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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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Esan O, Viljoen A, Wierzbicki AS. Colesevelam - a bile acid sequestrant for treating hypercholesterolemia and improving hyperglycemia. Expert Opin Pharmacother 2022; 23:1363-1370. [PMID: 35968655 DOI: 10.1080/14656566.2022.2112945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Low density Lipoprotein cholesterol)LDL-C) levels show a clear relationship with cardiovascular disease (CVD). Statins are first line agents to reduce LDL-C and CVD risk. However, combination lipid-lowering therapy is often required to achieve large reductions in LDL-C. AREA COVERED Colesevelam HCl is a bile acid sequestrant (BAS), which reduces LDL-C by 16-22% in monotherapy and adds a further 12-14% reduction in LDL-C when combined with other lipid-lowering drugs. Like statins, colesevelam reduces C-reactive protein levels by 16% in monotherapy and additional 6% when added to statins. Colesevelam also reduced HbA1c by 4mmol/mol (0.5%) when used alone and added to other hypoglycaemic drugs in studies of patients with diabetes . EXPERT OPINION Bile acid sequestrants reduce LDL-C and HbA1c and have some CVD outcome evidence. The uses of these agents are limited in patients with gastrointestinal disease or high triglycerides due to adverse effects on gut function and raising triglycerides and they interfere with the absorption of lipid-soluble drugs. Colesevelam has a higher bile acid binding capacity, and fewer adverse effects than other BAS. Colesevelam may be useful as a third line agent for treatment of hypercholesterolemia with some additional specific benefits on glycemic control.
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Affiliation(s)
- Oluwayemisi Esan
- Metabolic Medicine/Chemical Pathology, Guy's & St Thomas Hospitals, London SE1 7EH, UK
| | - Adie Viljoen
- Metabolic Medicine/Chemical Pathology, East & North Hertfordshire Hospitals, Lister Hospital, Stevenage, Hertfordshire SG1 4AB, UK
| | - Anthony S Wierzbicki
- Metabolic Medicine/Chemical Pathology, Guy's & St Thomas Hospitals, London SE1 7EH, UK
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Zhang B, Kuipers F, de Boer JF, Kuivenhoven JA. Modulation of Bile Acid Metabolism to Improve Plasma Lipid and Lipoprotein Profiles. J Clin Med 2021; 11:jcm11010004. [PMID: 35011746 PMCID: PMC8745251 DOI: 10.3390/jcm11010004] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/15/2021] [Accepted: 12/16/2021] [Indexed: 02/06/2023] Open
Abstract
New drugs targeting bile acid metabolism are currently being evaluated in clinical studies for their potential to treat cholestatic liver diseases, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Changes in bile acid metabolism, however, translate into an alteration of plasma cholesterol and triglyceride concentrations, which may also affect cardiovascular outcomes in such patients. This review attempts to gain insight into this matter and improve our understanding of the interactions between bile acid and lipid metabolism. Bile acid sequestrants (BAS), which bind bile acids in the intestine and promote their faecal excretion, have long been used in the clinic to reduce LDL cholesterol and, thereby, atherosclerotic cardiovascular disease (ASCVD) risk. However, BAS modestly but consistently increase plasma triglycerides, which is considered a causal risk factor for ASCVD. Like BAS, inhibitors of the apical sodium-dependent bile acid transporter (ASBTi’s) reduce intestinal bile acid absorption. ASBTi’s show effects that are quite similar to those obtained with BAS, which is anticipated when considering that accelerated faecal loss of bile acids is compensated by an increased hepatic synthesis of bile acids from cholesterol. Oppositely, treatment with farnesoid X receptor agonists, resulting in inhibition of bile acid synthesis, appears to be associated with increased LDL cholesterol. In conclusion, the increasing efforts to employ drugs that intervene in bile acid metabolism and signalling pathways for the treatment of metabolic diseases such as NAFLD warrants reinforcing interactions between the bile acid and lipid and lipoprotein research fields. This review may be considered as the first step in this process.
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Affiliation(s)
- Boyan Zhang
- Department of Pediatrics, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands; (B.Z.); (F.K.)
| | - Folkert Kuipers
- Department of Pediatrics, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands; (B.Z.); (F.K.)
- Department of Laboratory Medicine, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands
| | - Jan Freark de Boer
- Department of Pediatrics, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands; (B.Z.); (F.K.)
- Department of Laboratory Medicine, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands
- Correspondence: (J.F.d.B.); (J.A.K.)
| | - Jan Albert Kuivenhoven
- Department of Pediatrics, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands; (B.Z.); (F.K.)
- Correspondence: (J.F.d.B.); (J.A.K.)
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An Overview of the Roles of the Gut Microbiome in Obesity and Diabetes. NUTRITIONAL AND THERAPEUTIC INTERVENTIONS FOR DIABETES AND METABOLIC SYNDROME 2018. [DOI: 10.1016/b978-0-12-812019-4.00006-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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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: 13] [Impact Index Per Article: 1.6] [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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Hansen M, Sonne DP, Mikkelsen KH, Gluud LL, Vilsbøll T, Knop FK. Bile acid sequestrants for glycemic control in patients with type 2 diabetes: A systematic review with meta-analysis of randomized controlled trials. J Diabetes Complications 2017; 31:918-927. [PMID: 28238556 DOI: 10.1016/j.jdiacomp.2017.01.011] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Revised: 01/18/2017] [Accepted: 01/19/2017] [Indexed: 01/06/2023]
Abstract
AIM To evaluate the effects of bile acid sequestrants (BASs) versus placebo, no intervention or active comparators on glycemic control in type 2 diabetes. METHODS Data were retrieved and a systematic review with meta-analyses was performed. We evaluated bias control and subgroup and sensitivity analyses were performed to evaluate heterogeneity and bias. RESULTS We included 17 trials with a total of 2950 patients randomized to BASs (colesevelam or colestimide) versus placebo, no intervention, statins or sitagliptin. Random-effects meta-analysis showed that patients randomized to BASs had a lower hemoglobin A1c at the end of treatment compared with the control group (mean difference-0.55%; 95% confidence interval-0.64 to -0.46). Analysis of trials with low risk of bias in all domains confirmed the findings. Data on adverse events were limited. There were no differences between trials stratified by the control group and no evidence of publication bias or small study effects. CONCLUSIONS Our analyses found that BAS treatment improves glycemic control. The size of the effect was clinically relevant and despite limited safety data, our findings support the inclusion of BASs in current diabetes management algorithms for type 2 diabetes.
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Affiliation(s)
- Morten Hansen
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - David P Sonne
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Kristian H Mikkelsen
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lise Lotte Gluud
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Gastro Unit, Medical Division, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
| | - Tina Vilsbøll
- Center for Diabetes Research, 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
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, 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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Tahrani AA, Barnett AH, Bailey CJ. Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus. Nat Rev Endocrinol 2016; 12:566-92. [PMID: 27339889 DOI: 10.1038/nrendo.2016.86] [Citation(s) in RCA: 264] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies.
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Affiliation(s)
- Abd A Tahrani
- Centre of Endocrinology, Diabetes and Metabolism, 2nd Floor, Institute of Biomedical Research, University of Birmingham, Birmingham, B15 2TT, UK
- Department of Diabetes and Endocrinology, Heart of England NHS Foundation Trust, Birmingham, B9 5SS, UK
| | - Anthony H Barnett
- Centre of Endocrinology, Diabetes and Metabolism, 2nd Floor, Institute of Biomedical Research, University of Birmingham, Birmingham, B15 2TT, UK
- Department of Diabetes and Endocrinology, Heart of England NHS Foundation Trust, Birmingham, B9 5SS, UK
| | - Clifford J Bailey
- School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK
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Barlow GM, Yu A, Mathur R. Role of the Gut Microbiome in Obesity and Diabetes Mellitus. Nutr Clin Pract 2015; 30:787-97. [PMID: 26452391 DOI: 10.1177/0884533615609896] [Citation(s) in RCA: 172] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) and obesity represent two of the biggest global health challenges of this century and are associated with significant comorbidities and healthcare costs. Although multiple factors undoubtedly contribute to the development and progression of DM and obesity, research over the last decade has demonstrated that the microbes that colonize the human gut may play key contributory roles. Gut microbes are now known to codevelop with the human host and are strongly influenced by mode of birth and early diet and nutrition, as well as environmental and other factors including antibiotic exposure. Gut microbes contribute to human health through roles in polysaccharide breakdown, nutrient absorption, inflammatory responses, gut permeability, and bile acid modification. Numerous studies have suggested that disruptions in the relative proportions of gut microbial populations may contribute to weight gain and insulin resistance, including alterations in Gammaproteobacteria and Verrucomicrobia and the ratios of Firmicutes to Bacteroidetes in weight gain and possible alterations in butyrate-producing bacteria such as Faecalibacterium prausnitzii in DM. In addition, it has been shown that the methanogenic Archaea may contribute to altered metabolism and weight gain in the host. However, the majority of studies are performed with stool or colonic samples and may not be representative of the metabolically active small intestine. Studies predominantly in rodent models are beginning to elucidate the mechanisms by which gut microbes contribute to DM and obesity, but much remains to be learned before we can begin to approach targeted treatments.
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Affiliation(s)
- Gillian M Barlow
- GI Motility Program, Cedars-Sinai Medical Center, Los Angeles, California
| | - Allen Yu
- GI Motility Program, Cedars-Sinai Medical Center, Los Angeles, California
| | - Ruchi Mathur
- Division of Endocrine Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California
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Tomkin GH, Owens D. Dyslipidaemia of diabetes and the intestine. World J Diabetes 2015; 6:970-977. [PMID: 26185604 PMCID: PMC4499530 DOI: 10.4239/wjd.v6.i7.970] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Revised: 01/06/2015] [Accepted: 03/09/2015] [Indexed: 02/05/2023] Open
Abstract
Atherosclerosis is the major complication of diabetes and has become a major issue in the provision of medical care. In particular the economic burden is growing at an alarming rate in parallel with the increasing world-wide prevalence of diabetes. The major disturbance of lipid metabolism in diabetes relates to the effect of insulin on fat metabolism. Raised triglycerides being the hallmark of uncontrolled diabetes, i.e., in the presence of hyperglycaemia. The explosion of type 2 diabetes has generated increasing interest on the aetiology of atherosclerosis in diabetic patients. The importance of the atherogenic properties of triglyceride rich lipoproteins has only recently been recognised by the majority of diabetologists and cardiologists even though experimental evidence has been strong for many years. In the post-prandial phase 50% of triglyceride rich lipoproteins come from chylomicrons produced in the intestine. Recent evidence has secured the chylomicron as a major player in the atherogenic process. In diabetes chylomicron production is increased through disturbance in cholesterol absorption, in particular Neimann Pick C1-like1 activity is increased as is intestinal synthesis of cholesterol through 3-hydroxy-3-methyl glutaryl co enzyme A reductase. ATP binding cassette proteins G5 and G8 which regulate cholesterol in the intestine is reduced leading to chylomicronaemia. The chylomicron particle itself is atherogenic but the increase in the triglyceride-rich lipoproteins lead to an atherogenic low density lipoprotein and low high density lipoprotein. The various steps in the absorption process and the disturbance in chylomicron synthesis are discussed.
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