; and drug biotransformation capability close to those in fresh hepatocytes. Supplementation of thawing media with glucose led to a significant decrease in caspase-3 activation and to increased adhesion molecules preservation and Akt signal transduction after C/T. Minor nonsignificant changes in cell viability and attachment efficiency were observed. CONCLUSIONS These promising results could lead to a new cryopreservation procedure to improve human hepatocyte cryopreservation outcome.
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