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Matye DJ, Wang H, Wang Y, Xiong L, Li T. Bile acid sequestrant inhibits gluconeogenesis via inducing hepatic cysteine dioxygenase type 1 to reduce cysteine availability. Am J Physiol Gastrointest Liver Physiol 2025; 328:G166-G178. [PMID: 39819116 DOI: 10.1152/ajpgi.00353.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 11/28/2024] [Accepted: 12/11/2024] [Indexed: 01/19/2025]
Abstract
Bile acid sequestrants such as cholestyramine (ChTM) are gut-restricted bile acid-binding resins that block intestine bile acid absorption and attenuate hepatic bile acid signaling. Bile acid sequestrants induce hepatic bile acid synthesis to promote cholesterol catabolism and are cholesterol-lowering drugs. Bile acid sequestrants also reduce blood glucose in clinical trials and are approved drugs for treating hyperglycemia in type-2 diabetes. However, the mechanisms mediating the glucose-lowering effect of bile acid sequestrants are still incompletely understood. Here we showed that ChTM treatment decreased hepatic glucose production in Western diet-fed mice with paradoxically induced hepatic gluconeogenic genes. Cysteine dioxygenase type 1 (CDO1) mediates cysteine conversion to taurine and its expression is repressed by bile acids. We show that ChTM induced hepatic CDO1 and selectively reduced hepatic cysteine availability. Knockdown of liver CDO1 increased liver cysteine and glucose production in mice, whereas hepatocytes cultured in cystine-deficient medium showed reduced glucose production. By using dietary protein-restricted and cystine-modified Western diets that selectively alter hepatic cysteine availability, we found that reduced hepatic cysteine availability strongly inhibited glucose production in mice. Interestingly, chronic dietary protein restriction also prevented Western diet-induced obesity, which was fully reversed by restoring dietary cystine intake alone. Consistently, reduced cysteine availability dose-dependently inhibited adipogenesis in vitro. In conclusion, we report that the glucose-lowering effect of bile acid sequestrants is mediated by a CDO1-induced hepatic cysteine restriction mimetic effect. Furthermore, the anti-obesity effect of dietary protein restriction is largely mediated by reduced dietary cysteine intake.NEW & NOTEWORTHY Hepatic cysteine availability is a key driver of hepatic gluconeogenesis. Bile acid sequestrant inhibits gluconeogenesis by inducing CDO1-mediated cysteine catabolism to reduce cysteine availability. Dietary protein restriction causes hepatic cysteine deficiency without overall amino acid deficiency. The glucose-lowering effect of dietary protein restriction is largely mediated by lower dietary cysteine intake. The anti-obesity effect of chronic dietary protein restriction is largely mediated by lower dietary cysteine intake.
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Affiliation(s)
- David J Matye
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States
| | - Huaiwen Wang
- Laboratory for Molecular Biology and Cytometry Research, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
| | - Yifeng Wang
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States
| | - Lei Xiong
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
| | - Tiangang Li
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
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Li T, Chiang JYL. Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development. Pharmacol Rev 2024; 76:1221-1253. [PMID: 38977324 PMCID: PMC11549937 DOI: 10.1124/pharmrev.124.000978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/26/2024] [Accepted: 06/28/2024] [Indexed: 07/10/2024] Open
Abstract
Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders. SIGNIFICANCE STATEMENT: Bile acids facilitate biliary cholesterol solubilization and dietary lipid absorption, regulate host metabolism and immunity, and modulate gut microbiome. Targeting bile acid metabolism and signaling holds promise for treating metabolic and inflammatory diseases.
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Affiliation(s)
- Tiangang Li
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
| | - John Y L Chiang
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
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Newman NK, Monnier PM, Rodrigues RR, Gurung M, Vasquez-Perez S, Hioki KA, Greer RL, Brown K, Morgun A, Shulzhenko N. Host response to cholestyramine can be mediated by the gut microbiota. MICROBIOME RESEARCH REPORTS 2024; 3:40. [PMID: 39741955 PMCID: PMC11684918 DOI: 10.20517/mrr.2023.82] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 06/09/2024] [Accepted: 06/24/2024] [Indexed: 01/03/2025]
Abstract
Background: The gut microbiota has been implicated as a major factor contributing to metabolic diseases and the response to drugs used for the treatment of such diseases. In this study, we tested the effect of cholestyramine, a bile acid sequestrant that reduces blood cholesterol, on the murine gut microbiota and metabolism. We also explored the hypothesis that some effects of this drug on systemic metabolism can be attributed to alterations in the gut microbiota. Methods: We used a Western diet (WD) for 8 weeks to induce metabolic disease in mice, then treated some mice with cholestyramine added to WD. Metabolic phenotyping, gene expression in liver and ileum, and microbiota 16S rRNA genes were analyzed. Then, transkingdom network analysis was used to find candidate microbes for the cholestyramine effect. Results: We observed that cholestyramine decreased glucose and epididymal fat levels and detected dysregulation of genes known to be regulated by cholestyramine in the liver and ileum. Analysis of gut microbiota showed increased alpha diversity in cholestyramine-treated mice, with fourteen taxa showing restoration of relative abundance to levels resembling those in mice fed a control diet. Using transkingdom network analysis, we inferred two amplicon sequence variants (ASVs), one from the Lachnospiraceae family (ASV49) and the other from the Muribaculaceae family (ASV1), as potential regulators of cholestyramine effects. ASV49 was also negatively linked with glucose levels, further indicating its beneficial role. Conclusion: Our results indicate that the gut microbiota has a role in the beneficial effects of cholestyramine and suggest specific microbes as targets of future investigations.
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Affiliation(s)
- Nolan K. Newman
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA
| | - Philip M. Monnier
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA
| | - Richard R. Rodrigues
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA
| | - Manoj Gurung
- Department of Biomedical Sciences, Carson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA
| | - Stephany Vasquez-Perez
- Department of Biomedical Sciences, Carson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA
| | - Kaito A. Hioki
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA
| | - Renee L. Greer
- Department of Biomedical Sciences, Carson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA
| | - Kevin Brown
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA
| | - Andrey Morgun
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA
| | - Natalia Shulzhenko
- Department of Biomedical Sciences, Carson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA
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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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Hu T, Zhang W, Han F, Zhao R, Liu H, An Z. Machine learning reveals serum myristic acid, palmitic acid and heptanoylcarnitine as biomarkers of coronary artery disease risk in patients with type 2 diabetes mellitus. Clin Chim Acta 2024; 556:117852. [PMID: 38438006 DOI: 10.1016/j.cca.2024.117852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/25/2024] [Accepted: 03/01/2024] [Indexed: 03/06/2024]
Abstract
BACKGROUND Coronary heart disease (CHD) is the most important complication of type 2 diabetes mellitus (T2DM) and the leading cause of death. Identifying the risk of CHD in T2DM patients is important for early clinical intervention. METHODS A total of 213 participants, including 81 healthy controls (HCs), 69 T2DM patients and 63 T2DM patients complicated with CHD were recruited in this study. Serum metabolomics were conducted by using ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). Demographic information and clinical laboratory test results were also collected. RESULTS Metabolic phenotypes were significantly altered among HC, T2DM and T2DM-CHD. Acylcarnitines were the most disturbed metabolites between T2DM patients and HCs. Lower levels of bile acids and higher levels of fatty acids in serum were closely associated with CHD risk in T2DM patients. Artificial neural network model was constructed for the discrimination of T2DM and T2DM complicated with CHD based on myristic acid, palmitic acid and heptanoylcarnitine, with accuracy larger than 0.95 in both training set and testing set. CONCLUSION Altogether, these findings suggest that myristic acid, palmitic acid and heptanoylcarnitine have a good prospect for the warning of CHD complications in T2DM patients, and are superior to traditional lipid, blood glucose and blood pressure indicators.
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Affiliation(s)
- Ting Hu
- Beijing Chao-Yang Hospital, Capital Medical University, No.8 Gongti South Road, Chaoyang District, Beijing 100020, PR China.
| | - Wen Zhang
- Beijing Chao-Yang Hospital, Capital Medical University, No.8 Gongti South Road, Chaoyang District, Beijing 100020, PR China
| | - Feifei Han
- Beijing Chao-Yang Hospital, Capital Medical University, No.8 Gongti South Road, Chaoyang District, Beijing 100020, PR China
| | - Rui Zhao
- Beijing Chao-Yang Hospital, Capital Medical University, No.8 Gongti South Road, Chaoyang District, Beijing 100020, PR China
| | - Hongchuan Liu
- Beijing Chao-Yang Hospital, Capital Medical University, No.8 Gongti South Road, Chaoyang District, Beijing 100020, PR China
| | - Zhuoling An
- Beijing Chao-Yang Hospital, Capital Medical University, No.8 Gongti South Road, Chaoyang District, Beijing 100020, PR China.
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Palmiotti A, de Vries HD, Hovingh MV, Koehorst M, Mulder NL, Verkade E, Veentjer MK, van Dijk TH, Bloks VW, Havinga R, Verkade HJ, de Boer JF, Kuipers F. Bile Acid Sequestration via Colesevelam Reduces Bile Acid Hydrophobicity and Improves Liver Pathology in Cyp2c70-/- Mice with a Human-like Bile Acid Composition. Biomedicines 2023; 11:2495. [PMID: 37760936 PMCID: PMC10526181 DOI: 10.3390/biomedicines11092495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 09/04/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
Bile acids (BAs) and their signaling pathways have been identified as therapeutic targets for liver and metabolic diseases. We generated Cyp2c70-/- (KO) mice that were not able to convert chenodeoxycholic acid into rodent-specific muricholic acids (MCAs) and, hence, possessed a more hydrophobic, human-like BA pool. Recently, we have shown that KO mice display cholangiopathic features with the development of liver fibrosis. The aim of this study was to determine whether BA sequestration modulates liver pathology in Western type-diet (WTD)-fed KO mice. The BA sequestrant colesevelam was mixed into the WTD (2% w/w) of male Cyp2c70+/+ (WT) and KO mice and the effects were evaluated after 3 weeks of treatment. Colesevelam increased fecal BA excretion in WT and KO mice and reduced the hydrophobicity of biliary BAs in KO mice. Colesevelam ameliorated diet-induced hepatic steatosis in WT mice, whereas KO mice were resistant to diet-induced steatosis and BA sequestration had no additional effects on liver fat content. Total cholesterol concentrations in livers of colesevelam-treated WT and KO mice were significantly lower than those of untreated controls. Of particular note, colesevelam treatment normalized plasma levels of liver damage markers in KO mice and markedly decreased hepatic mRNA levels of fibrogenesis-related genes in KO mice. Lastly, colesevelam did not affect glucose excursions and insulin sensitivity in WT or KO mice. Our data show that BA sequestration ameliorates liver pathology in Cyp2c70-/- mice with a human-like bile acid composition without affecting insulin sensitivity.
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Affiliation(s)
- Anna Palmiotti
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (A.P.); (M.V.H.); (N.L.M.); (E.V.); (M.K.V.); (V.W.B.); (R.H.); (H.J.V.)
| | - Hilde D. de Vries
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (H.D.d.V.); (T.H.v.D.)
| | - Milaine V. Hovingh
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (A.P.); (M.V.H.); (N.L.M.); (E.V.); (M.K.V.); (V.W.B.); (R.H.); (H.J.V.)
| | - Martijn Koehorst
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (H.D.d.V.); (T.H.v.D.)
| | - Niels L. Mulder
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (A.P.); (M.V.H.); (N.L.M.); (E.V.); (M.K.V.); (V.W.B.); (R.H.); (H.J.V.)
| | - Esther Verkade
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (A.P.); (M.V.H.); (N.L.M.); (E.V.); (M.K.V.); (V.W.B.); (R.H.); (H.J.V.)
| | - Melany K. Veentjer
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (A.P.); (M.V.H.); (N.L.M.); (E.V.); (M.K.V.); (V.W.B.); (R.H.); (H.J.V.)
| | - Theo H. van Dijk
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (H.D.d.V.); (T.H.v.D.)
| | - Vincent W. Bloks
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (A.P.); (M.V.H.); (N.L.M.); (E.V.); (M.K.V.); (V.W.B.); (R.H.); (H.J.V.)
| | - Rick Havinga
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (A.P.); (M.V.H.); (N.L.M.); (E.V.); (M.K.V.); (V.W.B.); (R.H.); (H.J.V.)
| | - Henkjan J. Verkade
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (A.P.); (M.V.H.); (N.L.M.); (E.V.); (M.K.V.); (V.W.B.); (R.H.); (H.J.V.)
| | - Jan Freark de Boer
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (A.P.); (M.V.H.); (N.L.M.); (E.V.); (M.K.V.); (V.W.B.); (R.H.); (H.J.V.)
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (H.D.d.V.); (T.H.v.D.)
| | - Folkert Kuipers
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands; (A.P.); (M.V.H.); (N.L.M.); (E.V.); (M.K.V.); (V.W.B.); (R.H.); (H.J.V.)
- European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
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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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Cai J, Rimal B, Jiang C, Chiang JYL, Patterson AD. Bile acid metabolism and signaling, the microbiota, and metabolic disease. Pharmacol Ther 2022; 237:108238. [PMID: 35792223 DOI: 10.1016/j.pharmthera.2022.108238] [Citation(s) in RCA: 184] [Impact Index Per Article: 61.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/13/2022] [Accepted: 06/27/2022] [Indexed: 11/24/2022]
Abstract
The diversity, composition, and function of the bacterial community inhabiting the human gastrointestinal tract contributes to host health through its role in producing energy or signaling molecules that regulate metabolic and immunologic functions. Bile acids are potent metabolic and immune signaling molecules synthesized from cholesterol in the liver and then transported to the intestine where they can undergo metabolism by gut bacteria. The combination of host- and microbiota-derived enzymatic activities contribute to the composition of the bile acid pool and thus there can be great diversity in bile acid composition that depends in part on the differences in the gut bacteria species. Bile acids can profoundly impact host metabolic and immunological functions by activating different bile acid receptors to regulate signaling pathways that control a broad range of complex symbiotic metabolic networks, including glucose, lipid, steroid and xenobiotic metabolism, and modulation of energy homeostasis. Disruption of bile acid signaling due to perturbation of the gut microbiota or dysregulation of the gut microbiota-host interaction is associated with the pathogenesis and progression of metabolic disorders. The metabolic and immunological roles of bile acids in human health have led to novel therapeutic approaches to manipulate the bile acid pool size, composition, and function by targeting one or multiple components of the microbiota-bile acid-bile acid receptor axis.
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Affiliation(s)
- Jingwei Cai
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Bipin Rimal
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Changtao Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, PR China
| | - John Y L Chiang
- Department of Integrative Medical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Andrew D Patterson
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA.
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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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Reduced Cytokine Tumour Necrosis Factor by Pharmacological Intervention in a Preclinical Study. Biomolecules 2022; 12:biom12070877. [PMID: 35883432 PMCID: PMC9313251 DOI: 10.3390/biom12070877] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 06/15/2022] [Accepted: 06/22/2022] [Indexed: 02/04/2023] Open
Abstract
Recent preclinical studies in our laboratory have shown that the bile acid profile is altered during diabetes development and such alteration has been linked to the diabetes-associated inflammatory profile. Hence, this study aimed to investigate if the first-line antidiabetic drug metformin will alter the bile acid profile and diabetes-associated inflammation in a murine model of pre-type 2 diabetes. C57 mice were randomly allocated into three equal groups of eight. Group One was given a low-fat diet (LFD), Group Two was given a high-fat diet (HFD), and Group Three was given an HFD and, upon prediabetes confirmation, daily oral metformin for one month. Blood glucose, glycated haemoglobin, drug concentrations in tissues and faeces, and the inflammatory and bile acid profiles were measured. Metformin showed wide tissue distribution and was also present in faeces. The bile acid profile showed significant alteration due to prediabetes, and although metformin did not completely normalize it, it did exert significant effects on both the bile acid and the inflammatory profiles, suggesting a direct and, to some extent, positive impact, particularly on the diabetes-associated inflammatory profile.
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11
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Feng X, Chen W, Ni X, Little PJ, Xu S, Tang L, Weng J. Metformin, Macrophage Dysfunction and Atherosclerosis. Front Immunol 2021; 12:682853. [PMID: 34163481 PMCID: PMC8215340 DOI: 10.3389/fimmu.2021.682853] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 05/07/2021] [Indexed: 12/17/2022] Open
Abstract
Metformin is one of the most widely prescribed hypoglycemic drugs and has the potential to treat many diseases. More and more evidence shows that metformin can regulate the function of macrophages in atherosclerosis, including reducing the differentiation of monocytes and inhibiting the inflammation, oxidative stress, polarization, foam cell formation and apoptosis of macrophages. The mechanisms by which metformin regulates the function of macrophages include AMPK, AMPK independent targets, NF-κB, ABCG5/8, Sirt1, FOXO1/FABP4 and HMGB1. On the basis of summarizing these studies, we further discussed the future research directions of metformin: single-cell RNA sequencing, neutrophil extracellular traps (NETs), epigenetic modification, and metformin-based combination drugs. In short, macrophages play an important role in a variety of diseases, and improving macrophage dysfunction may be an important mechanism for metformin to expand its pleiotropic pharmacological profile. In addition, the combination of metformin with other drugs that improve the function of macrophages (such as SGLT2 inhibitors, statins and IL-1β inhibitors/monoclonal antibodies) may further enhance the pleiotropic therapeutic potential of metformin in conditions such as atherosclerosis, obesity, cancer, dementia and aging.
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Affiliation(s)
- Xiaojun Feng
- Department of Pharmacy, the First Affiliated Hospital of University of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, China
| | - Wenxu Chen
- Department of Pharmacy, the First Affiliated Hospital of University of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, China
| | - Xiayun Ni
- Department of Pharmacy, the First Affiliated Hospital of University of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, China
| | - Peter J. Little
- Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, QLD, Australia
- School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, QLD, Australia
| | - Suowen Xu
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China( USTC), Hefei, China
| | - Liqin Tang
- Department of Pharmacy, the First Affiliated Hospital of University of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, China
| | - Jianping Weng
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China( USTC), Hefei, China
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12
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Mercer KE, Maurer A, Pack LM, Ono-Moore K, Spray BJ, Campbell C, Chandler CJ, Burnett D, Souza E, Casazza G, Keim N, Newman J, Hunter G, Fernadez J, Garvey WT, Harper ME, Hoppel C, Adams SH, Thyfault J. Exercise training and diet-induced weight loss increase markers of hepatic bile acid (BA) synthesis and reduce serum total BA concentrations in obese women. Am J Physiol Endocrinol Metab 2021; 320:E864-E873. [PMID: 33645254 PMCID: PMC8238126 DOI: 10.1152/ajpendo.00644.2020] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Regular exercise has profound metabolic influence on the liver, but effects on bile acid (BA) metabolism are less well known. BAs are synthesized exclusively in the liver from cholesterol via the rate-limiting enzyme cholesterol 7 alpha-hydroxylase (CYP7A1). BAs contribute to the solubilization and absorption of lipids and serve as important signaling molecules, capable of systemic endocrine function. Circulating BAs increase with obesity and insulin resistance, but effects following exercise and diet-induced weight loss are unknown. To test if improvements in fitness and weight loss as a result of exercise training enhance BA metabolism, we measured serum concentrations of total BAs (conjugated and unconjugated primary and secondary BAs) in sedentary, obese, insulin-resistant women (N = 11) before (PRE) and after (POST) a ∼14-wk exercise and diet-induced weight loss intervention. BAs were measured in serum collected after an overnight fast and during an oral glucose tolerance test (OGTT). Serum fibroblast growth factor 19 (FGF19; a regulator of BA synthesis) and 7-alpha-hydroxy-cholesten-3-one (C4, a marker of CYP7A1 enzymatic activity) also were measured. Using linear mixed-model analyses and the change in V̇O2peak (mL/min/kg) as a covariate, we observed that exercise and weight loss intervention decreased total fasting serum BA by ∼30% (P = 0.001) and increased fasting serum C4 concentrations by 55% (P = 0.004). C4 was significantly correlated with serum total BAs only in the POST condition, whereas serum FGF19 was unchanged. These data indicate that a fitness and weight loss intervention modifies BA metabolism in obese women and suggest that improved metabolic health associates with higher postabsorptive (fasting) BA synthesis. Furthermore, pre- vs. postintervention patterns of serum C4 following an OGTT support the hypothesis that responsiveness of BA synthesis to postprandial inhibition is improved after exercise and weight loss.NEW & NOTEWORTHY Exercise and weight loss in previously sedentary, insulin-resistant women facilitates a significant improvement in insulin sensitivity and fitness that may be linked to changes in bile acid metabolism. Diet-induced weight loss plus exercise-induced increases in fitness promote greater postabsorptive bile acid synthesis while also sensitizing the bile acid metabolic system to feedback inhibition during a glucose challenge when glucose and insulin are elevated.
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Affiliation(s)
- Kelly E Mercer
- Arkansas Children's Nutrition Center, Little Rock, Arkansas
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Adrianna Maurer
- Departments of Molecular and Integrative Physiology and Internal Medicine, Kansas Medical Center, Kansas City, Kansas
| | - Lindsay M Pack
- Arkansas Children's Nutrition Center, Little Rock, Arkansas
| | | | - Beverly J Spray
- Arkansas Children's Research Institute, Little Rock, Arkansas
| | - Caitlin Campbell
- United States Department of Agriculture-Agricultural Research Service Western Human Nutrition Research Center, Davis, California
| | - Carol J Chandler
- United States Department of Agriculture-Agricultural Research Service Western Human Nutrition Research Center, Davis, California
| | - Dustin Burnett
- United States Department of Agriculture-Agricultural Research Service Western Human Nutrition Research Center, Davis, California
| | - Elaine Souza
- United States Department of Agriculture-Agricultural Research Service Western Human Nutrition Research Center, Davis, California
| | - Gretchen Casazza
- Sports Medicine Program, University of California, Davis School of Medicine, Sacramento, California
| | - Nancy Keim
- United States Department of Agriculture-Agricultural Research Service Western Human Nutrition Research Center, Davis, California
| | - John Newman
- United States Department of Agriculture-Agricultural Research Service Western Human Nutrition Research Center, Davis, California
| | - Gary Hunter
- Department of Nutrition Sciences, University of Alabama, Birmingham, Alabama
| | - Jose Fernadez
- Department of Nutrition Sciences, University of Alabama, Birmingham, Alabama
| | - W Timothy Garvey
- Department of Nutrition Sciences, University of Alabama, Birmingham, Alabama
| | - Mary-Ellen Harper
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario, Canada
| | - Charles Hoppel
- Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio
| | - Sean H Adams
- Department of Surgery, University of California, Davis School of Medicine, Sacramento, California
- Center for Alimentary and Metabolic Science, University of California, Davis School of Medicine, Sacramento, California
| | - John Thyfault
- Departments of Molecular and Integrative Physiology and Internal Medicine, Kansas Medical Center, Kansas City, Kansas
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13
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Bell DSH, Goncalves E. Diabetogenic effects of cardioprotective drugs. Diabetes Obes Metab 2021; 23:877-885. [PMID: 33319474 DOI: 10.1111/dom.14295] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 11/22/2020] [Accepted: 12/07/2020] [Indexed: 01/11/2023]
Abstract
Drugs that protect against cardiovascular events in the patient with diabetes may also positively or negatively affect glycaemic control in the patient with established diabetes and may induce the development of diabetes in the predisposed patient. Mainly through increasing insulin resistance, beta-blockers, statins and high-dose diuretics have the potential to worsen glycaemic control. Dihydropyridine calcium channel blockers, low-dose diuretics, vasodilating beta-blockers, alpha-blockers and pitavastatin have little or no effect on glycaemic control. Blockers of the renin-angiotensin-aldosterone system, colesevelam, ranolazine and verapamil, through slowing breakdown of bradykinin, vasodilation, increasing cholecystokinin levels, blocking sodium channels and decreasing beta cell apoptosis, may improve glycaemic control and avoid the development of diabetes.
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Xie C, Huang W, Young RL, Jones KL, Horowitz M, Rayner CK, Wu T. Role of Bile Acids in the Regulation of Food Intake, and Their Dysregulation in Metabolic Disease. Nutrients 2021; 13:1104. [PMID: 33800566 PMCID: PMC8066182 DOI: 10.3390/nu13041104] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/23/2021] [Accepted: 03/25/2021] [Indexed: 02/07/2023] Open
Abstract
Bile acids are cholesterol-derived metabolites with a well-established role in the digestion and absorption of dietary fat. More recently, the discovery of bile acids as natural ligands for the nuclear farnesoid X receptor (FXR) and membrane Takeda G-protein-coupled receptor 5 (TGR5), and the recognition of the effects of FXR and TGR5 signaling have led to a paradigm shift in knowledge regarding bile acid physiology and metabolic health. Bile acids are now recognized as signaling molecules that orchestrate blood glucose, lipid and energy metabolism. Changes in FXR and/or TGR5 signaling modulates the secretion of gastrointestinal hormones including glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), hepatic gluconeogenesis, glycogen synthesis, energy expenditure, and the composition of the gut microbiome. These effects may contribute to the metabolic benefits of bile acid sequestrants, metformin, and bariatric surgery. This review focuses on the role of bile acids in energy intake and body weight, particularly their effects on gastrointestinal hormone secretion, the changes in obesity and T2D, and their potential relevance to the management of metabolic disorders.
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Affiliation(s)
- Cong Xie
- Adelaide Medical School, Center of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5005, Australia; (C.X.); (W.H.); (R.L.Y.); (K.L.J.); (M.H.); (C.K.R.)
| | - Weikun Huang
- Adelaide Medical School, Center of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5005, Australia; (C.X.); (W.H.); (R.L.Y.); (K.L.J.); (M.H.); (C.K.R.)
- The ARC Center of Excellence for Nanoscale BioPhotonics, Institute for Photonics and Advanced Sensing, School of Physical Sciences, The University of Adelaide, Adelaide 5005, Australia
| | - Richard L. Young
- Adelaide Medical School, Center of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5005, Australia; (C.X.); (W.H.); (R.L.Y.); (K.L.J.); (M.H.); (C.K.R.)
- Nutrition, Diabetes & Gut Health, Lifelong Health Theme South Australian Health & Medical Research Institute, Adelaide 5005, Australia
| | - Karen L. Jones
- Adelaide Medical School, Center of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5005, Australia; (C.X.); (W.H.); (R.L.Y.); (K.L.J.); (M.H.); (C.K.R.)
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide 5005, Australia
| | - Michael Horowitz
- Adelaide Medical School, Center of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5005, Australia; (C.X.); (W.H.); (R.L.Y.); (K.L.J.); (M.H.); (C.K.R.)
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide 5005, Australia
| | - Christopher K. Rayner
- Adelaide Medical School, Center of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5005, Australia; (C.X.); (W.H.); (R.L.Y.); (K.L.J.); (M.H.); (C.K.R.)
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide 5005, Australia
| | - Tongzhi Wu
- Adelaide Medical School, Center of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5005, Australia; (C.X.); (W.H.); (R.L.Y.); (K.L.J.); (M.H.); (C.K.R.)
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide 5005, Australia
- Institute of Diabetes, School of Medicine, Southeast University, Nanjing 210009, China
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15
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Bajaj HS, Brown RE, Jiandani D, Venn K, Al-Asaad H, Khandwala H, Steen O, Abdel-Salam S, Aronson R. Goal achievement of HbA1c and LDL-cholesterol in a randomized trial comparing colesevelam with ezetimibe: GOAL-RCT. Diabetes Obes Metab 2020; 22:1722-1728. [PMID: 32406601 DOI: 10.1111/dom.14084] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 05/05/2020] [Accepted: 05/09/2020] [Indexed: 01/10/2023]
Abstract
AIM To compare the efficacy and safety of colesevelam and ezetimibe as second-line low density lipoprotein-cholesterol (LDL-c)-lowering options in type 2 diabetes (T2D). MATERIALS AND METHODS GOAL-RCT is a 24-week, open-label, randomized, pragmatic clinical trial. Subjects with T2D with uncontrolled HbA1c (7.1%-10%) and LDL-c (>2.0 mmol/L) were randomized 1:1 to colesevelam 3.75 g or ezetimibe 10 mg daily. The primary composite outcome was the proportion of participants achieving an LDL-c target of ≤2.0 mmol/L and HbA1c target of ≤7.0%. Intention to treat analysis was performed. RESULTS Two hundred subjects were enrolled: mean age 59 ± 10 years; mean HbA1c 8.0%; mean LDL-c 2.5 mmol/L; 97% on statin therapy. The primary composite outcome was achieved by similar proportions of participants with colesevelam (14.6%) and ezetimibe (10.5%) (Pnon-inferiority < .001, Psuperiority = .41). LDL-c reduction from baseline was less with colesevelam compared with ezetimibe (14.0% vs. 23.2%, P < .01), as was the proportion of subjects achieving an LDL-c target of ≤2.0 mmol/L (47.6% and 67.0%, respectively; P = .007). Mean HbA1c was reduced with colesevelam (-0.26 ± 0.10%), while no change was observed with ezetimibe (difference P = .06). Adverse events and discontinuation rates were higher for colesevelam (20.2% and 31.1%) compared with ezetimibe (7.2% and 6.2%), respectively. CONCLUSIONS Among subjects with T2D, the initiation of colesevelam or ezetimibe led to similar achievement of primary composite outcome (LDL-c and HbA1c within target), with ezetimibe recording a greater LDL-c reduction and better tolerability than colesevelam.
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Affiliation(s)
- Harpreet S Bajaj
- LMC Diabetes & Endocrinology, Toronto, Ontario, Canada
- Leadership Sinai Center for Diabetes, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Ruth E Brown
- LMC Diabetes & Endocrinology, Toronto, Ontario, Canada
| | | | - Karri Venn
- LMC Diabetes & Endocrinology, Toronto, Ontario, Canada
| | - Hani Al-Asaad
- LMC Diabetes & Endocrinology, Toronto, Ontario, Canada
| | | | - Oren Steen
- LMC Diabetes & Endocrinology, Toronto, Ontario, Canada
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16
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Zhu W, Wang S, Dai H, Xuan L, Deng C, Wang T, Zhao Z, Li M, Lu J, Xu Y, Chen Y, Wang W, Bi Y, Xu M, Ning G. Serum total bile acids associate with risk of incident type 2 diabetes and longitudinal changes in glucose-related metabolic traits. J Diabetes 2020; 12:616-625. [PMID: 32220107 DOI: 10.1111/1753-0407.13040] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 03/12/2020] [Accepted: 03/20/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Bile acids have been found to be related to changes in gut microbiota and multiple metabolic disorders, including type 2 diabetes (T2D). We aimed to prospectively investigate associations of serum total bile acids (TBAs) with risk of incident T2D and longitudinal changes in glycemic traits. METHODS A community-based study was conducted at baseline in 2010, including 4968 nondiabetic participants aged ≥40 years followed up for an average of 4.3 years. Incident T2D was defined by using the 1999 WHO criteria based on 75-g oral glucose tolerance tests. Multivariate Cox proportional hazards regression was used to examine the association of serum TBAs with incident T2D. Fasting plasma glucose (FPG), 2-hour postload plasma glucose (2-h PPG), and fasting serum insulin (FSI) were measured at baseline and follow-up. RESULTS During 21 653.7 person-years of follow-up, 605 cases of incident diabetes were identified (incidence rate 2.8%). Comparing to quartile 1 of serum TBAs, quartile 2, 3, and 4 were significantly associated with a 14.2%, 15.0%, and 31.4% higher risk of incident T2D (P = .029). Each one unit of log-TBAs was associated with an increase of 0.034 mmol/L in FPG, 0.111 mmol/L in 2-h PPG, 0.023 in log-FSI, and 0.012 in log-HOMA-IR (homeostasis model assessment of insulin resistance) (all P ≤ .024). The association was attenuated after further adjustment for HOMA-IR. Mediation analysis showed that insulin resistance indicated by HOMA-IR might mediate 28.5% of indirect effect on the association of TBAs with T2D (P = .0004). CONCLUSIONS Baseline serum TBAs were significantly associated with incident T2D and longitudinal changes in glycemic traits. Insulin resistance might partially mediate the association of TBAs and T2D.
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Affiliation(s)
- Wen Zhu
- State Key Laboratory of Medical Genomics, Shanghai National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuangyuan Wang
- State Key Laboratory of Medical Genomics, Shanghai National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huajie Dai
- State Key Laboratory of Medical Genomics, Shanghai National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liping Xuan
- State Key Laboratory of Medical Genomics, Shanghai National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chanjuan Deng
- State Key Laboratory of Medical Genomics, Shanghai National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tiange Wang
- State Key Laboratory of Medical Genomics, Shanghai National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhiyun Zhao
- State Key Laboratory of Medical Genomics, Shanghai National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mian Li
- State Key Laboratory of Medical Genomics, Shanghai National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jieli Lu
- State Key Laboratory of Medical Genomics, Shanghai National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu Xu
- State Key Laboratory of Medical Genomics, Shanghai National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuhong Chen
- State Key Laboratory of Medical Genomics, Shanghai National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiqing Wang
- State Key Laboratory of Medical Genomics, Shanghai National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yufang Bi
- State Key Laboratory of Medical Genomics, Shanghai National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Xu
- State Key Laboratory of Medical Genomics, Shanghai National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guang Ning
- State Key Laboratory of Medical Genomics, Shanghai National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Li B, Hu Y, Wang G, Liu L. The effect of exenatide on fasting bile acids in newly diagnosed type 2 diabetes mellitus patients, a pilot study. BMC Pharmacol Toxicol 2020; 21:44. [PMID: 32539783 PMCID: PMC7296654 DOI: 10.1186/s40360-020-00422-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Accepted: 05/26/2020] [Indexed: 11/10/2022] Open
Abstract
Background Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) demonstrated good glycemic efficacy in patients with type 2 diabetes mellitus (T2DM) recent years, whereas studies on GLP-1 RAs’ biliary effects were limited. Therefore, we aimed to assess the effect of exenatide on bile acids (BAs) and investigate the role of BAs in the glycemic control effect of exenatide. Methods Thirty-eight newly diagnosed T2DM participants without glucose-lowering drugs intake were recruited. Plasma total bile acids in fasting state (FTBAs) and other parameters were tested at baseline. Then exenatide were applied to the T2DM participants for 12 weeks. FTBAs and glycemic parameters were measured again after exenatide treatment, and correlation analysis between changes of FTBAs and glycemic parameters were conducted to investigate the role of BAs in the glycemic control effect of exenatide. Results The baseline FTBAs level of T2DM patients had no significance (3.84 ± 2.06 vs. 3.87 ± 2.89, P = 0.954) compared with healthy subjects. After 12-week exenatide treatment for the T2DM patients, FTBAs were decreased from 3.84 ± 2.06 μmol/L to 3.06 ± 1.27 μmol/L (P < 0.01). The correlation analysis showed that changes of FTBAs was positively correlated with changes of FPG (r = 0.355, P < 0.05). Conclusions Our results demonstrated a decreased FTBAs level after exenatide treatment for 12 weeks, without the interference of metformin and other glucose-lowering drugs. The reduction of FTBAs might not exert a positive role in the glycemic control effect of exenatide. Trial registration Trial registration number: NCT04303819. Registered in March 11, 2020 - Retrospectively registered.
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Affiliation(s)
- Boyu Li
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongtinan Road, Chaoyang District, Beijing, 100020, China
| | - Yanjin Hu
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongtinan Road, Chaoyang District, Beijing, 100020, China
| | - Guang Wang
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongtinan Road, Chaoyang District, Beijing, 100020, China.
| | - Lihong Liu
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongtinan Road, Chaoyang District, Beijing, 100020, China.
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18
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Wei J, Xia T, Chen W, Ran P, Chen M, Li X. Glucose and lipid metabolism screening models of hepatocyte spheroids after culture with injectable fiber fragments. J Tissue Eng Regen Med 2020; 14:774-788. [PMID: 32285997 DOI: 10.1002/term.3042] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 03/22/2020] [Accepted: 03/24/2020] [Indexed: 12/13/2022]
Abstract
With the rise of obesity, diabetes, and other metabolic diseases, in vitro hepatic cell and tissue models play an essential role in the identification of active pharmaceutical ingredients. Up to now, three-dimensional (3D) culture models have rarely focused on hepatic glucose and lipid metabolism. In addition, primary human liver cells suffer from limited availability and interdonor difference for establishing reproducible models. Thus, in the current study, the most available human liver cancer cell line (HepG2) and primary hepatocytes from rats (rPH) were proposed to construct 3D spheroids using injectable fiber fragments with galactose grafts (gSF) as the substrate. rPH and HepG2 spheroids show strong cell-cell and cell-fiber fragment interactions to promote the cell viability, albumin, and urea syntheses. Compared with HepG2 spheroids, rPH spheroids indicate stronger glucose metabolism abilities in terms of glucose consumption, intracellular glycogen content, gluconeogenesis rate, and sensitivity to glucose modulator hormones like insulin and glucagon. On the other hand, HepG2 spheroids display strong lipid metabolism abilities in producing significantly higher levels of total cholesterol and triglyceride. Compared with those without fiber fragments, the gSF-supported 3D culture establishes effective models for in vitro glucose (rPH spheroids) and lipid metabolisms (HepG2 spheroids). The screening models are confirmed from the respective enzyme activities and gene expressions and show significantly higher sensitivity and clinically related responses to hypoglycemic and lipid-lowering drugs. Thus, the culture configuration demonstrates a predictable in vitro platform for defining glucose and lipid metabolism profiles and screening therapeutic agents for metabolism disorders like diabetes and obesity.
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Affiliation(s)
- Jiaojun Wei
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, China.,School of Bioscience and Technology, Chengdu Medical College, Chengdu, China
| | - Tian Xia
- Department of Pathology, Western Theater Command Air Force Hospital, Chengdu, China
| | - Weijia Chen
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, China
| | - Pan Ran
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, China
| | - Maohua Chen
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, China
| | - Xiaohong Li
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, China
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Gilijamse PW, Hartstra AV, Levin E, Wortelboer K, Serlie MJ, Ackermans MT, Herrema H, Nederveen AJ, Imangaliyev S, Aalvink S, Sommer M, Levels H, Stroes ESG, Groen AK, Kemper M, de Vos WM, Nieuwdorp M, Prodan A. Treatment with Anaerobutyricum soehngenii: a pilot study of safety and dose-response effects on glucose metabolism in human subjects with metabolic syndrome. NPJ Biofilms Microbiomes 2020; 6:16. [PMID: 32221294 PMCID: PMC7101376 DOI: 10.1038/s41522-020-0127-0] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 03/09/2020] [Indexed: 01/25/2023] Open
Abstract
Dysbiosis of the intestinal microbiota has been implicated in insulin resistance, although evidence regarding causality in humans is scarce. We performed a phase I/II dose-finding and safety study on the effect of oral intake of the anaerobic butyrogenic strain Anaerobutyricum soehngenii on glucose metabolism in 24 subjects with metabolic syndrome. We found that treatment with A. soehngenii was safe and observed a significant correlation between the measured fecal abundance of administered A. soehngenii and improvement in peripheral insulin sensitivity after 4 weeks of treatment. This was accompanied by an altered microbiota composition and a change in bile acid metabolism. Finally, we show that metabolic response upon administration of A. soehngenii (defined as improved insulin sensitivity 4 weeks after A. soehngenii intake) is dependent on microbiota composition at baseline. These data in humans are promising, but additional studies are needed to reproduce our findings and to investigate long-term effects, as well as other modes of delivery.
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Affiliation(s)
- Pim W Gilijamse
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands.,Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Annick V Hartstra
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Evgeni Levin
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Koen Wortelboer
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Mireille J Serlie
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Mariette T Ackermans
- Laboratory of Endocrinology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Hilde Herrema
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Aart J Nederveen
- Department of Radiology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Sultan Imangaliyev
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Steven Aalvink
- Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands
| | | | - Han Levels
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Erik S G Stroes
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Albert K Groen
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Marleen Kemper
- Department of Clinical Pharmacy, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Willem M de Vos
- Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands.,Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Max Nieuwdorp
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Andrei Prodan
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
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20
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Flynn CR, Albaugh VL, Abumrad NN. Metabolic Effects of Bile Acids: Potential Role in Bariatric Surgery. Cell Mol Gastroenterol Hepatol 2019; 8:235-246. [PMID: 31075353 PMCID: PMC6664228 DOI: 10.1016/j.jcmgh.2019.04.014] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 04/23/2019] [Accepted: 04/24/2019] [Indexed: 02/08/2023]
Abstract
Bariatric surgery is the most effective and durable treatment for morbid obesity, with an unexplained yet beneficial side effect of restoring insulin sensitivity and improving glycemia, often before weight loss is observed. Among the many contributing mechanisms often cited, the altered handling of intestinal bile acids is of considerable therapeutic interest. Here, we review a growing body of literature examining the metabolic effects of bile acids ranging from their physical roles in dietary fat handling within the intestine to their functions as endocrine and paracrine hormones in potentiating responses to bariatric surgery. The roles of 2 important bile acid receptors, Takeda G-protein coupled receptor (also known as G-protein coupled bile acid receptor) and farnesoid X receptor, are highlighted as is downstream signaling through glucagon-like polypeptide 1 and its cognate receptor. Additional improvements in other phenotypes and potential contributions of commensal gut bacteria, such as Akkermansia muciniphila, which are manifest after Roux-en-Y gastric bypass and other emulations, such as gallbladder bile diversion to the ileum, are also discussed.
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Affiliation(s)
- Charles R. Flynn
- Correspondence Address correspondence to: Charles R. Flynn, PhD, 1161 21st Avenue S, CCC-2308 MCN, Nashville, Tennessee 37232-2730. fax: (615) 343-6456.
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21
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Jellinger PS, Handelsman Y, Rosenblit PD, Bloomgarden ZT, Fonseca VA, Garber AJ, Grunberger G, Guerin CK, Bell DSH, Mechanick JI, Pessah-Pollack R, Wyne K, Smith D, Brinton EA, Fazio S, Davidson M. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY GUIDELINES FOR MANAGEMENT OF DYSLIPIDEMIA AND PREVENTION OF CARDIOVASCULAR DISEASE. Endocr Pract 2019; 23:1-87. [PMID: 28437620 DOI: 10.4158/ep171764.appgl] [Citation(s) in RCA: 668] [Impact Index Per Article: 111.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE The development of these guidelines is mandated by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPGs). METHODS Recommendations are based on diligent reviews of the clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols. RESULTS The Executive Summary of this document contains 87 recommendations of which 45 are Grade A (51.7%), 18 are Grade B (20.7%), 15 are Grade C (17.2%), and 9 (10.3%) are Grade D. These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world medical care. The evidence base presented in the subsequent Appendix provides relevant supporting information for Executive Summary Recommendations. This update contains 695 citations of which 203 (29.2 %) are EL 1 (strong), 137 (19.7%) are EL 2 (intermediate), 119 (17.1%) are EL 3 (weak), and 236 (34.0%) are EL 4 (no clinical evidence). CONCLUSION This CPG is a practical tool that endocrinologists, other health care professionals, health-related organizations, and regulatory bodies can use to reduce the risks and consequences of dyslipidemia. It provides guidance on screening, risk assessment, and treatment recommendations for a range of individuals with various lipid disorders. The recommendations emphasize the importance of treating low-density lipoprotein cholesterol (LDL-C) in some individuals to lower goals than previously endorsed and support the measurement of coronary artery calcium scores and inflammatory markers to help stratify risk. Special consideration is given to individuals with diabetes, familial hypercholesterolemia, women, and youth with dyslipidemia. Both clinical and cost-effectiveness data are provided to support treatment decisions. ABBREVIATIONS 4S = Scandinavian Simvastatin Survival Study A1C = glycated hemoglobin AACE = American Association of Clinical Endocrinologists AAP = American Academy of Pediatrics ACC = American College of Cardiology ACE = American College of Endocrinology ACS = acute coronary syndrome ADMIT = Arterial Disease Multiple Intervention Trial ADVENT = Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study AHA = American Heart Association AHRQ = Agency for Healthcare Research and Quality AIM-HIGH = Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides trial ASCVD = atherosclerotic cardiovascular disease ATP = Adult Treatment Panel apo = apolipoprotein BEL = best evidence level BIP = Bezafibrate Infarction Prevention trial BMI = body mass index CABG = coronary artery bypass graft CAC = coronary artery calcification CARDS = Collaborative Atorvastatin Diabetes Study CDP = Coronary Drug Project trial CI = confidence interval CIMT = carotid intimal media thickness CKD = chronic kidney disease CPG(s) = clinical practice guideline(s) CRP = C-reactive protein CTT = Cholesterol Treatment Trialists CV = cerebrovascular CVA = cerebrovascular accident EL = evidence level FH = familial hypercholesterolemia FIELD = Secondary Endpoints from the Fenofibrate Intervention and Event Lowering in Diabetes trial FOURIER = Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk trial HATS = HDL-Atherosclerosis Treatment Study HDL-C = high-density lipoprotein cholesterol HeFH = heterozygous familial hypercholesterolemia HHS = Helsinki Heart Study HIV = human immunodeficiency virus HoFH = homozygous familial hypercholesterolemia HPS = Heart Protection Study HPS2-THRIVE = Treatment of HDL to Reduce the Incidence of Vascular Events trial HR = hazard ratio HRT = hormone replacement therapy hsCRP = high-sensitivity CRP IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial IRAS = Insulin Resistance Atherosclerosis Study JUPITER = Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin LDL-C = low-density lipoprotein cholesterol Lp-PLA2 = lipoprotein-associated phospholipase A2 MACE = major cardiovascular events MESA = Multi-Ethnic Study of Atherosclerosis MetS = metabolic syndrome MI = myocardial infarction MRFIT = Multiple Risk Factor Intervention Trial NCEP = National Cholesterol Education Program NHLBI = National Heart, Lung, and Blood Institute PCOS = polycystic ovary syndrome PCSK9 = proprotein convertase subtilisin/kexin type 9 Post CABG = Post Coronary Artery Bypass Graft trial PROSPER = Prospective Study of Pravastatin in the Elderly at Risk trial QALY = quality-adjusted life-year ROC = receiver-operator characteristic SOC = standard of care SHARP = Study of Heart and Renal Protection T1DM = type 1 diabetes mellitus T2DM = type 2 diabetes mellitus TG = triglycerides TNT = Treating to New Targets trial VA-HIT = Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial VLDL-C = very low-density lipoprotein cholesterol WHI = Women's Health Initiative.
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22
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Creation of Straight-Chain Cationic Polysaccharide-Based Bile Salt Sequestrants Made from Euglenoid β-1,3-Glucan as Potential Antidiabetic Agents. Pharm Res 2018; 36:23. [DOI: 10.1007/s11095-018-2553-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 11/30/2018] [Indexed: 12/12/2022]
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23
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Sedgeman LR, Beysen C, Allen RM, Ramirez Solano MA, Turner SM, Vickers KC. Intestinal bile acid sequestration improves glucose control by stimulating hepatic miR-182-5p in type 2 diabetes. Am J Physiol Gastrointest Liver Physiol 2018; 315:G810-G823. [PMID: 30160993 PMCID: PMC6415711 DOI: 10.1152/ajpgi.00238.2018] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Colesevelam is a bile acid sequestrant approved to treat both hyperlipidemia and type 2 diabetes, but the mechanism for its glucose-lowering effects is not fully understood. The aim of this study was to investigate the role of hepatic microRNAs (miRNAs) as regulators of metabolic disease and to investigate the link between the cholesterol and glucose-lowering effects of colesevelam. To quantify the impact of colesevelam treatment in rodent models of diabetes, metabolic studies were performed in Zucker diabetic fatty (ZDF) rats and db/db mice. Colesevelam treatments significantly decreased plasma glucose levels and increased glycolysis in the absence of changes to insulin levels in ZDF rats and db/db mice. High-throughput sequencing and real-time PCR were used to quantify hepatic miRNA and mRNA changes, and the cholesterol-sensitive miR-96/182/183 cluster was found to be significantly increased in livers from ZDF rats treated with colesevelam compared with vehicle controls. Inhibition of miR-182 in vivo attenuated colesevelam-mediated improvements to glycemic control in db/db mice. Hepatic expression of mediator complex subunit 1 (MED1), a nuclear receptor coactivator, was significantly decreased with colesevelam treatments in db/db mice, and MED1 was experimentally validated to be a direct target of miR-96/182/183 in humans and mice. In summary, these results support that colesevelam likely improves glycemic control through hepatic miR-182-5p, a mechanism that directly links cholesterol and glucose metabolism. NEW & NOTEWORTHY Colesevelam lowers systemic glucose levels in Zucker diabetic fatty rats and db/db mice and increases hepatic levels of the sterol response element binding protein 2-responsive microRNA cluster miR-96/182/183. Inhibition of miR-182 in vivo reverses the glucose-lowering effects of colesevelam in db/db mice. Mediator complex subunit 1 (MED1) is a novel, direct target of the miR-96/182/183 cluster in mice and humans.
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Affiliation(s)
- Leslie R. Sedgeman
- 1Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | | | - Ryan M. Allen
- 3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | | | | | - Kasey C. Vickers
- 1Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee,3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
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24
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Nerild HH, Christensen MB, Knop FK, Brønden A. Preclinical discovery and development of colesevelam for the treatment of type 2 diabetes. Expert Opin Drug Discov 2018; 13:1161-1167. [DOI: 10.1080/17460441.2018.1538206] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Henriette Holst Nerild
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Mikkel Bring Christensen
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Pharmacology, Bispebjerg and Frederiksberg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Filip Krag Knop
- Clinical Metabolic Physiology, 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
- Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Andreas Brønden
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
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25
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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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26
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Ramírez-Pérez O, Cruz-Ramón V, Chinchilla-López P, Méndez-Sánchez N. The Role of the Gut Microbiota in Bile Acid Metabolism. Ann Hepatol 2017; 16:s15-s20. [PMID: 29080339 DOI: 10.5604/01.3001.0010.5494] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 09/12/2017] [Indexed: 02/04/2023]
Abstract
The gut microbiota has been considered a cornerstone of maintaining the health status of its human host because it not only facilitates harvesting of nutrients and energy from ingested food, but also produces numerous metabolites that can regulate host metabolism. One such class of metabolites, the bile acids, are synthesized from cholesterol in the liver and further metabolized by the gut microbiota into secondary bile acids. These bioconversions modulate the signaling properties of bile acids through the nuclear farnesoid X receptor and the G protein-coupled membrane receptor 5, which regulate diverse metabolic pathways in the host. In addition, bile acids can regulate gut microbial composition both directly and indirectly by activation of innate immune response genes in the small intestine. Therefore, host metabolism can be affected by both microbial modifications of bile acids, which leads to altered signaling via bile acid receptors, and by alterations in the composition of the microbiota. In this review, we mainly describe the interactions between bile acids and intestinal microbiota and their roles in regulating host metabolism, but we also examine the impact of bile acid composition in the gut on the intestinal microbiome and on host physiology.
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Affiliation(s)
| | - Vania Cruz-Ramón
- Liver Research Unit, Medica Sur Clinic & Foundation, Mexico City, Mexico
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27
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Yang IF, Jayaprakasha GK, Patil BS. In Vitro Bile Acid Binding Capacities of Red Leaf Lettuce and Cruciferous Vegetables. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2017; 65:8054-8062. [PMID: 28812344 DOI: 10.1021/acs.jafc.7b02540] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
In the present study, we tested the bile acid binding capacity of red leaf lettuce, red cabbage, red kale, green kale, and Brussels sprouts through in vitro digestion process by simulating mouth, gastric, and intestinal digestion using six bile acids at physiological pH. Green and red kale exhibited significantly higher (86.5 ± 2.9 and 89.7 ± 0.9%, respectively) bile acid binding capacity compared to the other samples. Further, three different compositions of bile acids were tested to understand the effect on different health conditions. To predict the optimal dose for bile acid binding, we established a logistic relationship between kale dose and bile acid binding capacity. The results indicated that kale showed significantly higher bile acid binding capacity (82.5 ± 2.9% equivalent to 72.06 mg) at 1.5 g sample and remained constant up to 2.5 g. In addition, minimally processed (microwaved 3 min or steamed 8 min) green kale showed significantly enhanced bile acid binding capacity (91.1 ± 0.3 and 90.2 ± 0.7%, respectively) compared to lyophilized kale (85.5 ± 0.24%). Among the six bile acids tested, kale preferentially bound hydrophobic bile acids chenodeoxycholic acid and deoxycholic acid. Therefore, regular consumption of kale, especially minimally processed kale, can help excrete more bile acids and, thus, may lower the risk of hypercholesterolemia.
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Affiliation(s)
- Isabelle F Yang
- Vegetable and Fruit Improvement Center, Department of Horticultural Sciences, Texas A&M University , 1500 Research Parkway, Suite A120, College Station, Texas 77843, United States
| | - Guddadarangavvanahally K Jayaprakasha
- Vegetable and Fruit Improvement Center, Department of Horticultural Sciences, Texas A&M University , 1500 Research Parkway, Suite A120, College Station, Texas 77843, United States
| | - Bhimanagouda S Patil
- Vegetable and Fruit Improvement Center, Department of Horticultural Sciences, Texas A&M University , 1500 Research Parkway, Suite A120, College Station, Texas 77843, United States
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28
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Kårhus ML, Brønden A, Sonne DP, Vilsbøll T, Knop FK. Evidence connecting old, new and neglected glucose-lowering drugs to bile acid-induced GLP-1 secretion: A review. Diabetes Obes Metab 2017; 19:1214-1222. [PMID: 28304141 DOI: 10.1111/dom.12946] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2017] [Revised: 03/13/2017] [Accepted: 03/14/2017] [Indexed: 12/25/2022]
Abstract
Bile acids are amphipathic water-soluble steroid-based molecules best known for their important lipid-solubilizing role in the assimilation of fat. Recently, bile acids have emerged as metabolic integrators with glucose-lowering potential. Among a variety of gluco-metabolic effects, bile acids have been demonstrated to modulate the secretion of the gut-derived incretin hormone glucagon-like peptide-1 (GLP-1), possibly via the transmembrane receptor Takeda G-protein-coupled receptor 5 and the nuclear farnesoid X receptor, in intestinal L cells. The present article critically reviews current evidence connecting established glucose-lowering drugs to bile acid-induced GLP-1 secretion, and discusses whether bile acid-induced GLP-1 secretion may constitute a new basis for understanding how metformin, inhibitors of the apical sodium-dependent bile acids transporter, and bile acid sequestrants - old, new and neglected glucose-lowering drugs - improve glucose metabolism.
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Affiliation(s)
- Martin L Kårhus
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Andreas Brønden
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - David P Sonne
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center, Copenhagen, University of Copenhagen, Gentofte, Denmark
| | - Fillip K Knop
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Faculty of Health and Medical Sciences, The Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
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29
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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: 59] [Impact Index Per Article: 7.4] [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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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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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: 50] [Impact Index Per Article: 5.6] [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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Pandit A, Pandey AK. Obesity context of type 2 diabetes and medication perspectives. APOLLO MEDICINE 2016. [DOI: 10.1016/j.apme.2015.08.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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Hansen M, Scheltema MJ, Sonne DP, Hansen JS, Sperling M, Rehfeld JF, Holst JJ, Vilsbøll T, Knop FK. Effect of chenodeoxycholic acid and the bile acid sequestrant colesevelam on glucagon-like peptide-1 secretion. Diabetes Obes Metab 2016; 18:571-80. [PMID: 26888164 DOI: 10.1111/dom.12648] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Revised: 12/09/2015] [Accepted: 02/11/2016] [Indexed: 12/24/2022]
Abstract
AIM To evaluate the effects of the primary human bile acid, chenodeoxycholic acid (CDCA), and the bile acid sequestrant (BAS) colesevelam, instilled into the stomach, on plasma levels of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide, glucose, insulin, C-peptide, glucagon, cholecystokinin and gastrin, as well as on gastric emptying, gallbladder volume, appetite and food intake. METHODS On four separate days, nine patients with type 2 diabetes, and 10 matched healthy control subjects received bolus instillations of (i) CDCA, (ii) colesevelam, (iii) CDCA + colesevelam or (iv) placebo. At baseline and for 180 min after instillation, blood was sampled. RESULTS In both the type 2 diabetes group and the healthy control group, CDCA elicited an increase in GLP-1 levels compared with colesevelam, CDCA + colesevelam and placebo, respectively (p < 0.05). The interventions did not affect plasma glucose, insulin or C-peptide concentrations in any of the groups. CDCA elicited a small increase in plasma insulin : glucose ratio compared with colesevelam, CDCA + colesevelam and placebo in both groups. Compared with colesevelam, CDCA + colesevelam and placebo, respectively, CDCA increased glucagon and delayed gastric emptying in both groups. CONCLUSIONS CDCA increased GLP-1 and glucagon secretion, and delayed gastric emptying. We speculate that bile acid-induced activation of TGR5 on L cells increases GLP-1 secretion, which, in turn, may result in amplification of glucose-stimulated insulin secretion. Furthermore our data suggest that colesevelam does not have an acute effect on GLP-1 secretion in humans.
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Affiliation(s)
- M Hansen
- Center for Diabetes Research, Gentofte Hospital, University Copenhagen, Hellerup, Denmark
- NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University Copenhagen, Copenhagen, Denmark
| | - M J Scheltema
- Center for Diabetes Research, Gentofte Hospital, University Copenhagen, Hellerup, Denmark
- Department of Endocrinology and Metabolism, Amsterdam Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - D P Sonne
- Center for Diabetes Research, Gentofte Hospital, University Copenhagen, Hellerup, Denmark
- NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University Copenhagen, Copenhagen, Denmark
| | - J S Hansen
- Department of Clinical Biochemistry, University Copenhagen, Rigshospitalet, Copenhagen, Denmark
| | - M Sperling
- Center for Diabetes Research, Gentofte Hospital, University Copenhagen, Hellerup, Denmark
| | - J F Rehfeld
- Department of Clinical Biochemistry, University Copenhagen, Rigshospitalet, Copenhagen, Denmark
| | - J J Holst
- NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University Copenhagen, Copenhagen, Denmark
| | - T Vilsbøll
- Center for Diabetes Research, Gentofte Hospital, University Copenhagen, Hellerup, Denmark
| | - F K Knop
- Center for Diabetes Research, Gentofte Hospital, University Copenhagen, Hellerup, Denmark
- NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University Copenhagen, Copenhagen, Denmark
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Turner N, Zeng XY, Osborne B, Rogers S, Ye JM. Repurposing Drugs to Target the Diabetes Epidemic. Trends Pharmacol Sci 2016; 37:379-389. [PMID: 26900045 DOI: 10.1016/j.tips.2016.01.007] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Revised: 01/25/2016] [Accepted: 01/25/2016] [Indexed: 01/07/2023]
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Toth PP, Farnier M, Tomassini JE, Foody JM, Tershakovec AM. Statin combination therapy and cardiovascular risk reduction. Future Cardiol 2016; 12:289-315. [PMID: 27079178 DOI: 10.2217/fca-2015-0011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
In numerous clinical trials, lowering LDL-C with statin therapy has been demonstrated to reduce the risk of cardiovascular disease (CVD) in primary and secondary prevention settings. Guidelines recommend statins for first-line therapy in cholesterol-lowering management of patients with CVD risk. Despite increased statin monotherapy use over the last decade, a number of patients with high CVD risk do not achieve optimal LDL-C lowering. Guidelines recommend consideration of statin combination therapy with nonstatin agents for these patients. However, combination therapy approaches have been hampered by neutral findings. Recently, ezetimibe added to simvastatin therapy reduced cardiovascular events in acute coronary syndrome patients, more than simvastatin alone. This article provides an overview of various agents in combination with statin therapy on cardiovascular outcomes. Other lipid-lowering agents in development, including PCSK9 and CETP inhibitors in development, are also described.
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Affiliation(s)
- Peter P Toth
- CGH Medical Center, Sterling, Illinois, & Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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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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Type 2 Diabetes Medication Review. Am J Med Sci 2016; 351:342-55. [DOI: 10.1016/j.amjms.2016.01.019] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 01/27/2016] [Accepted: 01/28/2016] [Indexed: 12/19/2022]
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Lickteig AJ, Csanaky IL, Pratt-Hyatt M, Klaassen CD. Activation of Constitutive Androstane Receptor (CAR) in Mice Results in Maintained Biliary Excretion of Bile Acids Despite a Marked Decrease of Bile Acids in Liver. Toxicol Sci 2016; 151:403-18. [PMID: 26984780 DOI: 10.1093/toxsci/kfw054] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Activation of Constitutive Androstane Receptor (CAR) protects against bile acid (BA)-induced liver injury. This study was performed to determine the effect of CAR activation on bile flow, BA profile, as well as expression of BA synthesis and transport genes. Synthetic CAR ligand 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) was administered to mice for 4 days. BAs were quantified by UPLC-MS/MS (ultraperformance liquid chromatography-tandem mass spectrometry). CAR activation decreases total BAs in livers of male (49%) and female mice (26%), largely attributable to decreases of the 12α-hydroxylated BA taurocholic acid (T-CA) (males (M) 65%, females (F) 45%). Bile flow in both sexes was increased by CAR activation, and the increases were BA-independent. CAR activation did not alter biliary excretion of total BAs, but overall BA composition changed. Excretion of muricholic (6-hydroxylated) BAs was increased in males (101%), and the 12α-OH proportion of biliary BAs was decreased in both males (37%) and females (28%). The decrease of T-CA in livers of males and females correlates with the decreased mRNA of the sterol 12α-hydroxylase Cyp8b1 in males (71%) and females (54%). As a response to restore BAs to physiologic concentrations in liver, mRNA of Cyp7a1 is upregulated following TCPOBOP (males 185%, females 132%). In ilea, mRNA of the negative feedback regulator Fgf15 was unaltered by CAR activation, indicating biliary BA excretion was sufficient to maintain concentrations of total BAs in the small intestine. In summary, the effects of CAR activation on BAs in male and female mice are quite similar, with a marked decrease in the major BA T-CA in the liver.
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Affiliation(s)
- Andrew J Lickteig
- *Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Iván L Csanaky
- *Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160; Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Hospital & Clinics, Kansas City, Missouri 64108; Department of Pediatrics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Matthew Pratt-Hyatt
- *Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Curtis D Klaassen
- *Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160; *Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160;
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Gaitonde P, Garhyan P, Link C, Chien JY, Trame MN, Schmidt S. A Comprehensive Review of Novel Drug–Disease Models in Diabetes Drug Development. Clin Pharmacokinet 2016; 55:769-788. [DOI: 10.1007/s40262-015-0359-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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40
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Najam O, Lambert G, Ray KK. The past, present and future of lipid-lowering therapy. ACTA ACUST UNITED AC 2015. [DOI: 10.2217/clp.15.40] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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A Study to Inform the Design of a National Multicentre Randomised Controlled Trial to Evaluate If Reducing Serum Phosphate to Normal Levels Improves Clinical Outcomes including Mortality, Cardiovascular Events, Bone Pain, or Fracture in Patients on Dialysis. Int J Nephrol 2015; 2015:579434. [PMID: 26366297 PMCID: PMC4561107 DOI: 10.1155/2015/579434] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2015] [Accepted: 07/30/2015] [Indexed: 01/09/2023] Open
Abstract
Background. Retrospective, observational studies link high phosphate with mortality in dialysis patients. This generates research hypotheses but does not establish “cause-and-effect.” A large randomised controlled trial (RCT) of about 3000 patients randomised 50 : 50 to lower or higher phosphate ranges is required to answer the key question: does reducing phosphate levels improve clinical outcomes? Whether such a trial is technically possible is unknown; therefore, a study is necessary to inform the design and conduct of a future, definitive trial. Methodology. Dual centre prospective parallel group study: 100 dialysis patients randomized to lower (phosphate target 0.8 to 1.4 mmol/L) or higher range group (1.8 to 2.4 mmol/L). Non-calcium-containing phosphate binders and questionnaires will be used to achieve target phosphate. Primary endpoint: percentage successfully titrated to required range and percentage maintained in these groups over the maintenance period. Secondary endpoints: consent rate, drop-out rates, and cardiovascular events. Discussion. This study will inform design of a large definitive trial of the effect of phosphate on mortality and cardiovascular events in dialysis patients. If phosphate lowering improves outcomes, we would be reassured of the validity of this clinical practice. If, on the other hand, there is no improvement, a reassessment of resource allocation to therapies proven to improve outcomes will result. Trial Registration Number. This trial is registered with ISRCTN registration number ISRCTN24741445.
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Tagawa H, Irie J, Itoh A, Kusumoto Y, Kato M, Kobayashi N, Tanaka K, Morinaga R, Fujita M, Nakajima Y, Morimoto K, Sugizaki T, Kawano Y, Yamada S, Kawai T, Watanabe M, Itoh H. Bile acid binding resin improves hepatic insulin sensitivity by reducing cholesterol but not triglyceride levels in the liver. Diabetes Res Clin Pract 2015; 109:85-94. [PMID: 25981325 DOI: 10.1016/j.diabres.2015.04.025] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 03/16/2015] [Accepted: 04/15/2015] [Indexed: 01/06/2023]
Abstract
AIMS Bile acid binding resin (BAR) improves glycaemic control in patients with type 2 diabetes. Although the mechanism is hypothesised to involve the clearance of excess hepatic triglyceride, this hypothesis has not been examined in appropriately designed studies. Therefore, we investigated whether reduced hepatic triglyceride deposition is involved in BAR-mediated improvements in glycaemic control in spontaneous fatty liver diabetic mice without dietary interventions. METHODS Male 6-week-old fatty liver Shionogi (FLS) mice were fed a standard diet without or with 1.5% BAR (colestilan) for 6 weeks. Glucose tolerance, insulin sensitivity, hepatic lipid content, and gene expression were assessed. A liver X receptor (LXR) agonist was also administered to activate the LXR pathway. We also retrospectively analysed the medical records of 21 outpatients with type 2 diabetes who were treated with colestilan for ≥6 months. RESULTS BAR enhanced glucose tolerance and insulin sensitivity in FLS mice without altering fat mass. BAR improved hepatic insulin sensitivity, increased IRS2 expression, and decreased SREBP expression. BAR reduced hepatic cholesterol levels but not hepatic triglyceride levels. BAR also reduced the expression of LXR target genes, and LXR activation abolished the BAR-mediated improvements in glycaemic control. Colestilan significantly lowered serum cholesterol levels and improved glycaemic control in patients with type 2 diabetes. CONCLUSIONS BAR improved hepatic insulin resistance in FLS mice by reducing hepatic cholesterol without affecting hepatic triglyceride levels or body fat distribution. Our study revealed that BAR improves glycaemic control at least in part by downregulating the hepatic cholesterol-LXR-IRS2 pathway.
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Affiliation(s)
- Hirotsune Tagawa
- Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Junichiro Irie
- Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan.
| | - Arata Itoh
- Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Yukie Kusumoto
- Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Mari Kato
- Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Nana Kobayashi
- Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Kumiko Tanaka
- Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Rieko Morinaga
- Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Masataka Fujita
- Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Yuya Nakajima
- Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Kohkichi Morimoto
- Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Taichi Sugizaki
- Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Yoshinaga Kawano
- Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Satoru Yamada
- Diabetes Center, Kitasato Institute Hospital, Tokyo 108-8642, Japan
| | - Toshihide Kawai
- Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Mitsuhiro Watanabe
- Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Hiroshi Itoh
- Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan
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Ross S, D'Mello M, Anand SS, Eikelboom J, Stewart AFR, Samani NJ, Roberts R, Paré G. Effect of Bile Acid Sequestrants on the Risk of Cardiovascular Events: A Mendelian Randomization Analysis. ACTA ACUST UNITED AC 2015; 8:618-27. [PMID: 26043746 DOI: 10.1161/circgenetics.114.000952] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Accepted: 05/19/2015] [Indexed: 01/11/2023]
Abstract
BACKGROUND Statins lower low-density lipoprotein cholesterol (LDL-C) and risk of coronary artery disease (CAD), but they may be ineffective or not tolerated. Bile acid sequestrants (BAS) reduce LDL-C, yet their clinical efficacy on CAD remains controversial. METHODS AND RESULTS We conducted a systematic review and meta-analysis of randomized controlled trials to assess the effect of cholestyramine and colesevelam. We then used Mendelian randomization to estimate the effect of BAS on reducing the risk of CAD. First, we quantified the effect of rs4299376 (ABCG5/ABCG8), which affects the intestinal cholesterol absorption pathway targeted by BAS and then we used these estimates to predict the effect of BAS on CAD. Nineteen randomized controlled trials with a total of 7021 study participants were included. Cholestyramine 24 g/d was associated with a reduction in LDL-C of 23.5 mg/dL (95% confidence interval [CI] -26.8,-20.2; N=3806) and a trend toward reduced risk of CAD (odds ratio 0.81, 95% CI 0.70-1.02; P=0.07; N=3806), whereas colesevelam 3.75 g/d was associated with a reduction in LDL-C of 22.7 mg/dL (95% CI -28.3, -17.2; N=759). Based on the findings that rs4299376 was associated with a 2.75 mg/dL decrease in LDL-C and a 5% decrease in risk of CAD outcomes, we estimated that cholestyramine was associated with an odds ratio for CAD of 0.63 (95% CI 0.52-0.77; P=6.3×10(-6)) and colesevelam with an odds ratio of 0.64 (95% CI 0.52-0.79, P=4.3×10(-5)), which were not statistically different from BAS clinical trials (P>0.05). CONCLUSIONS The cholesterol lowering effect of BAS may translate into a clinically relevant reduction in CAD.
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Affiliation(s)
- Stephanie Ross
- From the Population Health Research Institute, Hamilton Health Sciences (S.R., M.D'M., S.S.A., J.E., G.P.), Department of Clinical Epidemiology & Biostatistics, Population Genomics Program (S.R., M.D'M., S.S.A., G.P.), Population Genomics Program, Chanchlani Research Centre (S.R., M.D'M., S.S.A., G.P.), Department of Medicine (S.S.A., J.E.), Department of Pathology & Molecular Medicine (G.P.), Thrombosis & Atherosclerosis Research Institute (G.P.), Hamilton Health Sciences, McMaster University, Hamilton; John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada (A.F.R.S., R.R.); Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (N.J.S.); National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); and Department of Medicine, University of Ottawa, Ottawa, ON, Canada (R.R.)
| | - Matthew D'Mello
- From the Population Health Research Institute, Hamilton Health Sciences (S.R., M.D'M., S.S.A., J.E., G.P.), Department of Clinical Epidemiology & Biostatistics, Population Genomics Program (S.R., M.D'M., S.S.A., G.P.), Population Genomics Program, Chanchlani Research Centre (S.R., M.D'M., S.S.A., G.P.), Department of Medicine (S.S.A., J.E.), Department of Pathology & Molecular Medicine (G.P.), Thrombosis & Atherosclerosis Research Institute (G.P.), Hamilton Health Sciences, McMaster University, Hamilton; John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada (A.F.R.S., R.R.); Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (N.J.S.); National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); and Department of Medicine, University of Ottawa, Ottawa, ON, Canada (R.R.)
| | - Sonia S Anand
- From the Population Health Research Institute, Hamilton Health Sciences (S.R., M.D'M., S.S.A., J.E., G.P.), Department of Clinical Epidemiology & Biostatistics, Population Genomics Program (S.R., M.D'M., S.S.A., G.P.), Population Genomics Program, Chanchlani Research Centre (S.R., M.D'M., S.S.A., G.P.), Department of Medicine (S.S.A., J.E.), Department of Pathology & Molecular Medicine (G.P.), Thrombosis & Atherosclerosis Research Institute (G.P.), Hamilton Health Sciences, McMaster University, Hamilton; John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada (A.F.R.S., R.R.); Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (N.J.S.); National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); and Department of Medicine, University of Ottawa, Ottawa, ON, Canada (R.R.)
| | - John Eikelboom
- From the Population Health Research Institute, Hamilton Health Sciences (S.R., M.D'M., S.S.A., J.E., G.P.), Department of Clinical Epidemiology & Biostatistics, Population Genomics Program (S.R., M.D'M., S.S.A., G.P.), Population Genomics Program, Chanchlani Research Centre (S.R., M.D'M., S.S.A., G.P.), Department of Medicine (S.S.A., J.E.), Department of Pathology & Molecular Medicine (G.P.), Thrombosis & Atherosclerosis Research Institute (G.P.), Hamilton Health Sciences, McMaster University, Hamilton; John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada (A.F.R.S., R.R.); Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (N.J.S.); National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); and Department of Medicine, University of Ottawa, Ottawa, ON, Canada (R.R.)
| | | | - Alexandre F R Stewart
- From the Population Health Research Institute, Hamilton Health Sciences (S.R., M.D'M., S.S.A., J.E., G.P.), Department of Clinical Epidemiology & Biostatistics, Population Genomics Program (S.R., M.D'M., S.S.A., G.P.), Population Genomics Program, Chanchlani Research Centre (S.R., M.D'M., S.S.A., G.P.), Department of Medicine (S.S.A., J.E.), Department of Pathology & Molecular Medicine (G.P.), Thrombosis & Atherosclerosis Research Institute (G.P.), Hamilton Health Sciences, McMaster University, Hamilton; John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada (A.F.R.S., R.R.); Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (N.J.S.); National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); and Department of Medicine, University of Ottawa, Ottawa, ON, Canada (R.R.)
| | - Nilesh J Samani
- From the Population Health Research Institute, Hamilton Health Sciences (S.R., M.D'M., S.S.A., J.E., G.P.), Department of Clinical Epidemiology & Biostatistics, Population Genomics Program (S.R., M.D'M., S.S.A., G.P.), Population Genomics Program, Chanchlani Research Centre (S.R., M.D'M., S.S.A., G.P.), Department of Medicine (S.S.A., J.E.), Department of Pathology & Molecular Medicine (G.P.), Thrombosis & Atherosclerosis Research Institute (G.P.), Hamilton Health Sciences, McMaster University, Hamilton; John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada (A.F.R.S., R.R.); Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (N.J.S.); National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); and Department of Medicine, University of Ottawa, Ottawa, ON, Canada (R.R.)
| | - Robert Roberts
- From the Population Health Research Institute, Hamilton Health Sciences (S.R., M.D'M., S.S.A., J.E., G.P.), Department of Clinical Epidemiology & Biostatistics, Population Genomics Program (S.R., M.D'M., S.S.A., G.P.), Population Genomics Program, Chanchlani Research Centre (S.R., M.D'M., S.S.A., G.P.), Department of Medicine (S.S.A., J.E.), Department of Pathology & Molecular Medicine (G.P.), Thrombosis & Atherosclerosis Research Institute (G.P.), Hamilton Health Sciences, McMaster University, Hamilton; John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada (A.F.R.S., R.R.); Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (N.J.S.); National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); and Department of Medicine, University of Ottawa, Ottawa, ON, Canada (R.R.)
| | - Guillaume Paré
- From the Population Health Research Institute, Hamilton Health Sciences (S.R., M.D'M., S.S.A., J.E., G.P.), Department of Clinical Epidemiology & Biostatistics, Population Genomics Program (S.R., M.D'M., S.S.A., G.P.), Population Genomics Program, Chanchlani Research Centre (S.R., M.D'M., S.S.A., G.P.), Department of Medicine (S.S.A., J.E.), Department of Pathology & Molecular Medicine (G.P.), Thrombosis & Atherosclerosis Research Institute (G.P.), Hamilton Health Sciences, McMaster University, Hamilton; John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada (A.F.R.S., R.R.); Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (N.J.S.); National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); and Department of Medicine, University of Ottawa, Ottawa, ON, Canada (R.R.).
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Bohannon NJV. Individualized Treatment of Type 2 Diabetes Mellitus Using Noninsulin Agents: Clinical Considerations for the Primary Care Physician. Postgrad Med 2015; 124:95-108. [DOI: 10.3810/pgm.2012.07.2572] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Abstract
Purpose In addition to lowering hemoglobin A1C, colesevelam has been shown to improve the atherogenic lipoprotein profile of subjects with type 2 diabetes mellitus (T2DM) when used in combination with metformin and/or sulfonylureas. A recent study evaluated the effects of colesevelam as antidiabetes monotherapy in adults with T2DM who had inadequate glycemic control (hemoglobin A1C ≥7.5 to ≤9.5 %) with diet and exercise alone; we report here the effects on lipoprotein particle subclasses. Methods Subjects were randomized to receive oral colesevelam 3.75 g/day (n = 176) or placebo (n = 181) for 24 weeks. Changes in lipoprotein particle subclasses were determined by nuclear magnetic resonance spectroscopy. Results At Week 24 with last observation carried forward, colesevelam produced a reduction in total low-density lipoprotein (LDL) particle concentration (baseline: 1,611 nmol/L; least-squares [LS] mean treatment difference: −143 nmol/L, p < 0.0001) versus placebo; reductions were also seen in large, small, and very small LDL particle concentrations (all p < 0.05). There was also a reduction in total very low-density lipoprotein (VLDL) and chylomicron particle concentration (baseline: 88 nmol/L; LS mean treatment difference: −1 nmol/L, p = 0.82) that resulted from a lowering in small VLDL particle concentration (baseline: 45 nmol/L; LS mean treatment difference: −5 nmol/L, p = 0.03). In addition, with colesevelam there was an increase in total high-density lipoprotein (HDL) particle concentration versus placebo (baseline: 31 μmol/L; LS mean treatment difference: +0.6 μmol/L, p = 0.20), due to increases in the large (baseline: 5 μmol/L; LS mean treatment difference: +0.5 μmol/L, p = 0.007) and medium (baseline: 3 μmol/L; LS mean treatment difference: +0.8 μmol/L, p = 0.02) HDL subclasses. Conclusions Colesevelam monotherapy in subjects with T2DM resulted in generally favorable changes in certain lipoprotein subclass profiles compared with placebo.
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Tran L, Zielinski A, Roach AH, Jende JA, Householder AM, Cole EE, Atway SA, Amornyard M, Accursi ML, Shieh SW, Thompson EE. Pharmacologic treatment of type 2 diabetes: oral medications. Ann Pharmacother 2015; 49:540-56. [PMID: 25667196 DOI: 10.1177/1060028014558289] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE To review the oral and injectable pharmacologic treatment options for type 2 diabetes. DATA SOURCES A literature search was conducted using PubMed electronic database for studies published in English between 1993 and September 2014. Search terms included diabetes mellitus, type 2 diabetes, and the individual name for each antidiabetic medication reviewed. In addition, manual searches were performed for cross-references from publications. Package inserts, United States Food and Drug Administration (FDA) Web site, Institute for Safe Medication Practices Web site, American Diabetes Association Web site and scientific session poster presentations, and individual drug company Web pages were also reviewed. STUDY SELECTION AND DATA EXTRACTION This review focused on information elucidated over the past 10 years to assist prescribers in choosing optimal therapy based on individual patient characteristics. Studies leading to the approval of or raising safety concerns for the antidiabetic medications reviewed in this article were included. DATA SYNTHESIS In the past 10 years, there have been 4 novel oral antidiabetic medication classes and 9 new injectable agents and insulin products approved by the FDA for the treatment of type 2 diabetes as well as new information regarding the safety and use of several older antidiabetic medication classes. The distinctions were reviewed for each individual agent, and a comparison was completed if there was more than one agent in a particular therapeutic class. Using current information available, select investigational agents in phase III trials or those with a pending new drug application were highlighted. CONCLUSION There are now 9 distinct oral pharmacologic classes and a variety of insulin and noninsulin injectable medications available for the treatment of type 2 diabetes. Metformin remains the first-line treatment option for most patients. When considering options for alternative or additional treatment, prescribers must weigh the benefits and risks using individual patient characteristics.
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Affiliation(s)
- Linda Tran
- Chalmers P. Wylie Veterans Affairs Ambulatory Care Center, Columbus, OH, USA
| | - Angela Zielinski
- Chalmers P. Wylie Veterans Affairs Ambulatory Care Center, Columbus, OH, USA
| | - Arpi H Roach
- Chalmers P. Wylie Veterans Affairs Ambulatory Care Center, Columbus, OH, USA
| | - Jennifer A Jende
- Chalmers P. Wylie Veterans Affairs Ambulatory Care Center, Columbus, OH, USA
| | | | - Emily E Cole
- Chalmers P. Wylie Veterans Affairs Ambulatory Care Center, Columbus, OH, USA
| | - Shuruq A Atway
- Chalmers P. Wylie Veterans Affairs Ambulatory Care Center, Columbus, OH, USA
| | - Melinda Amornyard
- Chalmers P. Wylie Veterans Affairs Ambulatory Care Center, Columbus, OH, USA
| | - Mallory L Accursi
- Chalmers P. Wylie Veterans Affairs Ambulatory Care Center, Columbus, OH, USA
| | - Suzanna W Shieh
- Chalmers P. Wylie Veterans Affairs Ambulatory Care Center, Columbus, OH, USA
| | - Erin E Thompson
- Chalmers P. Wylie Veterans Affairs Ambulatory Care Center, Columbus, OH, USA
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Abstract
Table 3 provides an overview of the oral antihyperglycemic drugs reviewed in this article. A 2011 meta-analysis by Bennett and colleagues found low or insufficient quality of evidence favoring an initial choice of metformin, SUs, glinides, TZDs, or (table see text) DPP-4 inhibitors (alpha-glucosidase inhibitors, bromocriptine mesylate, and SGLT2 inhibitors were not included in this meta-analysis) with regard to the outcomes measures of all-cause mortality, cardiovascular events and mortality, and incidence of microvascular disease (retinopathy, nephropathy, and neuropathy) in previously healthy individuals with newly diagnosed T2DM. Likewise, the Bennett and colleagues meta-analysis judged these drugs to be of roughly equal efficacy with regard to reduction of HbA1c (1%–1.6%) from the pretreatment baseline. The ADOPT clinical trial of 3 different and, at the time, popular, oral monotherapies for T2DM provides support for the consensus recommendation of metformin as first-line therapy. The ADOPT trial showed slightly superior HbA1c reduction for rosiglitazone compared with metformin, which was in turn superior to glyburide. However, significant adverse events, including edema, weight gain, and fractures, were more common in the rosiglitazone-treated patients. The implication of this trial is that the combination of low cost, low risk, minimal adverse effects, and efficacy of metformin justifies use of this agent as the cornerstone of oral drug treatment of T2DM. Judicious use of metformin in groups formerly thought to be at high risk for lactic acidosis (ie, those with CHF, chronic kidney disease [eGFR >30 mL/min/1.73 m2], and the elderly) may be associated with mortality benefit rather than increased risk. Secondary and tertiary add-on drug therapy should be individualized based on cost, personal preferences, and overall treatment goals, taking into account the wishes and priorities of the patient.
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Affiliation(s)
- Stephen A Brietzke
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Missouri-Columbia, DC043 UMHC, 1 Hospital Drive, Columbia, MO 65212, USA.
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Evidence of insulin resistance in adult uncomplicated malaria: result of a two-year prospective study. Malar Res Treat 2014; 2014:136148. [PMID: 25587486 PMCID: PMC4284981 DOI: 10.1155/2014/136148] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 11/25/2014] [Accepted: 12/08/2014] [Indexed: 01/11/2023] Open
Abstract
The study aimed at investigating the effects of adult uncomplicated malaria on insulin resistance. Fasting levels of blood glucose (FBG), glycosylated hemoglobin (HbA1c), and serum insulin were measured in 100 diabetics and 100 age-matched controls before and during Plasmodium falciparum malaria. Insulin resistance and beta cell function were computed by homeostatic models assessment of insulin resistance (HOMAIR) and beta cell function (HOMAB) formulae, respectively. Body mass index (BMI) was computed. At baseline, diabetics had significantly (P < 0.05) higher levels of BMI, FBG, HbA1c, and HOMAIR but lower level of HOMAB than controls. Baseline insulin levels were comparable (P > 0.05) between the two study groups. During malaria, diabetics maintained significantly (P < 0.05) higher levels of BMI, FBG, and HbA1c but lower levels of insulin and HOMAB than controls. Malaria-induced HOMAIR levels were comparable (P > 0.05) between the two study groups but higher than baseline levels. Apart from BMI and HOMAB, mean levels of all the remaining parameters increased in malaria-infected controls. In malaria-infected diabetics, significant (P < 0.05) increase was only observed for insulin and HOMAIR but not the other measured parameters. Uncomplicated malaria increased insulin resistance in diabetics and controls independent of BMI. This finding may have implications for the evolution of T2DM in malaria-endemic regions.
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Valencia WM, Florez H. Pharmacological treatment of diabetes in older people. Diabetes Obes Metab 2014; 16:1192-203. [PMID: 25073699 DOI: 10.1111/dom.12362] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Revised: 07/23/2014] [Accepted: 07/23/2014] [Indexed: 12/21/2022]
Abstract
The pharmacological management of diabetes in older people is complex and challenging. It requires a comprehensive understanding of the individual beyond the diabetes itself. Through the ageing years, the older individual presents with diabetes-related and non-related comorbidities and complications, develops functional limitations and psychological issues, and may lack social support and access to care. A disturbance in these categories, known as the four geriatric domains, will negatively affect diabetes self-management and self-efficacy, leading to poor outcomes and complications. Furthermore, older people with diabetes may be more interested in the management of other chronic conditions such as pain or impaired mobility, and diabetes may be lower in their list of priorities. Proper education must be provided to the older individual and caregivers, with continuous monitoring and counselling, especially when pharmacological interventions offer risks of side effects, adverse reactions and interactions with other medications. Informed shared medical decisions will help to improve adherence to the regimen; however, such discussions ought to be based on the best evidence available, which is unfortunately limited in this age group. We performed a review focused on pharmacological agents and summarize current evidence on their use for the treatment of diabetes in older people. We encourage clinicians to investigate and incorporate the four geriatrics domains in the selection and monitoring of these agents.
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Affiliation(s)
- W M Valencia
- Geriatrics Research, Education and Clinical Center, Miami Bruce W. Carter VA Medical Center, Miami, FL, USA; Department of Public Health Sciences, Division of Epidemiology, University of Miami Miller School of Medicine, Miami, FL, USA
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Du YF, Ou HY, Beverly EA, Chiu CJ. Achieving glycemic control in elderly patients with type 2 diabetes: a critical comparison of current options. Clin Interv Aging 2014; 9:1963-80. [PMID: 25429208 PMCID: PMC4241951 DOI: 10.2147/cia.s53482] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The prevalence of type 2 diabetes mellitus (T2DM) is increasing in the elderly. Because of the unique characteristics of elderly people with T2DM, therapeutic strategy and focus should be tailored to suit this population. This article reviews the guidelines and studies related to older people with T2DM worldwide. A few important themes are generalized: 1) the functional and cognitive status is critical for older people with T2DM considering their life expectancy compared to younger counterparts; 2) both severe hypoglycemia and persistent hyperglycemia are deleterious to older adults with T2DM, and both conditions should be avoided when determining therapeutic goals; 3) recently developed guidelines emphasize the avoidance of hypoglycemic episodes in older people, even in the absence of symptoms. In addition, we raise the concern of glycemic variability, and discuss the rationale for the selection of current options in managing this patient population.
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Affiliation(s)
- Ye-Fong Du
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Horng-Yih Ou
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Elizabeth A Beverly
- Department of Social Medicine, Ohio University Heritage College of Osteopathic Medicine, Athens, OH, USA
| | - Ching-Ju Chiu
- Institute of Gerontology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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