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Sha D, Yuan M, Zhang L, Li H. Characterization of insulin and bile acid complexes in liposome by different mass spectrometry techniques. Anal Bioanal Chem 2025; 417:1635-1647. [PMID: 39870873 DOI: 10.1007/s00216-025-05753-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 12/28/2024] [Accepted: 01/17/2025] [Indexed: 01/29/2025]
Abstract
Insulin bound with ligand molecules can improve its bioavailability in oral formulations. In this work, the interactions between insulin and bile acids of taurocholic acid (TCA) and glycocholic acid (GCA) are characterized using different mass spectrometry (MS) methods. Electrospray (ESI)-MS analysis revealed that GCA and TCA could interact with insulin individually or together through non-covalent bonds, and the products included mGCA-insulin, nTCA-insulin, and mGCA-nTCA-insulin complexes. Their binding stoichiometry, relative intensity ratio (IRa), and binding affinity were determined. ESI-MS/MS data and the calculated association constants both suggest that TCA has stronger affinity to insulin than GCA. The mixtures of various insulin, GCA, and TCA complexes with different charge states were separated, and distinct trend lines were observed using ion mobility mass spectrometry (IMMS). Moreover, liposomes containing insulin and GCA and/or TCA were prepared, and directly characterized using ESI-MS, and the interaction products of insulin with GCA and TCA were found in the liposome formulation. AutoDock was used to simulate molecular binding and select binding sites between insulin and GCA or TCA to explore the interaction mechanisms. The findings in this work could help understand the mechanism of action of insulin protection with bile acids in the body.
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Affiliation(s)
- Dandan Sha
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Jiangsu Key Laboratory of Biomedical Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing, 210023, China
| | - Minghui Yuan
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Jiangsu Key Laboratory of Biomedical Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing, 210023, China
| | - Lin Zhang
- Waters Corporation (Shanghai) Ltd, Shanghai, 200126, China
| | - Hongli Li
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Jiangsu Key Laboratory of Biomedical Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing, 210023, China.
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Radkiewicz C, Ludvigsson JF, Sparrelid E, Emilsson L. Pancreatic cancer risk after benign gallbladder disease: A Swedish population-based cohort study. Eur J Cancer 2025; 214:115140. [PMID: 39579639 DOI: 10.1016/j.ejca.2024.115140] [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: 05/08/2024] [Revised: 11/04/2024] [Accepted: 11/12/2024] [Indexed: 11/25/2024]
Abstract
AIM The purpose of this nationwide registry-based cohort study was to outline pancreatic cancer risk after benign gallbladder disease (GBD). Anatomically adjacent cancers were investigated to address incidental findings. METHODS We included all Swedes aged 20-79 years with histologically confirmed GBD (cholecystitis and/or cholecystectomy) in 1992-2016 and five matched non-exposed population comparators. Follow-up started one month after GBD and incidence rates (IR) and hazard ratios (HR) with 95 % confidence intervals (CI) up to 15 years after GBD were estimated using Poisson and Cox regression, respectively. Fully adjusted models included sex, age, year, education, type 2 diabetes, obesity, smoking-, and alcohol-related disorders. Analyses were stratified by follow-up and flexible parametric models applied to assess time-varying effects. Interaction models were used to identify patient groups at risk. RESULTS 680 and 1890 incident pancreatic cancers were detected over 15 years in 130907 GBD exposed and 571618 non-exposed, respectively. An excess pancreatic cancer risk was mainly seen within the first 2 years; IR: 84 [95 % CI 73,95] versus 31 [95 % CI 27,34] per 100000 person-years corresponding to an HR of 2.74 [95 % CI 2.31,3.25]. The same pattern was noted for duodenal cancer while primary liver cancer risk was elevated across follow-up. An initial extrahepatic biliary cancer risk elevation shifted to a reduction over time. The 2-year pancreatic cancer risk was augmented in younger (age 20-49) individuals, HR 7.64 [95 % CI 3.73,15.65]. CONCLUSION Our findings urge more studies on the clinical follow-up the first years after cholecystitis to detect early pancreatic cancer.
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Affiliation(s)
- Cecilia Radkiewicz
- Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Surgery and Oncology, Capio Sankt Görans Sjukhus, Stockholm, Sweden.
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden
| | - Ernesto Sparrelid
- Division of Surgery and Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Louise Emilsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; General Practice Research Unit (AFE) and Department of General Practice, Institute of Health and Society, University of Oslo, Oslo, Norway; Vårdcentralen Värmlands Nysäter and Centre for Clinical Research, County Council of Värmland, Värmland, Sweden
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Wang Y, Yu J, Chen B, Jin W, Wang M, Chen X, Jian M, Sun L, Piao C. Bile acids as a key target: traditional Chinese medicine for precision management of insulin resistance in type 2 diabetes mellitus through the gut microbiota-bile acids axis. Front Endocrinol (Lausanne) 2024; 15:1481270. [PMID: 39720247 PMCID: PMC11666381 DOI: 10.3389/fendo.2024.1481270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 11/25/2024] [Indexed: 12/26/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease caused by insulin resistance (IR) and insufficient insulin secretion. Its characteristic pathophysiological processes involve the interaction of multiple mechanisms. In recent years, globally, the prevalence of T2DM has shown a sharp rise due to profound changes in socio-economic structure, the persistent influence of environmental factors, and the complex role of genetic background. It is worth noting that most T2DM patients show significant IR, which further exacerbates the difficulty of disease progression and prevention. In the process of extensively exploring the pathogenesis of T2DM, the dynamic equilibrium of gut microbes and its diverse metabolic activities have increasingly emphasized its central role in the pathophysiological process of T2DM. Bile acids (BAs) metabolism, as a crucial link between gut microbes and the development of T2DM, not only precisely regulates lipid absorption and metabolism but also profoundly influences glucose homeostasis and energy balance through intricate signaling pathways, thus playing a pivotal role in IR progression in T2DM. This review aims to delve into the specific mechanism through which BAs contribute to the development of IR in T2DM, especially emphasizing how gut microbes mediate the metabolic transformation of BAs based on current traditional Chinese medicine research. Ultimately, it seeks to offer new insights into the prevention and treatment of T2DM. Diet, genetics, and the environment intricately sculpt the gut microbiota and BAs metabolism, influencing T2DM-IR. The research has illuminated the significant impact of single herbal medicine, TCM formulae, and external therapeutic methods such as electroacupuncture on the BAs pool through perturbations in gut microbiota structure. This interaction affects glucose and lipid metabolism as well as insulin sensitivity. Additionally, multiple pathways including BA-FXR-SHP, BA-FXR-FGFR15/19, BA-FXR-NLRP3, BA-TGR5-GLP-1, BAs-TGR5/FXR signaling pathways have been identified through which the BAs pool significantly alter blood glucose levels and improve IR. These findings offer novel approaches for enhancing IR and managing metabolic disorders among patients with T2DM.
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Affiliation(s)
- Yu Wang
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Jing Yu
- Department of Endocrinology, the Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Binqin Chen
- Applicants with Equivalent Academic Qualifications for Master Degree, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- Shenzhen Hospital (Futian), Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Wenqi Jin
- Research Center of Traditional Chinese Medicine, the Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Meili Wang
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Xuenan Chen
- Research Center of Traditional Chinese Medicine, the Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Mengqiong Jian
- Research Center of Traditional Chinese Medicine, the Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, China
- Northeast Asian Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Liwei Sun
- Research Center of Traditional Chinese Medicine, the Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Chunli Piao
- Shenzhen Hospital (Futian), Guangzhou University of Chinese Medicine, Shenzhen, China
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Hernández-Martín M, Garcimartín A, Bocanegra A, Macho-González A, García-Fernández RA, de Pascual-Teresa S, Redondo-Castillejo R, Bastida S, Sánchez-Muniz FJ, Benedí J, López-Oliva ME. Silicon-Enriched Meat Ameliorates Diabetic Dyslipidemia by Improving Cholesterol, Bile Acid Metabolism and Ileal Barrier Integrity in Rats with Late-Stage Type 2 Diabetes. Int J Mol Sci 2024; 25:11405. [PMID: 39518958 PMCID: PMC11547133 DOI: 10.3390/ijms252111405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 10/07/2024] [Accepted: 10/11/2024] [Indexed: 11/16/2024] Open
Abstract
Silicon as a functional ingredient of restructured meat (RM) shows antidiabetic and hypocholesterolemic effects in a type 2 diabetes mellitus (T2DM) rat model. The present paper investigated the mechanisms involved in this cholesterol-lowering effect by studying the impact of silicon-RM consumption on bile acid (BA) and cholesterol metabolism. In addition, the main effects of cecal BA and short-chain fatty acids derived from the microbiota on intestinal barrier integrity were also tested. Rats were fed an RM high-saturated-fat, high-cholesterol diet (HSFHCD) combined with a low dose of streptozotocin plus nicotinamide injection (LD group) and for an 8 wk. period. Silicon-RM was included in the HSFHCD as a functional food (LD-Si group). An early-stage T2DM group fed a high-saturated-fat diet (ED group) was used as a reference. Silicon decreased the BA pool with a higher hydrophilic BA profile and a lower ability to digest fat and decreased the damaging effects, increasing the occludin levels and the integrity of the intestinal barrier. The ileal BA uptake and hepatic BA synthesis through CYP7A1 were reduced by FXR/FGF15 signaling activation. The silicon up-regulated the hepatic and ileal FXR and LXRα/β, improving transintestinal cholesterol (TICE), biliary BA and cholesterol effluxes. The inclusion of silicon in meat products could be used as a new therapeutic nutritional tool in the treatment of diabetic dyslipidemia.
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Affiliation(s)
- Marina Hernández-Martín
- Departmental Section of Physiology, Pharmacy School, Complutense University of Madrid, 28040 Madrid, Spain;
- AFUSAN Research Group, Sanitary Research Institute of the San Carlos Clinical Hospital (IdISSC), 28040 Madrid, Spain; (A.G.); (A.B.); (A.M.-G.); (R.R.-C.); (S.B.); (F.J.S.-M.); (J.B.)
| | - Alba Garcimartín
- AFUSAN Research Group, Sanitary Research Institute of the San Carlos Clinical Hospital (IdISSC), 28040 Madrid, Spain; (A.G.); (A.B.); (A.M.-G.); (R.R.-C.); (S.B.); (F.J.S.-M.); (J.B.)
- Pharmacology, Pharmacognosy and Botany Department, Pharmacy School, Complutense University of Madrid, 28040 Madrid, Spain
| | - Aránzazu Bocanegra
- AFUSAN Research Group, Sanitary Research Institute of the San Carlos Clinical Hospital (IdISSC), 28040 Madrid, Spain; (A.G.); (A.B.); (A.M.-G.); (R.R.-C.); (S.B.); (F.J.S.-M.); (J.B.)
- Pharmacology, Pharmacognosy and Botany Department, Pharmacy School, Complutense University of Madrid, 28040 Madrid, Spain
| | - Adrián Macho-González
- AFUSAN Research Group, Sanitary Research Institute of the San Carlos Clinical Hospital (IdISSC), 28040 Madrid, Spain; (A.G.); (A.B.); (A.M.-G.); (R.R.-C.); (S.B.); (F.J.S.-M.); (J.B.)
- Nutrition and Food Science Department, Pharmacy School, Complutense University of Madrid, 28040 Madrid, Spain
| | - Rosa A. García-Fernández
- Animal Medicine and Surgery Department, Veterinary School, Complutense University of Madrid, 28040 Madrid, Spain;
| | - Sonia de Pascual-Teresa
- Department of Metabolism and Nutrition, Institute of Food Science, Technology and Nutrition (ICTAN-CSIC), 28040 Madrid, Spain;
| | - Rocío Redondo-Castillejo
- AFUSAN Research Group, Sanitary Research Institute of the San Carlos Clinical Hospital (IdISSC), 28040 Madrid, Spain; (A.G.); (A.B.); (A.M.-G.); (R.R.-C.); (S.B.); (F.J.S.-M.); (J.B.)
- Pharmacology, Pharmacognosy and Botany Department, Pharmacy School, Complutense University of Madrid, 28040 Madrid, Spain
| | - Sara Bastida
- AFUSAN Research Group, Sanitary Research Institute of the San Carlos Clinical Hospital (IdISSC), 28040 Madrid, Spain; (A.G.); (A.B.); (A.M.-G.); (R.R.-C.); (S.B.); (F.J.S.-M.); (J.B.)
- Nutrition and Food Science Department, Pharmacy School, Complutense University of Madrid, 28040 Madrid, Spain
| | - Francisco J. Sánchez-Muniz
- AFUSAN Research Group, Sanitary Research Institute of the San Carlos Clinical Hospital (IdISSC), 28040 Madrid, Spain; (A.G.); (A.B.); (A.M.-G.); (R.R.-C.); (S.B.); (F.J.S.-M.); (J.B.)
- Nutrition and Food Science Department, Pharmacy School, Complutense University of Madrid, 28040 Madrid, Spain
| | - Juana Benedí
- AFUSAN Research Group, Sanitary Research Institute of the San Carlos Clinical Hospital (IdISSC), 28040 Madrid, Spain; (A.G.); (A.B.); (A.M.-G.); (R.R.-C.); (S.B.); (F.J.S.-M.); (J.B.)
- Pharmacology, Pharmacognosy and Botany Department, Pharmacy School, Complutense University of Madrid, 28040 Madrid, Spain
| | - Mª Elvira López-Oliva
- Departmental Section of Physiology, Pharmacy School, Complutense University of Madrid, 28040 Madrid, Spain;
- AFUSAN Research Group, Sanitary Research Institute of the San Carlos Clinical Hospital (IdISSC), 28040 Madrid, Spain; (A.G.); (A.B.); (A.M.-G.); (R.R.-C.); (S.B.); (F.J.S.-M.); (J.B.)
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Singh V, Mahra K, Jung D, Shin JH. Gut Microbes in Polycystic Ovary Syndrome and Associated Comorbidities; Type 2 Diabetes, Non-Alcoholic Fatty Liver Disease (NAFLD), Cardiovascular Disease (CVD), and the Potential of Microbial Therapeutics. Probiotics Antimicrob Proteins 2024; 16:1744-1761. [PMID: 38647957 DOI: 10.1007/s12602-024-10262-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/13/2024] [Indexed: 04/25/2024]
Abstract
Polycystic ovary syndrome (PCOS) is one of the most common endocrine anomalies among females of reproductive age, highlighted by hyperandrogenism. PCOS is multifactorial as it can be associated with obesity, insulin resistance, low-grade chronic inflammation, and dyslipidemia. PCOS also leads to dysbiosis by lowering microbial diversity and beneficial microbes, such as Faecalibacterium, Roseburia, Akkermenisa, and Bifidobacterium, and by causing a higher load of opportunistic pathogens, such as Escherichia/Shigella, Fusobacterium, Bilophila, and Sutterella. Wherein, butyrate producers and Akkermansia participate in the glucose uptake by inducing glucagon-like peptide-1 (GLP-1) and glucose metabolism, respectively. The abovementioned gut microbes also maintain the gut barrier function and glucose homeostasis by releasing metabolites such as short-chain fatty acids (SCFAs) and Amuc_1100 protein. In addition, PCOS-associated gut is found to be higher in gut-microbial enzyme β-glucuronidase, causing the de-glucuronidation of conjugated androgen, making it susceptible to reabsorption by entero-hepatic circulation, leading to a higher level of androgen in the circulatory system. Overall, in PCOS, such dysbiosis increases the gut permeability and LPS in the systemic circulation, trimethylamine N-oxide (TMAO) in the circulatory system, chronic inflammation in the adipose tissue and liver, and oxidative stress and lipid accumulation in the liver. Thus, in women with PCOS, dysbiosis can promote the progression and severity of type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases (CVD). To alleviate such PCOS-associated complications, microbial therapeutics (probiotics and fecal microbiome transplantation) can be used without any side effects, unlike in the case of hormonal therapy. Therefore, this study sought to understand the mechanistic significance of gut microbes in PCOS and associated comorbidities, along with the role of microbial therapeutics that can ease the life of PCOS-affected women.
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Affiliation(s)
- Vineet Singh
- Department of Applied Biosciences, Kyungpook National University, Daegu, South Korea
| | - Kanika Mahra
- Department of Applied Biosciences, Kyungpook National University, Daegu, South Korea
| | - DaRyung Jung
- Department of Applied Biosciences, Kyungpook National University, Daegu, South Korea
| | - Jae-Ho Shin
- Department of Applied Biosciences, Kyungpook National University, Daegu, South Korea.
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Ravat FK, Goswami JR, Nair SM, Thummar KN. A review of metabolic and microbial influences on women with polycystic ovarian syndrome. Steroids 2024; 212:109512. [PMID: 39278517 DOI: 10.1016/j.steroids.2024.109512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/08/2024] [Accepted: 09/11/2024] [Indexed: 09/18/2024]
Abstract
INTRODUCTION Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine and metabolic disorder affecting reproductive-aged women worldwide. Characterized by irregular menstruation, signs of hyperandrogenism, polycystic ovaries via ultrasound ovarian dysfunction. AREA COVERED The review delves into the intricate pathophysiological mechanisms underlying the syndrome. Dysregulation of the hypothalamic-pituitary-ovarian axis, IR, obesity, and hyperandrogenism contribute to anovulation and follicular dysfunction which is associated with gut dysbiosis, bile metabolites, and an unhealthy diet. Metabolomics and genomics analyses offer insights into the metabolism of bile acids (BAs) and gut microbiota dysbiosis in PCOS. BAs, crucial for metabolic regulation, are influenced by microbes, impacting hormonal balance. Disruptions in gut microbiota contribute to hormonal dysregulation. Interconnected pathways involving BAs and gut microbiota are pivotal in PCOS. Therapeutic implications include a healthy diet, exercise, and interventions targeting gut microbiota modulation and BAs metabolite to alleviate PCOS symptoms and improve metabolic health. CONCLUSION PCOS requires a multifaceted, multidisciplinary approach for effective management, including lifestyle changes, medications, and emerging therapies. Tailored strategies considering individual needs and personalized treatment plans are crucial for successful PCOS management. Despite existing knowledge, comprehensive investigations are needed to bridge research gaps and discern the interconnected pathways linking the development of PCOS and the gut-bile axis which are interconnected with metabolic disorders and the development of PCOS. Gut microbiota and hormonal regulation offer promising avenues for innovative therapeutic strategies aimed at addressing the root causes of PCOS and improving patient outcomes.
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Affiliation(s)
- Foram K Ravat
- Gujarat Technological University School of Pharmacy, Gandhinagar, Gujarat, India.
| | - Janki R Goswami
- Gujarat Technological University School of Pharmacy, Gandhinagar, Gujarat, India.
| | - Sneha M Nair
- Gujarat Technological University School of Pharmacy, Gandhinagar, Gujarat, India.
| | - Kashyap N Thummar
- Gujarat Technological University School of Pharmacy, Gandhinagar, Gujarat, India.
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He S, Li L, Yao Y, Su J, Lei S, Zhang Y, Zeng H. Bile acid and its bidirectional interactions with gut microbiota: a review. Crit Rev Microbiol 2024; 50:684-701. [PMID: 37766478 DOI: 10.1080/1040841x.2023.2262020] [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: 06/27/2023] [Revised: 09/14/2023] [Accepted: 09/18/2023] [Indexed: 09/29/2023]
Abstract
Bile acids (BAs) are an important metabolite produced by cholesterol catabolism. It serves important roles in glucose and lipid metabolism and host-microbe interaction. Recent research has shown that different gut-microbiota can secrete different metabolic-enzymes to mediate the deconjugation, dehydroxylation and epimerization of BAs. In addition, microbes mediate BAs transformation and exert physiological functions in metabolic diseases may have a potentially close relationship with diet. Therefore, elaborating the pathways by which gut microbes mediate the transformation of BAs through enzymatic reactions involved are principal to understand the mechanism of effects between dietary patterns, gut microbes and BAs, and to provide theoretical knowledge for the development of functional foods to regulate metabolic diseases. In the present review, we summarized works on the physiological function of BAs, as well as the classification and composition of BAs in different animal models and its organs. In addition, we mainly focus on the bidirectional interactions of gut microbes with BAs transformation, and discuss the effects of diet on microbial transformation of BAs. Finally, we raised the question of further in-depth investigation of the food-gut microbial-BAs relationship, which might contribute to the improvement of metabolic diseases through dietary interventions in the future.
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Affiliation(s)
- Shuqi He
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, China
- Fujian Provincial Key Laboratory of Quality Science and Processing Technology in Special Starch, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Lanxin Li
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, China
- Fujian Provincial Key Laboratory of Quality Science and Processing Technology in Special Starch, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Yingning Yao
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, China
- Fujian Provincial Key Laboratory of Quality Science and Processing Technology in Special Starch, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Jinhan Su
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, China
- Fujian Provincial Key Laboratory of Quality Science and Processing Technology in Special Starch, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Suzhen Lei
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, China
- Fujian Provincial Key Laboratory of Quality Science and Processing Technology in Special Starch, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Yi Zhang
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, China
- Fujian Provincial Key Laboratory of Quality Science and Processing Technology in Special Starch, Fujian Agriculture and Forestry University, Fuzhou, China
- Engineering Research Centre of Fujian-Taiwan Special Marine Food Processing and Nutrition, Ministry of Education, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Hongliang Zeng
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, China
- Fujian Provincial Key Laboratory of Quality Science and Processing Technology in Special Starch, Fujian Agriculture and Forestry University, Fuzhou, China
- Engineering Research Centre of Fujian-Taiwan Special Marine Food Processing and Nutrition, Ministry of Education, Fujian Agriculture and Forestry University, Fuzhou, China
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Zhou T, Du Z, Luo Z, Li X, Wu D, Huang Y, Yong K, Yao X, Shen L, Yu S, Yan Z, Cao S. Alteration of Fecal Microbiota, Fecal Metabolites, and Serum Metabolites in Dairy Cows with Pre-Retained Placenta. Metabolites 2024; 14:386. [PMID: 39057709 PMCID: PMC11279091 DOI: 10.3390/metabo14070386] [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: 06/25/2024] [Revised: 07/11/2024] [Accepted: 07/12/2024] [Indexed: 07/28/2024] Open
Abstract
Retained placenta (RP) affects lactation and fertility in dairy cows and causes economic losses to the dairy industry. Therefore, screening for early warning of this disease is important. This study used multi omics techniques to reveal the metabolic differences of dairy cows before RP onset and to find potential warning markers. Fecal samples and serum samples of 90 healthy Holstein cows were collected 7 days pre-calving; 10 healthy and 10 RP cows were enrolled according to normal expulsion of fetal membranes after calving. Fecal samples were subjected to 16S rRNA sequencing and untargeted metabolomics analysis, while plasma was analyzed using targeted metabolomics. Pathogenic bacteria levels increased in the intestines of cows with RP compared to those in healthy cows. Lipid metabolites constituted the largest proportion of differential metabolites between feces and plasma. Six potential warning markers for RP in cows were identified, including two fecal microbiomics markers (Oscillospiraceae UCG-005 and Escherichia-Shigella), one fecal untargeted metabolomics marker (N-acetylmuramic acid), and three plasma targeted metabolomics markers (glycylcholic acid-3 sulfate, 7-ketolithocholic acid, and 12-ketolithocholic acid). These biomarkers can predict RP occurrence in the early perinatal period. These results lay a theoretical foundation for early nutritional intervention and pathogenesis research in dairy cows.
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Affiliation(s)
- Tao Zhou
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
- Lanzhou Institute of Animal Husbandry and Veterinary Pharmaceutical, Chinese Academy of Agricultural Sciences, Lanzhou 730050, China
| | - Zhenlong Du
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
- Lanzhou Institute of Animal Husbandry and Veterinary Pharmaceutical, Chinese Academy of Agricultural Sciences, Lanzhou 730050, China
| | - Zhengzhong Luo
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Xiaoping Li
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100000, China
| | - Dan Wu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Yixin Huang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Kang Yong
- Department of Animal Husbandry & Veterinary Medicine, College of Animal Science and Technology, Chongqing Three Gorges Vocational College, Chongqing 404105, China
| | - Xueping Yao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Liuhong Shen
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Shumin Yu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Zuoting Yan
- Lanzhou Institute of Animal Husbandry and Veterinary Pharmaceutical, Chinese Academy of Agricultural Sciences, Lanzhou 730050, China
| | - Suizhong Cao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
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Singh K, Aulakh SK, Nijjar GS, Singh S, Sandhu APS, Luthra S, Tanvir F, Kaur Y, Singla A, Kaur MS. Rebalancing the Gut: Glucagon-Like Peptide-1 Agonists as a Strategy for Obesity and Metabolic Health. Cureus 2024; 16:e64738. [PMID: 39156410 PMCID: PMC11329331 DOI: 10.7759/cureus.64738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/17/2024] [Indexed: 08/20/2024] Open
Abstract
Obesity significantly impacts gut microbial composition, exacerbating metabolic dysfunction and weight gain. Traditional treatment methods often fall short, underscoring the need for innovative approaches. Glucagon-like peptide-1 (GLP-1) agonists have emerged as promising agents in obesity management, demonstrating significant potential in modulating gut microbiota. These agents promote beneficial bacterial populations, such as Bacteroides, Lactobacillus, and Bifidobacterium, while reducing harmful species like Enterobacteriaceae. By influencing gut microbiota composition, GLP-1 agonists enhance gut barrier integrity, reducing permeability and systemic inflammation, which are hallmarks of metabolic dysfunction in obesity. Additionally, GLP-1 agonists improve metabolic functions by increasing the production of short-chain fatty acids like butyrate, propionate, and acetate, which serve as energy sources for colonocytes, modulate immune responses, and enhance the production of gut hormones that regulate appetite and glucose homeostasis. By increasing microbial diversity, GLP-1 agonists create a more resilient gut microbiome capable of resisting pathogenic invasions and maintaining metabolic balance. Thus, by shifting the gut microbiota toward a healthier profile, GLP-1 agonists help disrupt the vicious cycle of obesity-induced gut dysbiosis and inflammation. This review highlights the intricate relationship between obesity, gut microbiota, and GLP-1 agonists, providing valuable insights into their combined role in effective obesity treatment and metabolic health enhancement.
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Affiliation(s)
| | - Smriti K Aulakh
- Internal Medicine, Sri Guru Ram Das University of Health Sciences and Research, Amritsar, IND
| | | | - Sumerjit Singh
- Internal Medicine, Government Medical College, Amritsar, IND
| | - Ajay Pal Singh Sandhu
- Internal Medicine, Sri Guru Ram Das University of Health Sciences and Research, Amritsar, IND
| | - Shivansh Luthra
- Internal Medicine, Government Medical College, Amritsar, IND
| | - Fnu Tanvir
- Internal Medicine, Government Medical College, Amritsar, IND
| | - Yasmeen Kaur
- Internal Medicine, Government Medical College, Amritsar, IND
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10
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Bertran L, Capellades J, Abelló S, Aguilar C, Auguet T, Richart C. Untargeted lipidomics analysis in women with morbid obesity and type 2 diabetes mellitus: A comprehensive study. PLoS One 2024; 19:e0303569. [PMID: 38743756 PMCID: PMC11093320 DOI: 10.1371/journal.pone.0303569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 04/26/2024] [Indexed: 05/16/2024] Open
Abstract
There is a phenotype of obese individuals termed metabolically healthy obese that present a reduced cardiometabolic risk. This phenotype offers a valuable model for investigating the mechanisms connecting obesity and metabolic alterations such as Type 2 Diabetes Mellitus (T2DM). Previously, in an untargeted metabolomics analysis in a cohort of morbidly obese women, we observed a different lipid metabolite pattern between metabolically healthy morbid obese individuals and those with associated T2DM. To validate these findings, we have performed a complementary study of lipidomics. In this study, we assessed a liquid chromatography coupled to a mass spectrometer untargeted lipidomic analysis on serum samples from 209 women, 73 normal-weight women (control group) and 136 morbid obese women. From those, 65 metabolically healthy morbid obese and 71 with associated T2DM. In this work, we find elevated levels of ceramides, sphingomyelins, diacyl and triacylglycerols, fatty acids, and phosphoethanolamines in morbid obese vs normal weight. Conversely, decreased levels of acylcarnitines, bile acids, lyso-phosphatidylcholines, phosphatidylcholines (PC), phosphatidylinositols, and phosphoethanolamine PE (O-38:4) were noted. Furthermore, comparing morbid obese women with T2DM vs metabolically healthy MO, a distinct lipid profile emerged, featuring increased levels of metabolites: deoxycholic acid, diacylglycerol DG (36:2), triacylglycerols, phosphatidylcholines, phosphoethanolamines, phosphatidylinositols, and lyso-phosphatidylinositol LPI (16:0). To conclude, analysing both comparatives, we observed decreased levels of deoxycholic acid, PC (34:3), and PE (O-38:4) in morbid obese women vs normal-weight. Conversely, we found elevated levels of these lipids in morbid obese women with T2DM vs metabolically healthy MO. These profiles of metabolites could be explored for the research as potential markers of metabolic risk of T2DM in morbid obese women.
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Affiliation(s)
- Laia Bertran
- Department of Medicine and Surgery, Study Group on Metabolic Diseases Associated with Insulin-Resistance (GEMMAIR), Rovira i Virgili University, Hospital Universitari de Tarragona Joan XXIII, IISPV, Tarragona, Spain
| | - Jordi Capellades
- Department of Electronic, Electric and Automatic Engineering, Higher Technical School of Engineering, Rovira i Virgili University, IISPV, Tarragona, Spain
| | - Sonia Abelló
- Scientific and Technical Service, Rovira i Virgili University, Tarragona, Spain
| | - Carmen Aguilar
- Department of Medicine and Surgery, Study Group on Metabolic Diseases Associated with Insulin-Resistance (GEMMAIR), Rovira i Virgili University, Hospital Universitari de Tarragona Joan XXIII, IISPV, Tarragona, Spain
| | - Teresa Auguet
- Department of Medicine and Surgery, Study Group on Metabolic Diseases Associated with Insulin-Resistance (GEMMAIR), Rovira i Virgili University, Hospital Universitari de Tarragona Joan XXIII, IISPV, Tarragona, Spain
| | - Cristóbal Richart
- Department of Medicine and Surgery, Study Group on Metabolic Diseases Associated with Insulin-Resistance (GEMMAIR), Rovira i Virgili University, Hospital Universitari de Tarragona Joan XXIII, IISPV, Tarragona, Spain
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11
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Li X, Cai QY, Luo X, Wang YH, Shao LZ, Luo SJ, Wang L, Wang YX, Lan X, Liu TH. Gestational diabetes mellitus aggravates adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. Diabetol Metab Syndr 2024; 16:57. [PMID: 38429774 PMCID: PMC10908036 DOI: 10.1186/s13098-024-01294-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 02/17/2024] [Indexed: 03/03/2024] Open
Abstract
PURPOSE To evaluate the effect of intrahepatic cholestasis of pregnancy (ICP) with gestational diabetes mellitus (GDM) on perinatal outcomes and establish a prediction model of adverse perinatal outcomes in women with ICP. METHODS This multicenter retrospective cohort study included the clinical data of 2,178 pregnant women with ICP, including 1,788 women with ICP and 390 co-occurrence ICP and GDM. The data of all subjects were collected from hospital electronic medical records. Univariate and multivariate logistic regression analysis were used to compare the incidence of perinatal outcomes between ICP with GDM group and ICP alone group. RESULTS Baseline characteristics of the population revealed that maternal age (p < 0.001), pregestational weight (p = 0.01), pre-pregnancy BMI (p < 0.001), gestational weight gain (p < 0.001), assisted reproductive technology (ART) (p < 0.001), and total bile acid concentration (p = 0.024) may be risk factors for ICP with GDM. Furthermore, ICP with GDM demonstrated a higher association with both polyhydramnios (OR 2.66) and preterm labor (OR 1.67) compared to ICP alone. Further subgroup analysis based on the severity of ICP showed that elevated total bile acid concentrations were closely associated with an increased risk of preterm labour, meconium-stained amniotic fluid, and low birth weight in both ICP alone and ICP with GDM groups. ICP with GDM further worsened these outcomes, especially in women with severe ICP. The nomogram prediction model effectively predicted the occurrence of preterm labour in the ICP population. CONCLUSIONS ICP with GDM may result in more adverse pregnancy outcomes, which are associated with bile acid concentrations.
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Affiliation(s)
- Xia Li
- Department of Bioinformatics, School of Basic Medical Sciences , Chongqing Medical University, No.1 Yixueyuan Rd, Yuzhong District, 400016, Chongqing, China
- Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University, 400016, Chongqing, China
| | - Qin-Yu Cai
- Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University, 400016, Chongqing, China
- Department of Obstetrics, Women and Children's Hospital of Chongqing Medical University, 401147, Chongqing, China
| | - Xin Luo
- Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University, 400016, Chongqing, China
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China
| | - Yong-Heng Wang
- Department of Bioinformatics, School of Basic Medical Sciences , Chongqing Medical University, No.1 Yixueyuan Rd, Yuzhong District, 400016, Chongqing, China
- Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University, 400016, Chongqing, China
| | - Li-Zhen Shao
- Department of Bioinformatics, School of Basic Medical Sciences , Chongqing Medical University, No.1 Yixueyuan Rd, Yuzhong District, 400016, Chongqing, China
- Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University, 400016, Chongqing, China
| | - Shu-Juan Luo
- Department of Obstetrics, Women and Children's Hospital of Chongqing Medical University, 401147, Chongqing, China
| | - Lan Wang
- Department of Obstetrics, Women and Children's Hospital of Chongqing Medical University, 401147, Chongqing, China
| | - Ying-Xiong Wang
- Department of Bioinformatics, School of Basic Medical Sciences , Chongqing Medical University, No.1 Yixueyuan Rd, Yuzhong District, 400016, Chongqing, China
- Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University, 400016, Chongqing, China
| | - Xia Lan
- Department of Obstetrics, Women and Children's Hospital of Chongqing Medical University, 401147, Chongqing, China.
| | - Tai-Hang Liu
- Department of Bioinformatics, School of Basic Medical Sciences , Chongqing Medical University, No.1 Yixueyuan Rd, Yuzhong District, 400016, Chongqing, China.
- Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University, 400016, Chongqing, China.
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12
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Benchoula K, Serpell CJ, Mediani A, Albogami A, Misnan NM, Ismail NH, Parhar IS, Ogawa S, Hwa WE. 1H NMR metabolomics insights into comparative diabesity in male and female zebrafish and the antidiabetic activity of DL-limonene. Sci Rep 2024; 14:3823. [PMID: 38360784 PMCID: PMC10869695 DOI: 10.1038/s41598-023-45608-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 10/21/2023] [Indexed: 02/17/2024] Open
Abstract
Zebrafish have been utilized for many years as a model animal for pharmacological studies on diabetes and obesity. High-fat diet (HFD), streptozotocin and alloxan injection, and glucose immersion have all been used to induce diabetes and obesity in zebrafish. Currently, studies commonly used both male and female zebrafish, which may influence the outcomes since male and female zebrafish are biologically different. This study was designed to investigate the difference between the metabolites of male and female diabetic zebrafish, using limonene - a natural product which has shown several promising results in vitro and in vivo in treating diabetes and obesity-and provide new insights into how endogenous metabolites change following limonene treatment. Using HFD-fed male and female zebrafish, we were able to develop an animal model of T2D and identify several endogenous metabolites that might be used as diagnostic biomarkers for diabetes. The endogenous metabolites in males and females were different, even though both genders had high blood glucose levels and a high BMI. Treatment with limonene prevented high blood glucose levels and improved in diabesity zebrafish by limonene, through reversal of the metabolic changes caused by HFD in both genders. In addition, limonene was able to reverse the elevated expression of AKT during HFD.
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Affiliation(s)
- Khaled Benchoula
- School of Medicine, Faculty of Health and Medical Sciences, Taylor's University, 1, Jalan Taylors, 47500, Subang Jaya, Selangor, Malaysia
| | | | - Ahmed Mediani
- Institute of Systems Biology (INBIOSIS), Universiti Kebangsaan Malaysia, 43600, UKM Bangi, Selangor, Malaysia
| | - Abdulaziz Albogami
- Biology Department, Faculty of Science, Al-Baha University, 65779-7738, Alaqiq, Saudi Arabia
| | - Norazlan Mohmad Misnan
- Institute for Medical Research Malaysia, No.1, Jalan Setia Murni U13/52, Seksyen U13, Setia Alam, 40170, Shah Alam, Selangor Darul Ehsan, Malaysia
| | - Nor Hadiani Ismail
- Atta-ur-Rahman Institute for Natural Products Discovery, UiTM Puncak Alam Campus, 42300, Puncak Alam, Selangor, Malaysia
| | - Ishwar S Parhar
- Monash University (Malaysia) BRIMS, Jeffrey Cheah School of Medicine and Health Sciences, Jalan Lagoon Selatan, Bandar Sunway, 47500, Subang Jaya, Selangor, Malaysia
| | - Satoshi Ogawa
- Monash University (Malaysia) BRIMS, Jeffrey Cheah School of Medicine and Health Sciences, Jalan Lagoon Selatan, Bandar Sunway, 47500, Subang Jaya, Selangor, Malaysia
| | - Wong Eng Hwa
- School of Medicine, Faculty of Health and Medical Sciences, Taylor's University, 1, Jalan Taylors, 47500, Subang Jaya, Selangor, Malaysia.
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13
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Jin Y, Sun F, Yang A, Yu X, Li Y, Liang S, Jing X, Wang K, Zhang L, Xiao S, Zhang W, Wang X, Zhao G, Gao B. Insulin-like growth factor binding protein-1 and insulin in polycystic ovary syndrome: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 2023; 14:1279717. [PMID: 38174331 PMCID: PMC10762309 DOI: 10.3389/fendo.2023.1279717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 11/27/2023] [Indexed: 01/05/2024] Open
Abstract
Background Insulin-like growth factor binding protein-1 (IGFBP-1) is considered a decline in polycystic ovary syndrome (PCOS), but it remains controversial that whether such reduction is attributed to obesity. Aims This systematic review aims to explore whether IGFBP-1 is reduced in PCOS, and whether such reduction is associated with obesity. Results Our pooled study included 12 studies with a total of 450 participants. IGFBP-1 levels in PCOS were significantly lower than that in non-PCOS (SMD (95%CI)=-0.49(-0.89, -0.09), P=0.02). No significant difference in IGFBP-1 levels between patients with or without PCOS classified by BMI. Whilst, stratification by PCOS status revealed a significant decrease in IGFBP-1 in overweight (SMD (95%CI)=-0.92(-1.46, -0.37), P=0.001). When comparing fasting insulin in the same way, PCOS patients had significantly elevated fasting insulin level but not statistically declined IGFBP-1 after classified by BMI. Conclusion This meta-analysis provides evidence that the decrease of IGFBP-1 in PCOS was more strongly influenced by comorbid obesity than by PCOS itself. Additionally, contrast to previous findings that insulin significantly suppresses IGFBP-1, our results suggested that the suppression of PCOS-related hyperinsulinemia on IGFBP-1 seemed diminished. Overall, our work may provide a novel perspective on the mechanism between insulin and IGFBP-1 underlying PCOS development.
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Affiliation(s)
- Yuxin Jin
- Department of Endocrinology, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Fei Sun
- Department of Endocrinology, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Aili Yang
- Department of Endocrinology, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Xinwen Yu
- Department of Endocrinology, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Yi Li
- Department of Gynaecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Shengru Liang
- Department of Endocrinology, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Xiaorui Jing
- Department of Endocrinology, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Kai Wang
- Department of Endocrinology, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Lan Zhang
- Department of Endocrinology, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Sa Xiao
- Department of Endocrinology, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - WenCheng Zhang
- Department of Endocrinology, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Xiaoguang Wang
- Department of Endocrinology, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Guohong Zhao
- Department of Endocrinology, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Bin Gao
- Department of Endocrinology, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
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Andrade LJDO, Oliveira GCMD, Oliveira LMD. THE CONNECTION BETWEEN BILE ACIDS AND TYPE 2 DIABETES MELLITUS - A REVIEW. ARQUIVOS DE GASTROENTEROLOGIA 2023; 60:536-542. [PMID: 38018556 DOI: 10.1590/s0004-2803.230402023-86] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 09/05/2023] [Indexed: 11/30/2023]
Abstract
BACKGROUND Bile acids (BAs) are steroid molecules synthesized exclusively in the liver, being end products of cholesterol catabolism. BAs are known to be involved in several metabolic alterations, including metabolic syndrome and type 2 diabetes mellitus (DM2). DM2 is a chronic degenerative disease characterized by insulin resistance, insulin deficiency due to insufficient production of pancreatic ß-cells, and elevated serum glucose levels leading to multiple complications. OBJECTIVE The objective of this study is to investigate the role of BAs in the pathophysiology of DM2, highlighting the possibilities in the development of therapeutic procedures targeting BAs as an optional pathway in the treatment of DM2. METHODS The research was carried out through narrative review and publications on the relationship between BAs and DM2. The databases used for the search include PubMed, Scopus, and Web of Science. The keywords used for the search include bile acids, type 2 diabetes mellitus, metabolic syndrome, and metabolic disorders. RESULTS The studies have reported the involvement of BAs in the pathophysiology of DM2. BAs act as a ligand for the nuclear farnesoid X receptor, regulating glucose metabolism, lipid metabolism, and cellular energy production. Additionally, BAs modulate the production, elimination, and mobilization of BAs through the farnesoid X receptor. BAs also act as a signaling pathway through Takeda G protein-coupled receptor 5, further contributing to metabolic regulation. These findings suggest that targeting BAs may offer a novel therapeutic approach in the treatment of DM2. CONCLUSION This study highlights the important role of BAs in DM2, specifically through their interactions with key metabolic pathways. Targeting BAs may represent an innovative and effective approach to the treatment of DM2.
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15
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Izbicka E, Streeper RT. Mitigation of Insulin Resistance by Natural Products from a New Class of Molecules, Membrane-Active Immunomodulators. Pharmaceuticals (Basel) 2023; 16:913. [PMID: 37513825 PMCID: PMC10386479 DOI: 10.3390/ph16070913] [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: 04/10/2023] [Revised: 06/14/2023] [Accepted: 06/15/2023] [Indexed: 07/30/2023] Open
Abstract
Insulin resistance (IR), accompanied by an impaired cellular glucose uptake, characterizes diverse pathologies that include, but are not limited to, metabolic disease, prediabetes and type 2 diabetes. Chronic inflammation associated with deranged cellular signaling is thought to contribute to IR. The key molecular players in IR are plasma membrane proteins, including the insulin receptor and glucose transporter 4. Certain natural products, such as lipids, phenols, terpenes, antibiotics and alkaloids have beneficial effects on IR, yet their mode of action remains obscured. We hypothesized that these products belong to a novel class of bioactive molecules that we have named membrane-active immunomodulators (MAIMs). A representative MAIM, the naturally occurring medium chain fatty acid ester diethyl azelate (DEA), has been shown to increase the fluidity of cell plasma membranes with subsequent downstream effects on cellular signaling. DEA has also been shown to improve markers of IR, including blood glucose, insulin and lipid levels, in humans. The literature supports the notion that DEA and other natural MAIMs share similar mechanisms of action in improving IR. These findings shed a new light on the mechanism of IR mitigation using natural products, and may facilitate the discovery of other compounds with similar activities.
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16
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Auguet T, Bertran L, Capellades J, Abelló S, Aguilar C, Sabench F, del Castillo D, Correig X, Yanes O, Richart C. LC/MS-Based Untargeted Metabolomics Analysis in Women with Morbid Obesity and Associated Type 2 Diabetes Mellitus. Int J Mol Sci 2023; 24:7761. [PMID: 37175468 PMCID: PMC10177925 DOI: 10.3390/ijms24097761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/17/2023] [Accepted: 04/18/2023] [Indexed: 05/15/2023] Open
Abstract
Obesity is a chronic and complex disease, with an increasing incidence worldwide that is associated with metabolic disorders such as type 2 diabetes mellitus (T2DM). Thus, it is important to determine the differences between metabolically healthy obese individuals and those with metabolic disorders. The aim of this study was to perform an untargeted metabolomics assay in women with morbid obesity (MO) compared to a normal weight group, and to differentiate the metabolome of these women with MO who present with T2DM. We carried out a liquid chromatography-mass spectrometry-based untargeted metabolomics assay using serum samples of 209 Caucasian women: 73 with normal weight and 136 with MO, of which 71 had T2DM. First, we found increased levels of choline and acylglycerols and lower levels of bile acids, steroids, ceramides, glycosphingolipids, lysophosphatidylcholines, and lysophosphatidylethanolamines in MO women than in the control group. Then, in MO women with T2DM, we found increased levels of glutamate, propionyl-carnitine, bile acids, ceramides, lysophosphatidylcholine 14:0, phosphatidylinositols and phosphoethanolamines, and lower levels of Phe-Ile/Leu. Thus, we found metabolites with opposite trends of concentration in the two metabolomic analyses. These metabolites could be considered possible new factors of study in the pathogenesis of MO and associated T2DM in women.
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Affiliation(s)
- Teresa Auguet
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), IISPV, 43005 Tarragona, Spain; (T.A.); (L.B.); (C.A.); (F.S.); (D.d.C.)
| | - Laia Bertran
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), IISPV, 43005 Tarragona, Spain; (T.A.); (L.B.); (C.A.); (F.S.); (D.d.C.)
| | - Jordi Capellades
- Department of Electronic Engineering, Universitat Rovira i Virgili (URV), IISPV, 43007 Tarragona, Spain; (J.C.); (X.C.); (O.Y.)
| | - Sonia Abelló
- Servei de Recursos Científics i Tècnics, Universitat Rovira i Virgili (URV), 43007 Tarragona, Spain;
| | - Carmen Aguilar
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), IISPV, 43005 Tarragona, Spain; (T.A.); (L.B.); (C.A.); (F.S.); (D.d.C.)
| | - Fàtima Sabench
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), IISPV, 43005 Tarragona, Spain; (T.A.); (L.B.); (C.A.); (F.S.); (D.d.C.)
- Unitat de Cirurgia, Facultad de Medicina i Ciències de la Salut, Hospital Universitari Sant Joan de Reus, Universitat Rovira i Virgili (URV), IISPV, 43204 Reus, Spain
| | - Daniel del Castillo
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), IISPV, 43005 Tarragona, Spain; (T.A.); (L.B.); (C.A.); (F.S.); (D.d.C.)
- Unitat de Cirurgia, Facultad de Medicina i Ciències de la Salut, Hospital Universitari Sant Joan de Reus, Universitat Rovira i Virgili (URV), IISPV, 43204 Reus, Spain
| | - Xavier Correig
- Department of Electronic Engineering, Universitat Rovira i Virgili (URV), IISPV, 43007 Tarragona, Spain; (J.C.); (X.C.); (O.Y.)
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, 43204 Madrid, Spain
| | - Oscar Yanes
- Department of Electronic Engineering, Universitat Rovira i Virgili (URV), IISPV, 43007 Tarragona, Spain; (J.C.); (X.C.); (O.Y.)
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, 43204 Madrid, Spain
| | - Cristóbal Richart
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili (URV), IISPV, 43005 Tarragona, Spain; (T.A.); (L.B.); (C.A.); (F.S.); (D.d.C.)
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Sarnobat D, Moffett RC, Ma J, Flatt PR, McClenaghan NH, Tarasov AI. Taurine rescues pancreatic β-cell stress by stimulating α-cell transdifferentiation. Biofactors 2023. [PMID: 36714992 DOI: 10.1002/biof.1938] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 01/05/2023] [Indexed: 01/31/2023]
Abstract
The semi-essential ubiquitous amino acid taurine has been shown to alleviate obesity and hyperglycemia in humans; however, the pathways underlying the antidiabetic actions have not been characterized. We explored the effect of chronic taurine exposure on cell biology of pancreatic islets, in degenerative type 1-like diabetes. The latter was modeled by small dose of streptozotocin (STZ) injection for 5 days in mice, followed by a 10-day administration of taurine (2% w/v, orally) in the drinking water. Taurine treatment opposed the detrimental changes in islet morphology and β-/α-cell ratio, induced by STZ diabetes, coincidentally with a significant 3.9 ± 0.7-fold enhancement of proliferation and 40 ± 5% reduction of apoptosis in β-cells. In line with these findings, the treatment counteracted an upregulation of antioxidant (Sod1, Sod2, Cat, Gpx1) and downregulation of islet expansion (Ngn3, Itgb1) genes induced by STZ, in a pancreatic β-cell line. At the same time, taurine enhanced the transdifferentiation of α-cells into β-cells by 2.3 ± 0.8-fold, echoed in strong non-metabolic elevation of cytosolic Ca2+ levels in pancreatic α-cells. Our data suggest a bimodal effect of dietary taurine on islet β-cell biology, which combines the augmentation of α-/β-cell transdifferentiation with downregulation of apoptosis. The dualism of action, stemming presumably from the intra- and extracellular modality of the signal, is likely to explain the antidiabetic potential of taurine supplementation.
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Affiliation(s)
- Dipak Sarnobat
- School of Biomedical Sciences, Ulster University, Coleraine, UK
| | | | - Jinfang Ma
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
| | - Peter R Flatt
- School of Biomedical Sciences, Ulster University, Coleraine, UK
| | - Neville H McClenaghan
- School of Biomedical Sciences, Ulster University, Coleraine, UK
- Department of Life Sciences, Atlantic Technological University, Sligo, Ireland
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Wise JL, Cummings BP. The 7-α-dehydroxylation pathway: An integral component of gut bacterial bile acid metabolism and potential therapeutic target. Front Microbiol 2023; 13:1093420. [PMID: 36699589 PMCID: PMC9868651 DOI: 10.3389/fmicb.2022.1093420] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 12/13/2022] [Indexed: 01/11/2023] Open
Abstract
The gut microbiome plays a significant role in maintaining host metabolic health through the production of metabolites. Comprising one of the most abundant and diverse forms of gut metabolites, bile acids play a key role in blood glucose regulation, insulin sensitivity, obesity, and energy expenditure. A central pathway in gut bacterial bile acid metabolism is the production of secondary bile acids via 7-ɑ-dehydroxylation. Despite the important role of 7-ɑ-dehydroxylation in gut bacterial bile acid metabolism and the pathophysiology of metabolic disease, the regulation of this pathway is not completely understood. This review aims to outline our current understanding of 7-ɑ-dehydroxylation and to identify key knowledge gaps that will be integral in further characterizing gut bacterial bile acid metabolism as a potential therapeutic target for treating metabolic dysregulation.
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Affiliation(s)
- Journey L. Wise
- Department of Biomedical Sciences, Cornell University, Ithaca, NY, United States
| | - Bethany P. Cummings
- Department of Surgery, Center for Alimentary and Metabolic Sciences, School of Medicine, University of California, Davis, Sacramento, CA, United States
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Resveratrol Modulates the Redox Response and Bile Acid Metabolism to Maintain the Cholesterol Homeostasis in Fish Megalobrama amblycephala Offered a High-Carbohydrate Diet. Antioxidants (Basel) 2023; 12:antiox12010121. [PMID: 36670983 PMCID: PMC9854748 DOI: 10.3390/antiox12010121] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 12/21/2022] [Accepted: 12/30/2022] [Indexed: 01/06/2023] Open
Abstract
This study aimed to characterize the effects of resveratrol on the redox balance, cholesterol homeostasis and bile acid metabolism of Megalobrama amblycephala offered a high-carbohydrate diet. Fish (35.0 ± 0.15 g) were fed four diets including one control diet (32% nitrogen-free extract), one high-carbohydrate diet (45% nitrogen-free extract, HC), and the HC diet supplemented with different levels (0.04%, HCR1; 0.08%, HCR2) of resveratrol for 12 weeks. The HC diet-induced redox imbalance is characterized by increased MDA content and decreased T-SOD and CAT activities in the liver. Resveratrol attenuated this by up-regulating the transcription of Cu/Zn-sod, and increasing the activities of T-SOD, CAT, and GPX. The HC diet enhanced the cholesterol synthesis, but decreased the bile acid synthesis via up-regulating both hmgcr and acat2, and down-regulating cyp7a1, thus resulting in excessive cholesterol accumulation. Resveratrol supplement decreased cholesterol synthesis, and increased cholesterol uptake in the liver by down-regulating both hmgcr and acat2, and up-regulating ldlr. It also increased bile acid synthesis and biliary excretion by up-regulating cyp7a1, and down-regulating mrp2, oatp1, and oatp4 in the hindgut, thereby decreasing cholesterol accumulation. In conclusion, resveratrol improves the cholesterol homeostasis of Megalobrama amblycephala fed a high-carbohydrate diet by modulating the redox response and bile acid metabolism.
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20
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Rafaqat S, Sattar A, Khalid A, Rafaqat S. Role of liver parameters in diabetes mellitus - a narrative review. Endocr Regul 2023; 57:200-220. [PMID: 37715985 DOI: 10.2478/enr-2023-0024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/18/2023] Open
Abstract
Diabetes mellitus is characterized by hyperglycemia and abnormalities in insulin secretion and function. This review article focuses on various liver parameters, including albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), alpha fetoprotein (AFP), alpha 1 antitrypsin (AAT), ammonia, bilirubin, bile acid, gamma-glutamyl transferase (GGT), immunoglobulin, lactate dehydrogenase (LDH), and total protein. These parameters play significant roles in the development of different types of diabetes such as type 1 diabetes (T1DM), type 2 diabetes (T2DM) and gestational diabetes (GDM). The article highlights that low albumin levels may indicate inflammation, while increased ALT and AST levels are associated with liver inflammation or injury, particularly in non-alcoholic fatty liver disease (NAFLD). Elevated ALP levels can be influenced by liver inflammation, biliary dysfunction, or bone metabolism changes. High bilirubin levels are independently linked to albuminuria in T1DM and an increased risk of T2DM. Elevated GGT levels are proposed as markers of oxidative stress and liver dysfunction in T2DM. In GDM, decreased serum AFP levels may indicate impaired embryo growth. Decreased AFP levels in T2DM can hinder the detection of hepatocellular carcinoma. Hyperammonemia can cause encephalopathy in diabetic ketoacidosis, and children with T1DM and attention deficit hyperactivity disorder often exhibit higher ammonia levels. T2DM disrupts the regulation of nitrogen-related metabolites, leading to increased blood ammonia levels. Bile acids affect glucose regulation by activating receptors on cell surfaces and nuclei, and changes in bile acid metabolism are observed in T2DM. Increased LDH activity reflects metabolic disturbances in glucose utilization and lactate production, contributing to diabetic complications. Poor glycemic management may be associated with elevated levels of IgA and IgG serum antibodies, and increased immunoglobulin levels are also associated with T2DM.
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Affiliation(s)
- Sana Rafaqat
- 1Department of Biotechnology, Lahore College for Women University, Lahore, Punjab, Pakistan
| | - Aqsa Sattar
- 2Department of Zoology, Lahore College for Women University, Lahore, Punjab, Pakistan
| | - Amber Khalid
- 3Department of Zoology, University of Narowal, Punjab, Pakistan
| | - Saira Rafaqat
- 2Department of Zoology, Lahore College for Women University, Lahore, Punjab, Pakistan
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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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22
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Rehman AU, Siddiqui NZ, Farooqui NA, Alam G, Gul A, Ahmad B, Asim M, Khan AI, Xin Y, Zexu W, Song Ju H, Xin W, Lei S, Wang L. Morchella esculenta mushroom polysaccharide attenuates diabetes and modulates intestinal permeability and gut microbiota in a type 2 diabetic mice model. Front Nutr 2022; 9:984695. [PMID: 36276816 PMCID: PMC9582931 DOI: 10.3389/fnut.2022.984695] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 09/15/2022] [Indexed: 11/26/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a health issue that causes serious worldwide economic problems. It has previously been reported that natural polysaccharides have been studied with regard to regulating the gut microbiota, which plays an important role in T2DM. Here, we investigate the effects of Morchella esculenta polysaccharide (MEP) on a high-fat diet (HFD) and streptozotocin (STZ)-induced T2DM in BALB/c mice. The administration of MEP effectively regulated hyperglycemia and hyperlipidemia and improved insulin sensitivity. We also determined an improvement in gut microbiota composition by 16sRNA pyrosequencing. Treatment with MEP showed an increase in beneficial bacteria, i.e., Lactobacillus and Firmicutes, while the proportion of the opportunistic bacteria Actinobacteria, Corynebacterium, and Facklamia decreased. Furthermore, the treatment of T2DM mice with MEP resulted in reduced endotoxemia and insulin resistance-related pro-inflammatory cytokines interleukin 1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6). Moreover, MEP treatment improved intestinal permeability by modulating the expression of the colon tight-junction proteins zonula occludens-1 (ZO-1), occludin, claudin-1, and mucin-2 protein (MUC2). Additionally, MEP administration affects the metagenome of microbial communities in T2DM mice by altering the functional metabolic pathways. All these findings suggested that MEP is a beneficial prebiotic associated with ameliorating the gut microbiota and its metabolites in T2DM.
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Affiliation(s)
- Ata Ur Rehman
- Department of Biotechnology, College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Nimra Zafar Siddiqui
- Department of Biotechnology, College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Nabeel Ahmed Farooqui
- Department of Biotechnology, College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Gulzar Alam
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
| | - Aneesa Gul
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
| | - Bashir Ahmad
- Department of Biology, University of Haripur, Haripur, Pakistan
| | - Muhammad Asim
- Department of Biology, University of Haripur, Haripur, Pakistan
| | - Asif Iqbal Khan
- Department of Biotechnology, College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Yi Xin
- Department of Biotechnology, College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Wang Zexu
- Department of Biotechnology, College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Hyo Song Ju
- Department of Biotechnology, College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Wang Xin
- Department of Biotechnology, College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Sun Lei
- Department of Biotechnology, College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Liang Wang
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China,*Correspondence: Liang Wang,
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Luo X, Yang W, Joshi AD, Wu K, Simon TG, Yuan C, Jin L, Long L, Kim MN, Lo CH, Liu X, Abrams TA, Wolpin BM, Chan AT, Giovannucci EL, Zhang X. Gallstones and risk of cancers of the liver, biliary tract and pancreas: a prospective study within two U.S. cohorts. Br J Cancer 2022; 127:1069-1075. [PMID: 35715632 PMCID: PMC9470543 DOI: 10.1038/s41416-022-01877-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 05/12/2022] [Accepted: 05/31/2022] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Gallstones may result in inflammation, altered bile flow, and changes in metabolic hormone levels, thereby increasing cancer risk. However, previous studies for gallstones and cancers of the liver, biliary tract and pancreas in the U.S. were relatively limited. METHODS We followed 115,036 women from the Nurses' Health Study (1982-2012) and 49,729 men from the Health Professionals Follow-up Study (1986-2012). History of gallstones, including with or without performed cholecystectomy, was reported at baseline and updated through biennial questionnaires. The Cox proportional hazard regression model was used to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs). RESULTS During up to 30-year follow-up, we identified 204 incidents of liver cancer, 225 biliary tract cancer and 1147 pancreatic cancer cases. Compared to those without gallstones diagnosis, the multivariable HRs for individuals with gallstones (untreated or with cholecystectomy) were 1.60 for liver cancer (95% CI: 1.14-2.26), 4.79 for biliary tract cancer (95% CI: 3.02-7.58), and 1.13 for pancreatic cancer (95% CI: 0.96-1.32). The multivariable HRs for individuals with cholecystectomy were 1.33 for liver cancer (95% CI: 0.90-1.95) and 1.15 for pancreatic cancer (95% CI: 0.98-1.36). CONCLUSIONS Gallstones were associated with a higher risk of cancers of the liver, biliary tract and possibly pancreas.
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Affiliation(s)
- Xiao Luo
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Health Statistics, School of Public Health, China Medical University, Shenyang, Liaoning, P. R. China
| | - Wanshui Yang
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- School of Public Health, Anhui Medical University, Hefei, Anhui, P. R. China
| | - Amit D Joshi
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Kana Wu
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Tracey G Simon
- Liver Center, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Clinical and Translational Epidemiology Unit (CTEU), Massachusetts General Hospital, Boston, MA, USA
| | - Chen Yuan
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Lina Jin
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Epidemiology and Biostatistics, Jilin University School of Public Health, Changchun, Jilin, P. R. China
| | - Lu Long
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Sichuan, P. R. China
| | - Mi Na Kim
- Division of Gastroenterology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
- Laboratory of Clinical Epidemiology in Hepatology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - Chun-Han Lo
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Clinical and Translational Epidemiology Unit (CTEU), Massachusetts General Hospital, Boston, MA, USA
| | - Xing Liu
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, P. R. China
| | | | - Brian M Wolpin
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Andrew T Chan
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Clinical and Translational Epidemiology Unit (CTEU), Massachusetts General Hospital, Boston, MA, USA
| | - Edward L Giovannucci
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Xuehong Zhang
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
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24
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Interfacial behavior and emulsion stability of lipid delivery system regulated by two-dimensional facial amphiphiles bile salts. J Mol Liq 2022. [DOI: 10.1016/j.molliq.2022.119744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Ge YP, Chen WL, Sun M, Zhang L, Liu WB, Li XF. Molecular characterization of farnesoid X receptor alpha in Megalobrama amblycephala and its potential roles in high-carbohydrate diet-induced alterations of bile acid metabolism. J Steroid Biochem Mol Biol 2022; 219:106065. [PMID: 35091085 DOI: 10.1016/j.jsbmb.2022.106065] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 12/24/2021] [Accepted: 01/23/2022] [Indexed: 11/22/2022]
Abstract
Farnesoid X receptorα (FXRα) plays a central role in maintaining the bile acid homeostasis in mammals, while relevant processes are still poorly interpreted in aquatic species. This study was conducted to characterize the fxrα gene in a cyprinidae species: blunt snout bream (Megalobrama amblycephala), and investigate its potential roles in bile acid metabolism. The Fxrα protein contains one DNA binding domain, one ligand binding domain, one His-Try "switch" and two modifies residues. A high degree of conservation (53.18-100.00 %) was observed in the Fxrα protein among most aquatic species and higher vertebrates. The transcription of fxrα was mainly observed in intestine, liver and kidney. Then fish (35.0 ± 0.15 g) were fed two diets containing 33 % and 45 % carbohydrate levels for 12weeks. High-carbohydrate diet significantly elevated the total cholesterol concentrations in plasma, liver and hindgut as well as the triglyceride concentrations in both liver and hindgut, but decreased the total bile acid concentrations in plasma, liver and hindgut. High dietary carbohydrate levels also significantly enhanced hepatic transcriptions of 3-hydroxy-3-methylglutaryl-CoA reductase (the rate-limiting enzyme in cholesterol synthesis), and those of fxrα (a bile acid receptor) and multidrug resistance associated protein 2 (a bile acid transporter) in hindgut. Furthermore, high dietary carbohydrate levels significantly decreased the transcriptions of cholesterol 7α-hydroxylase (the rate-limiting enzyme in bile acid synthesis) and organic anion-transporting polypeptides (a bile acid transporter) in liver as well as that of takeda G-protein-coupled bile acid receptor in hindgut. The results demonstrated that the fxrα gene of blunt snout bream is highly conserved compared with other vertebrates. Besides, high dietary carbohydrate levels increased total cholesterol concentrations, and up-regulated the transcription of fxrα, thus decreasing the biosynthesis and reabsorption of bile acids by mediating various target genes.
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Affiliation(s)
- Ya-Ping Ge
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang Road, Nanjing, 210095, People's Republic of China
| | - Wei-Liang Chen
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang Road, Nanjing, 210095, People's Republic of China
| | - Miao Sun
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang Road, Nanjing, 210095, People's Republic of China
| | - Ling Zhang
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang Road, Nanjing, 210095, People's Republic of China
| | - Wen-Bin Liu
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang Road, Nanjing, 210095, People's Republic of China
| | - Xiang-Fei Li
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang Road, Nanjing, 210095, People's Republic of China.
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Kim Y, Lee S, Kim S, Kim TY, Lee SH, Chang JH, Kweon MN. LKB1 in Intestinal Epithelial Cells Regulates Bile Acid Metabolism by Modulating FGF15/19 Production. Cell Mol Gastroenterol Hepatol 2021; 13:1121-1139. [PMID: 34973477 PMCID: PMC8873961 DOI: 10.1016/j.jcmgh.2021.12.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 12/22/2021] [Accepted: 12/27/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Liver kinase B1 (LKB1) is a master upstream protein kinase involved in nutrient sensing and glucose and lipid metabolism in many tissues; however, its metabolic role in intestinal epithelial cells (IEC) remains unclear. In this study, we investigated the regulatory role of LKB1 on bile acid (BA) homeostasis. METHODS We generated mice with IEC-specific deletion of LKB1 (LKB1ΔIEC) and analyzed the characteristics of IEC development and BA level. In vitro assays with small interfering RNA, liquid chromatography/mass spectrometry, metagenomics, and RNA-sequencing were used to elucidate the regulatory mechanisms underlying perturbed BA homeostasis. RESULTS LKB1 deletion resulted in abnormal differentiation of secretory cell lineages. Unexpectedly, BA pool size increased substantially in LKB1ΔIEC mice. A significant reduction of the farnesoid X receptor (FXR) target genes, including fibroblast growth factor 15/19 (FGF15/19), known to inhibit BA synthesis, was found in the small intestine (SI) ileum of LKB1ΔIEC mice. We observed that LKB1 depletion reduced FGF15/19 protein level in human IECs in vitro. Additionally, a lower abundance of bile salt hydrolase-producing bacteria and elevated levels of FXR antagonist (ie, T-βMCA) were observed in the SI of LKB1ΔIEC mice. Moreover, LKB1ΔIEC mice showed impaired conversion of retinol to retinoic acids in the SI ileum. Subsequently, vitamin A treatment failed to induce FGF15 production. Thus, LKB1ΔIEC mice fed with a high-fat diet showed improved glucose tolerance and increased energy expenditure. CONCLUSIONS LKB1 in IECs manages BA homeostasis by controlling FGF15/19 production.
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Affiliation(s)
- Yeji Kim
- Mucosal Immunology Laboratory, Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sohyeon Lee
- Mucosal Immunology Laboratory, Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seungil Kim
- Mucosal Immunology Laboratory, Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea,Digestive Diseases Research Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Tae-Young Kim
- Mucosal Immunology Laboratory, Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Su-Hyun Lee
- Mucosal Immunology Laboratory, Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jae-Hoon Chang
- College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea
| | - Mi-Na Kweon
- Mucosal Immunology Laboratory, Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea,Digestive Diseases Research Center, University of Ulsan College of Medicine, Seoul, Republic of Korea,Correspondence Address correspondence to: Dr Mi-Na Kweon, Asan Medical Center, Department of Convergence Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505 Republic of Korea. tel: 82-2-3010-2096.
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Mashburn S, Schleckman E, Cackovic P, Shellhaas C, Rood KM, Ma'ayeh M. Intrahepatic cholestasis of pregnancy: risk factors for severe disease. J Matern Fetal Neonatal Med 2021; 35:8566-8570. [PMID: 34632916 DOI: 10.1080/14767058.2021.1988924] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
INTRODUCTION Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-associated hepatic disorder characterized by pruritus in the setting of elevated serum bile acids (BA). Risk factors for the disease include preexisting hepatobiliary disease, personal or family history of ICP, and advanced maternal age. Recent data suggests that patients with severe ICP (BA ≥100 μmol/L) have a higher risk of adverse pregnancy outcomes including stillbirth. MATERIAL AND METHODS This was a retrospective cohort study of patients diagnosed with ICP between 2012 and 2019 at a tertiary referral center. ICP was defined as symptomatic pruritus combined with serum BA >10 μmol/L. Maternal characteristics and outcomes were abstracted from electronic medical records. Baseline characteristics were compared between patients with mild (BA <40 μmol/L), moderate (BA 40-99 μmol/L) and severe (BA ≥100 μmol/L) ICP. Obstetrics and neonatal outcomes for patients in each category were then analyzed. Shapiro-Wilk test was used to test for normality for continuous variables, and ANOVA, Kruskal-Wallis, Chi-squared or Fisher's exact tests were used as appropriate. A p-value <.05 was considered statistically significant. RESULTS 438 patients were included in the analysis. Individuals with pregestational diabetes (p < .01), history of ICP (p < .01), prior cholecystectomy (p < .01), and tobacco use (p < .05) were more likely to have severe disease. When compared to individuals with moderate and mild disease, individuals with severe disease were more likely to be diagnosed earlier (29w1d vs 34w1d vs 34w1d, p < .05), have gestational diabetes (50% vs 6% vs 13%, p < .01), hypertensive disorders of pregnancy (42% vs 10% vs 15%, p = .02), and abnormal aspartate aminotransferase (91% vs 65% vs 27%, p < .01) and alanine aminotransferase levels (91% vs 60% vs 26%, p < .01). There were no differences in preterm labor, meconium-stained amniotic fluid, or neonatal respiratory distress syndrome and no stillbirths in this cohort. CONCLUSIONS In patients with ICP, those with pregestational diabetes, history of ICP, prior cholecystectomy, and tobacco use are more likely to develop severe disease. Given the adverse outcomes associated with severe disease, serial BA measurements to monitor for development of severe disease may be warranted in this population.
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Affiliation(s)
- Sarah Mashburn
- Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Ellen Schleckman
- Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Paige Cackovic
- Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Cynthia Shellhaas
- Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Kara M Rood
- Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Marwan Ma'ayeh
- Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, OH, USA
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Bermingham KM, Brennan L, Segurado R, Gray IJ, Barron RE, Gibney ER, Ryan MF, Gibney MJ, Newman JW, O'Sullivan DAM. Genetic and environmental influences on serum oxylipins, endocannabinoids, bile acids and steroids. Prostaglandins Leukot Essent Fatty Acids 2021; 173:102338. [PMID: 34500309 DOI: 10.1016/j.plefa.2021.102338] [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: 03/19/2021] [Revised: 08/06/2021] [Accepted: 08/16/2021] [Indexed: 12/12/2022]
Abstract
Lipid bioactivity is a result of direct action and the action of lipid mediators including oxylipins, endocannabinoids, bile acids and steroids. Understanding the factors contributing to biological variation in lipid mediators may inform future approaches to understand and treat complex metabolic diseases. This research aims to determine the contribution of genetic and environmental influences on lipid mediators involved in the regulation of inflammation and energy metabolism. This study recruited 138 monozygotic (MZ) and dizygotic (DZ) twins aged 18-65 years and measured serum oxylipins, endocannabinoids, bile acids and steroids using liquid chromatography mass-spectrometry (LC-MS). In this classic twin design, the similarities and differences between MZ and DZ twins are modelled to estimate the contribution of genetic and environmental influences to variation in lipid mediators. Heritable lipid mediators included the 12-lipoxygenase products 12-hydroxyeicosatetraenoic acid [0.70 (95% CI: 0.12,0.82)], 12-hydroxyeicosatetraenoic acid [0.73 (95% CI: 0.30,0.83)] and 14‑hydroxy-docosahexaenoic acid [0.51 (95% CI: 0.07,0.71)], along with the endocannabinoid docosahexaenoy-lethanolamide [0.52 (95% CI: 0.15,0.72)]. For others such as 13-hydroxyoctadecatrienoic acid and lithocholic acid the contribution of environment to variation was stronger. With increased understanding of lipid mediator functions in health, it is important to understand the factors contributing to their variance. This study provides a comprehensive analysis of lipid mediators and extends pre-existing knowledge of the genetic and environmental influences on the human lipidome.
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MESH Headings
- 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid/blood
- 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid/genetics
- Adolescent
- Adult
- Aged
- Bile Acids and Salts/blood
- Bile Acids and Salts/genetics
- Dehydroepiandrosterone/blood
- Dehydroepiandrosterone/genetics
- Docosahexaenoic Acids/blood
- Docosahexaenoic Acids/genetics
- Eicosapentaenoic Acid/analogs & derivatives
- Eicosapentaenoic Acid/blood
- Eicosapentaenoic Acid/genetics
- Endocannabinoids/blood
- Endocannabinoids/genetics
- Fatty Acids, Omega-3/blood
- Fatty Acids, Omega-3/genetics
- Female
- Gene-Environment Interaction
- Humans
- Lipid Metabolism/genetics
- Male
- Middle Aged
- Oxylipins/blood
- Steroids/blood
- Twins, Dizygotic/genetics
- Twins, Monozygotic/genetics
- Young Adult
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Affiliation(s)
- K M Bermingham
- UCD Institute of Food and Health, School of Agriculture and Food Science, University College Dublin, Belfield, Dublin 4, Ireland
| | - L Brennan
- UCD Institute of Food and Health, School of Agriculture and Food Science, University College Dublin, Belfield, Dublin 4, Ireland; UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
| | - R Segurado
- UCD School of Public Health, Physiotherapy and Sports Science, University College Dublin, Belfield, Dublin 4, Ireland
| | - I J Gray
- Obesity and Metabolism Research Unit, United States Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA, USA; West Coast Metabolomics Center, UC Davis Genome Center, University of California Davis, Davis, CA, USA
| | - R E Barron
- UCD Institute of Food and Health, School of Agriculture and Food Science, University College Dublin, Belfield, Dublin 4, Ireland
| | - E R Gibney
- UCD Institute of Food and Health, School of Agriculture and Food Science, University College Dublin, Belfield, Dublin 4, Ireland
| | - M F Ryan
- UCD Institute of Food and Health, School of Agriculture and Food Science, University College Dublin, Belfield, Dublin 4, Ireland
| | - M J Gibney
- UCD Institute of Food and Health, School of Agriculture and Food Science, University College Dublin, Belfield, Dublin 4, Ireland
| | - J W Newman
- Obesity and Metabolism Research Unit, United States Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA, USA; West Coast Metabolomics Center, UC Davis Genome Center, University of California Davis, Davis, CA, USA; Dept of Nutrition, University of California Davis, Davis, CA, USA
| | - Dr A M O'Sullivan
- UCD Institute of Food and Health, School of Agriculture and Food Science, University College Dublin, Belfield, Dublin 4, Ireland
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Chenodeoxycholic Acid Pharmacology in Biotechnology and Transplantable Pharmaceutical Applications for Tissue Delivery: An Acute Preclinical Study. Cells 2021; 10:cells10092437. [PMID: 34572086 PMCID: PMC8472107 DOI: 10.3390/cells10092437] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/30/2021] [Accepted: 09/06/2021] [Indexed: 12/19/2022] Open
Abstract
INTRODUCTION Primary bile acids (PBAs) are produced and released into human gut as a result of cholesterol catabolism in the liver. A predominant PBA is chenodeoxycholic acid (CDCA), which in a recent study in our laboratory, showed significant excipient-stabilizing effects on microcapsules carrying insulinoma β-cells, in vitro, resulting in improved cell functions and insulin release, in the hyperglycemic state. Hence, this study aimed to investigate the applications of CDCA in bio-encapsulation and transplantation of primary healthy viable islets, preclinically, in type 1 diabetes. METHODS Healthy islets were harvested from balb/c mice, encapsulated in CDCA microcapsules, and transplanted into the epididymal tissues of 6 syngeneic diabetic mice, post diabetes confirmation. Pre-transplantation, the microcapsules' morphology, size, CDCA-deep layer distribution, and physical features such as swelling ratio and mechanical strength were analyzed. Post-transplantation, animals' weight, bile acids', and proinflammatory biomarkers' concentrations were analyzed. The control group was diabetic mice that were transplanted encapsulated islets (without PBA). RESULTS AND CONCLUSION Islet encapsulation by PBA microcapsules did not compromise the microcapsules' morphology or features. Furthermore, the PBA-graft performed better in terms of glycemic control and resulted in modulation of the bile acid profile in the brain. This is suggestive that the improved glycemic control was mediated via brain-related effects. However, the improvement in graft insulin delivery and glycemic control was short-term.
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Serum Metabolite Profile Associated with Sex-Dependent Visceral Adiposity Index and Low Bone Mineral Density in a Mexican Population. Metabolites 2021; 11:metabo11090604. [PMID: 34564420 PMCID: PMC8472083 DOI: 10.3390/metabo11090604] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 08/27/2021] [Accepted: 08/30/2021] [Indexed: 01/03/2023] Open
Abstract
Recent evidence shows that obesity correlates negatively with bone mass. However, traditional anthropometric measures such as body mass index could not discriminate visceral adipose tissue from subcutaneous adipose tissue. The visceral adiposity index (VAI) is a reliable sex-specified indicator of visceral adipose distribution and function. Thus, we aimed to identify metabolomic profiles associated with VAI and low bone mineral density (BMD). A total of 602 individuals from the Health Workers Cohort Study were included. Forty serum metabolites were measured using the targeted metabolomics approach, and multivariate regression models were used to test associations of metabolomic profiles with anthropometric, clinical, and biochemical parameters. The analysis showed a serum amino acid signature composed of glycine, leucine, arginine, valine, and acylcarnitines associated with high VAI and low BMD. In addition, we found a sex-dependent VAI in pathways related to primary bile acid biosynthesis, branched-chain amino acids, and the biosynthesis of pantothenate and coenzyme A (CoA). In conclusion, a metabolic profile differs by VAI and BMD status, and these changes are gender-dependent.
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Ben Guebila M, Thiele I. Dynamic flux balance analysis of whole-body metabolism for type 1 diabetes. NATURE COMPUTATIONAL SCIENCE 2021; 1:348-361. [PMID: 38217214 DOI: 10.1038/s43588-021-00074-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 04/21/2021] [Indexed: 01/15/2024]
Abstract
Type 1 diabetes (T1D) mellitus is a systemic disease triggered by a local autoimmune inflammatory reaction in insulin-producing cells that induce organ-wide, long-term metabolic effects. Mathematical modeling of the whole-body regulatory bihormonal system has helped to identify therapeutic interventions but is limited to a coarse-grained representation of metabolism. To extend the depiction of T1D, we developed a whole-body model of organ-specific regulation and metabolism that highlighted chronic inflammation as a hallmark of the disease, identified processes related to neurodegenerative disorders and suggested calcium channel blockers as adjuvants for diabetes control. In addition, whole-body modeling of a patient population allowed for the assessment of between-individual variability to insulin and suggested that peripheral glucose levels are degenerate biomarkers of the internal metabolic state. Taken together, the organ-resolved, dynamic modeling approach enables modeling and simulation of metabolic disease at greater levels of coverage and precision and the generation of hypothesis from a molecular level up to the population level.
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Affiliation(s)
- Marouen Ben Guebila
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Ines Thiele
- School of Medicine, National University of Ireland, Galway, Ireland.
- Discipline of Microbiology, School of Natural Sciences, National University of Ireland, Galway, Galway, Ireland.
- APC Microbiome, Cork, Ireland.
- Ryan Institute, National University of Ireland, Galway, Ireland.
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Jia B, Park D, Chun BH, Hahn Y, Jeon CO. Diet-Related Alterations of Gut Bile Salt Hydrolases Determined Using a Metagenomic Analysis of the Human Microbiome. Int J Mol Sci 2021; 22:ijms22073652. [PMID: 33915727 PMCID: PMC8038126 DOI: 10.3390/ijms22073652] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/04/2021] [Accepted: 03/30/2021] [Indexed: 02/06/2023] Open
Abstract
The metabolism of bile acid by the gut microbiota is associated with host health. Bile salt hydrolases (BSHs) play a crucial role in controlling microbial bile acid metabolism. Herein, we conducted a comparative study to investigate the alterations in the abundance of BSHs using data from three human studies involving dietary interventions, which included a ketogenetic diet (KD) versus baseline diet (BD), overfeeding diet (OFD) versus underfeeding diet, and low-carbohydrate diet (LCD) versus BD. The KD increased BSH abundance compared to the BD, while the OFD and LCD did not change the total abundance of BSHs in the human gut. BSHs can be classified into seven clusters; Clusters 1 to 4 are relatively abundant in the gut. In the KD cohort, the levels of BSHs from Clusters 1, 3, and 4 increased significantly, whereas there was no notable change in the levels of BSHs from the clusters in the OFD and LCD cohorts. Taxonomic studies showed that members of the phyla Bacteroidetes, Firmicutes, and Actinobacteria predominantly produced BSHs. The KD altered the community structure of BSH-active bacteria, causing an increase in the abundance of Bacteroidetes and decrease in Actinobacteria. In contrast, the abundance of BSH-active Bacteroidetes decreased in the OFD cohort, and no significant change was observed in the LCD cohort. These results highlight that dietary patterns are associated with the abundance of BSHs and community structure of BSH-active bacteria and demonstrate the possibility of manipulating the composition of BSHs in the gut through dietary interventions to impact human health.
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Affiliation(s)
- Baolei Jia
- State Key Laboratory of Biobased Material and Green Papermaking, School of Bioengineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China;
- Department of Life Science, Chung-Ang University, Seoul 06974, Korea; (D.P.); (B.H.C.); (Y.H.)
| | - Dongbin Park
- Department of Life Science, Chung-Ang University, Seoul 06974, Korea; (D.P.); (B.H.C.); (Y.H.)
| | - Byung Hee Chun
- Department of Life Science, Chung-Ang University, Seoul 06974, Korea; (D.P.); (B.H.C.); (Y.H.)
| | - Yoonsoo Hahn
- Department of Life Science, Chung-Ang University, Seoul 06974, Korea; (D.P.); (B.H.C.); (Y.H.)
| | - Che Ok Jeon
- Department of Life Science, Chung-Ang University, Seoul 06974, Korea; (D.P.); (B.H.C.); (Y.H.)
- Correspondence: ; Tel.: +82-2-820-5864
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Borkowski K, Newman JW, Aghaeepour N, Mayo JA, Blazenović I, Fiehn O, Stevenson DK, Shaw GM, Carmichael SL. Mid-gestation serum lipidomic profile associations with spontaneous preterm birth are influenced by body mass index. PLoS One 2020; 15:e0239115. [PMID: 33201881 PMCID: PMC7671555 DOI: 10.1371/journal.pone.0239115] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 08/31/2020] [Indexed: 01/11/2023] Open
Abstract
Spontaneous preterm birth (sPTB) is a major cause of infant morbidity and mortality. While metabolic changes leading to preterm birth are unknown, several factors including dyslipidemia and inflammation have been implicated and paradoxically both low (<18.5 kg/m2) and high (>30 kg/m2) body mass indices (BMIs) are risk factors for this condition. The objective of the study was to identify BMI-associated metabolic perturbations and potential mid-gestation serum biomarkers of preterm birth in a cohort of underweight, normal weight and obese women experiencing either sPTB or full-term deliveries (n = 102; n = 17/group). For this purpose, we combined untargeted metabolomics and lipidomics with targeted metabolic profiling of major regulators of inflammation and metabolism, including oxylipins, endocannabinoids, bile acids and ceramides. Women who were obese and had sPTB showed elevated oxidative stress and dyslipidemia characterized by elevated serum free fatty acids. Women who were underweight-associated sPTB also showed evidence of dyslipidemia characterized by elevated phospholipids, unsaturated triglycerides, sphingomyelins, cholesteryl esters and long-chain acylcarnitines. In normal weight women experiencing sPTB, the relative abundance of 14(15)-epoxyeicosatrienoic acid and 14,15-dihydroxyeicosatrienoic acids to other regioisomers were altered at mid-pregnancy. This phenomenon is not yet associated with any biological process, but may be linked to estrogen metabolism. These changes were differentially modulated across BMI groups. In conclusion, using metabolomics we observed distinct BMI-dependent metabolic manifestations among women who had sPTB. These observations suggest the potential to predict sPTB mid-gestation using a new set of metabolomic markers and BMI stratification. This study opens the door to further investigate the role of cytochrome P450/epoxide hydrolase metabolism in sPTB.
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Affiliation(s)
- Kamil Borkowski
- West Coast Metabolomic Center, Genome Center, University of California-Davis, Davis, CA, United States of America
- * E-mail:
| | - John W. Newman
- West Coast Metabolomic Center, Genome Center, University of California-Davis, Davis, CA, United States of America
- United States Department of Agriculture-Agriculture Research Service-Western Human Nutrition Research Center, Davis, CA, United States of America
- Department of Nutrition, University of California-Davis, Davis, CA, United States of America
| | - Nima Aghaeepour
- Department of Anesthesiology, Pain, and Perioperative Medicine, Stanford University School of Medicine, Stanford, CA, United States of America
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States of America
- Department of Biomedical Data Sciences, Stanford University School of Medicine, Stanford, CA, United States of America
| | - Jonathan A. Mayo
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States of America
| | - Ivana Blazenović
- West Coast Metabolomic Center, Genome Center, University of California-Davis, Davis, CA, United States of America
| | - Oliver Fiehn
- West Coast Metabolomic Center, Genome Center, University of California-Davis, Davis, CA, United States of America
| | - David K. Stevenson
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States of America
| | - Gary M. Shaw
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States of America
| | - Suzan L. Carmichael
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States of America
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34
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Jia B, Park D, Hahn Y, Jeon CO. Metagenomic analysis of the human microbiome reveals the association between the abundance of gut bile salt hydrolases and host health. Gut Microbes 2020; 11:1300-1313. [PMID: 32329665 PMCID: PMC7524343 DOI: 10.1080/19490976.2020.1748261] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Bile acid metabolism by the gut microbiome exerts both beneficial and harmful effects on host health. Microbial bile salt hydrolases (BSHs), which initiate bile acid metabolism, exhibit both positive and negative effects on host physiology. In this study, 5,790 BSH homologs were collected and classified into seven clusters based on a sequence similarity network. Next, the abundance and distribution of BSH in 380 metagenomes from healthy participants were analyzed. It was observed that different clusters occupied diverse ecological niches in the human microbiome and that the clusters with signal peptides were relatively abundant in the gut. Then, the association between BSH clusters and 12 human diseases was analyzed by comparing the abundances of BSH genes in patients (n = 1,605) and healthy controls (n = 1,540). The analysis identified a significant association between BSH gene abundance and 10 human diseases, including gastrointestinal diseases, obesity, type 2 diabetes, liver diseases, cardiovascular diseases, and neurological diseases. The associations were further validated by separate cohorts with inflammatory bowel diseases and colorectal cancer. These large-scale studies of enzyme sequences combined with metagenomic data provide a reproducible assessment of the association between gut BSHs and human diseases. This information can contribute to future diagnostic and therapeutic applications of BSH-active bacteria for improving human health.
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Affiliation(s)
- Baolei Jia
- State Key Laboratory of Biobased Material and Green Papermaking, School of Bioengineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China,Department of Life Science, Chung-Ang University, Seoul, Republic of Korea,Baolei Jia Department of Life Science, Chung-Ang University, Seoul06974, Republic of Korea
| | - Dongbin Park
- Department of Life Science, Chung-Ang University, Seoul, Republic of Korea
| | - Yoonsoo Hahn
- Department of Life Science, Chung-Ang University, Seoul, Republic of Korea
| | - Che Ok Jeon
- Department of Life Science, Chung-Ang University, Seoul, Republic of Korea,CONTACT Che Ok Jeon
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Jain AK, le Roux CW, Puri P, Tavakkoli A, Gletsu-Miller N, Laferrère B, Kellermayer R, DiBaise JK, Martindale RG, Wolfe BM. Proceedings of the 2017 ASPEN Research Workshop-Gastric Bypass: Role of the Gut. JPEN J Parenter Enteral Nutr 2019; 42:279-295. [PMID: 29443403 DOI: 10.1002/jpen.1121] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 11/16/2017] [Indexed: 12/11/2022]
Abstract
The goal of the National Institutes of Health-funded American Society for Parenteral and Enteral Nutrition 2017 research workshop (RW) "Gastric Bypass: Role of the Gut" was to focus on the exciting research evaluating gut-derived signals in modulating outcomes after bariatric surgery. Although gastric bypass surgery has undoubted positive effects, the mechanistic basis of improved outcomes cannot be solely explained by caloric restriction. Emerging data suggest that bile acid metabolic pathways, luminal contents, energy balance, gut mucosal integrity, as well as the gut microbiota are significantly modulated after bariatric surgery and may be responsible for the variable outcomes, each of which was rigorously evaluated. The RW served as a timely and novel academic meeting that brought together clinicians and researchers across the scientific spectrum, fostering a unique venue for interdisciplinary collaboration among investigators. It promoted engaging discussion and evolution of new research hypotheses and ideas, driving the development of novel ameliorative, therapeutic, and nonsurgical interventions targeting obesity and its comorbidities. Importantly, a critical evaluation of the current knowledge regarding gut-modulated signaling after bariatric surgery, potential pitfalls, and lacunae were thoroughly addressed.
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Affiliation(s)
- Ajay Kumar Jain
- Department of Pediatrics, SSM Cardinal Glennon Children's Medical Center, Saint Louis University School of Medicine, Saint Louis, Missouri, USA
| | - Carel W le Roux
- Diabetes Complications Research Center, University College Dublin, School of Medicine, Dublin, Ireland
| | - Puneet Puri
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, Vieginia, USA
| | - Ali Tavakkoli
- Brigham and Women's Hospital, Center for Weight Management and Metabolic Surgery, Harvard Medical School, Boston, Massachusetts, USA
| | | | - Blandine Laferrère
- Department of Medicine, Division of Endocrinology, Columbia University, New York, New York, USA
| | | | - John K DiBaise
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona, USA
| | | | - Bruce M Wolfe
- Oregon Health and Science University, Portland, Oregon, USA
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Zeng Y, Mtintsilana A, Goedecke JH, Micklesfield LK, Olsson T, Chorell E. Alterations in the metabolism of phospholipids, bile acids and branched-chain amino acids predicts development of type 2 diabetes in black South African women: a prospective cohort study. Metabolism 2019; 95:57-64. [PMID: 30954560 DOI: 10.1016/j.metabol.2019.04.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 03/12/2019] [Accepted: 04/01/2019] [Indexed: 01/04/2023]
Abstract
BACKGROUND South Africa (SA) has the highest global projected increase in diabetes risk. Factors typically associated with insulin resistance and type 2 diabetes risk in Caucasians are not significant correlates in black African populations. Therefore, we aimed to identify circulating metabolite patterns that predict type 2 diabetes development in this high-risk, yet understudied SA population. METHODS We conducted a prospective cohort study in black SA women with normal glucose tolerance (NGT). Participants were followed for 13 years and developed (i) type 2 diabetes (n = 20, NGT-T2D), (ii) impaired glucose tolerance (IGT) (n = 27, NGT-IGT), or (iii) remained NGT (n = 28, NGT-NGT). Mass-spectrometry based metabolomics and multivariate analyses were used to elucidate metabolite patterns at baseline and at follow-up that were associated with type 2 diabetes development. RESULTS Metabolites of phospholipid, bile acid and branched-chain amino acid (BCAA) metabolism, differed significantly between the NGT-T2D and NGT-NGT groups. At baseline: the NGT-T2D group had i) a higher lysophosphatidylcholine:lysophosphatidylethanolamine ratio containing linoleic acid (LPC(C18:2):LPE(C18:2)), ii) lower proliferation-related bile acids (ursodeoxycholic- and chenodeoxycholic acid), iii) higher levels of leucine and its catabolic intermediates (ketoleucine and C5-carnitine), compared to the NGT-NGT group. At follow-up: the NGT-T2D group had i) lower LPC(C18:2) levels, ii) higher apoptosis-related bile acids (deoxycholic- and glycodeoxycholic acid), and iii) higher levels of all BCAAs and their catabolic intermediates. CONCLUSIONS Changes in lysophospholipid metabolism and the bile acid pool occur during the development of type 2 diabetes in black South African women. Further, impaired leucine catabolism precedes valine and isoleucine catabolism in the development of type 2 diabetes. These metabolite patterns can be useful to identify and monitor type 2 diabetes risk >10 years prior to disease onset and provide insight into the pathophysiology of type 2 diabetes in this high risk, but under-studied population.
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Affiliation(s)
- Yingxu Zeng
- Department of Public Health and Clinical Medicine, Umeå University, Sweden
| | - Asanda Mtintsilana
- MRC/Wits Developmental Pathways for Health Research Unit, Department of Paediatrics, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa
| | - Julia H Goedecke
- MRC/Wits Developmental Pathways for Health Research Unit, Department of Paediatrics, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa; Non-Communicable Diseases Research Unit, South African Medical Research Council, Cape Town, South Africa
| | - Lisa K Micklesfield
- MRC/Wits Developmental Pathways for Health Research Unit, Department of Paediatrics, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa
| | - Tommy Olsson
- Department of Public Health and Clinical Medicine, Umeå University, Sweden
| | - Elin Chorell
- Department of Public Health and Clinical Medicine, Umeå University, Sweden.
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Adamska-Patruno E, Godzien J, Ciborowski M, Samczuk P, Bauer W, Siewko K, Gorska M, Barbas C, Kretowski A. The Type 2 Diabetes Susceptibility PROX1 Gene Variants Are Associated with Postprandial Plasma Metabolites Profile in Non-Diabetic Men. Nutrients 2019; 11:nu11040882. [PMID: 31010169 PMCID: PMC6520869 DOI: 10.3390/nu11040882] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 04/04/2019] [Accepted: 04/17/2019] [Indexed: 02/07/2023] Open
Abstract
The prospero homeobox 1 (PROX1) gene may show pleiotropic effects on metabolism. We evaluated postprandial metabolic alterations dependently on the rs340874 genotypes, and 28 non-diabetic men were divided into two groups: high-risk (HR)-genotype (CC-genotype carriers, n = 12, 35.3 ± 9.5 years old) and low-risk (LR)-genotype (allele T carriers, n = 16, 36.3 ± 7.0 years old). Subjects participated in two meal-challenge-tests with high-carbohydrate (HC, carbohydrates 89%) and normo-carbohydrate (NC, carbohydrates 45%) meal intake. Fasting and 30, 60, 120, and 180 min after meal intake plasma samples were fingerprinted by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). In HR-genotype men, the area under the curve (AUC) of acetylcarnitine levels was higher after the HC-meal [+92%, variable importance in the projection (VIP) = 2.88] and the NC-meal (+55%, VIP = 2.00) intake. After the NC-meal, the HR-risk genotype carriers presented lower AUCs of oxidized fatty acids (−81–66%, VIP = 1.43–3.16) and higher linoleic acid (+80%, VIP = 2.29), while after the HC-meal, they presented lower AUCs of ornithine (−45%, VIP = 1.83), sphingosine (−48%, VIP = 2.78), linoleamide (−45%, VIP = 1.51), and several lysophospholipids (−40–56%, VIP = 1.72–2.16). Moreover, lower AUC (−59%, VIP = 2.43) of taurocholate after the HC-meal and higher (+70%, VIP = 1.42) glycodeoxycholate levels after the NC-meal were observed. Our results revealed differences in postprandial metabolites from inflammatory and oxidative stress pathways, bile acids signaling, and lipid metabolism in PROX1 HR-genotype men. Further investigations of diet–genes interactions by which PROX1 may promote T2DM development are needed.
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Affiliation(s)
- Edyta Adamska-Patruno
- Clinical Research Centre, Medical University of Bialystok, 15-089 Bialystok, Poland.
| | - Joanna Godzien
- Clinical Research Centre, Medical University of Bialystok, 15-089 Bialystok, Poland.
| | - Michal Ciborowski
- Clinical Research Centre, Medical University of Bialystok, 15-089 Bialystok, Poland.
| | - Paulina Samczuk
- Clinical Research Centre, Medical University of Bialystok, 15-089 Bialystok, Poland.
| | - Witold Bauer
- Clinical Research Centre, Medical University of Bialystok, 15-089 Bialystok, Poland.
| | - Katarzyna Siewko
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, 15-089 Bialystok, Poland.
| | - Maria Gorska
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, 15-089 Bialystok, Poland.
| | - Coral Barbas
- Center for Metabolomics and Bioanalysis (CEMBIO), Universidad CEU San Pablo, 28003 Madrid, Spain.
| | - Adam Kretowski
- Clinical Research Centre, Medical University of Bialystok, 15-089 Bialystok, Poland.
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, 15-089 Bialystok, Poland.
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Chen YS, Liu HM, Lee TY. Ursodeoxycholic Acid Regulates Hepatic Energy Homeostasis and White Adipose Tissue Macrophages Polarization in Leptin-Deficiency Obese Mice. Cells 2019; 8:cells8030253. [PMID: 30884843 PMCID: PMC6468643 DOI: 10.3390/cells8030253] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 03/12/2019] [Accepted: 03/13/2019] [Indexed: 12/15/2022] Open
Abstract
Obesity has been shown to play a role in the pathogenesis of several forms of metabolic syndrome, including non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes. Ursodeoxycholic acid (UDCA) has been shown to possess antioxidant and anti-inflammatory properties and prevents mitochondrial dysfunction in the progression of obesity-associated diseases. The aim of the study was to evaluate the mechanisms of UDCA during obesity-linked hepatic mitochondrial dysfunction and obesity-associated adipose tissue macrophage-induced inflammation in obese mice. UDCA significantly decreased lipid droplets, reduced free fatty acids (FFA) and triglycerides (TG), improved mitochondrial function, and enhanced white adipose tissue browning in ob/ob mice. This is associated with increased hepatic energy expenditure, mitochondria biogenesis, and incorporation of bile acid metabolism (Abca1, Abcg1 mRNA and BSEP, FGFR4, and TGR5 protein). In addition, UDCA downregulated NF-κB and STAT3 phosphorylation by negative regulation of the expression of SOCS1 and SOCS3 signaling. These changes were accompanied by decreased angiogenesis, as shown by the downregulation of VEGF, VCAM, and TGF-βRII expression. Importantly, UDCA is equally effective in reducing whole body adiposity. This is associated with decreased adipose tissue expression of macrophage infiltration (CD11b, CD163, and CD206) and lipogenic capacity markers (lipofuscin, SREBP-1, and CD36). Furthermore, UDCA significantly upregulated adipose browning in association with upregulation of SIRT-1-PGC1-α signaling in epididymis adipose tissue (EWAT). These results suggest that multi-targeted therapies modulate glucose and lipid biosynthesis fluxes, inflammatory response, angiogenesis, and macrophage differentiation. Therefore, it may be suggested that UDCA treatment may be a novel therapeutic agent for obesity.
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Affiliation(s)
- Yu-Sheng Chen
- Graduate Institute of Clinical Medical Science, College of Medicine, Chang Gung University, No. 259, Wen-Hwa 1st Road, Kwei-Shan, Taoyuan 333, Taiwan.
- Division of Chinese Acupuncture, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, No. 123, Dinghu Road, Guishan District, Taoyuan 333, Taiwan.
| | - Hsuan-Miao Liu
- Graduate Institute of Traditional Chinese Medicine, School of Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
| | - Tzung-Yan Lee
- Graduate Institute of Traditional Chinese Medicine, School of Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung 204, Taiwan.
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Sun L, Xu H, Ye J, Gaikwad NW. Comparative effect of black, green, oolong, and white tea intake on weight gain and bile acid metabolism. Nutrition 2019; 65:208-215. [PMID: 31031064 DOI: 10.1016/j.nut.2019.02.006] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 01/23/2019] [Accepted: 02/14/2019] [Indexed: 02/07/2023]
Abstract
OBJECTIVE The beneficial effects of tea on health, including obesity, are well known. However, the comparative effects of black, green, white, and oolong teas, which are prepared from the same fresh leaves, on weight gain and the potential mechanisms involved are not yet fully understood. Bile acids (BAs) are shown to be powerful regulators of metabolism; however, to our knowledge, no studies have investigated the effect of tea on BA metabolism. The aim of this study was to investigate the modulatory effects that green, black, white, and oolong teas that were prepared from the same raw tea leaves have on the plasma BA profile. METHODS Female rats were dosed with the aforementioned tea types as their sole source of drinking fluid for 28 d. We then investigated their weight and effect on BA metabolic profile using advanced ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS)-based metabolomics. RESULTS The UPLC-MS/MS analysis of the plasma show that the levels of murocholic acid, glycochenodeoxycholic acid, glycocholic acid, glycodeoxycholic acid, taurochenodeoxycholic acid, tauroursodeoxycholic acid, taurodeoxycholic acid, tauromuricholic acid, and taurocholic acid were increased; whereas levels of taurolithocholic acid and isolithocholic acid were decreased after drinking green, oolong, and white tea types compared with control. Surprisingly, oolong tea significantly influenced reduction in relative weight compared with control, black, and green tea; whereas black, green, and white teas had no effects on weight compared with control. CONCLUSIONS Green, black, oolong, and white teas altered the BA metabolism. This change in BA metabolism could be associated with the health benefit effects of tea. Oolong tea was most effective in reducing weight.
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Affiliation(s)
- Lili Sun
- Tea Research Institute, Zhejiang University, Hangzhou, China
| | - Hairong Xu
- Tea Research Institute, Zhejiang University, Hangzhou, China
| | - Jianhui Ye
- Tea Research Institute, Zhejiang University, Hangzhou, China
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40
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41
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Andrew CA, Umashanker D, Aronne LJ, Shukla AP. Intestinal and Gastric Origins for Diabetes Resolution After Bariatric Surgery. Curr Obes Rep 2018; 7:139-146. [PMID: 29637413 DOI: 10.1007/s13679-018-0302-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW This paper will review the intestinal and gastric origins for diabetes resolution after bariatric surgery. RECENT FINDINGS In addition to the known metabolic effects of changes in the gut hormonal milieu, more recent studies investigating the role of the microbiome and bile acids and changes in nutrient sensing mechanisms have been shown to have glycemic effects in human and animal models. Independent of weight loss, there are multiple mechanisms that may lead to amelioration or resolution of diabetes following bariatric surgery. There is abundant evidence pointing to changes in gut hormones, bile acids, gut microbiome, and intestinal nutrient sensing; more research is needed to clearly delineate their role in regulating energy and glucose homeostasis after bariatric surgery.
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MESH Headings
- Animals
- Bariatric Surgery
- Bile Acids and Salts/metabolism
- Biomarkers/blood
- Biomarkers/metabolism
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/physiopathology
- Diabetes Mellitus, Type 2/therapy
- Diet, Reducing
- Dysbiosis/complications
- Dysbiosis/etiology
- Dysbiosis/microbiology
- Dysbiosis/prevention & control
- Gastrointestinal Microbiome
- Humans
- Insulin Resistance
- Intestinal Mucosa/innervation
- Intestinal Mucosa/metabolism
- Intestinal Mucosa/microbiology
- Intestinal Mucosa/physiopathology
- Intestines/innervation
- Intestines/microbiology
- Intestines/physiopathology
- Neurons, Afferent/metabolism
- Neurons, Efferent/metabolism
- Obesity, Morbid/complications
- Obesity, Morbid/diet therapy
- Obesity, Morbid/physiopathology
- Obesity, Morbid/surgery
- Weight Loss
- Weight Reduction Programs
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Affiliation(s)
- Caroline A Andrew
- Comprehensive Weight Control Center, Division of Endocrinology, Diabetes & Metabolism, Weill Cornell Medical College, 1165 York Avenue, New York, NY, 10065, USA
| | - Devika Umashanker
- Comprehensive Medical Weight Management, Department of Bariatric Surgery, Hartford HealthCare Medical Group, Hartford, CT, USA
| | - Louis J Aronne
- Comprehensive Weight Control Center, Division of Endocrinology, Diabetes & Metabolism, Weill Cornell Medical College, 1165 York Avenue, New York, NY, 10065, USA
| | - Alpana P Shukla
- Comprehensive Weight Control Center, Division of Endocrinology, Diabetes & Metabolism, Weill Cornell Medical College, 1165 York Avenue, New York, NY, 10065, USA.
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Agustí A, García-Pardo MP, López-Almela I, Campillo I, Maes M, Romaní-Pérez M, Sanz Y. Interplay Between the Gut-Brain Axis, Obesity and Cognitive Function. Front Neurosci 2018; 12:155. [PMID: 29615850 PMCID: PMC5864897 DOI: 10.3389/fnins.2018.00155] [Citation(s) in RCA: 191] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 02/26/2018] [Indexed: 12/12/2022] Open
Abstract
Obesity continues to be one of the major public health problems due to its high prevalence and co-morbidities. Common co-morbidities not only include cardiometabolic disorders but also mood and cognitive disorders. Obese subjects often show deficits in memory, learning and executive functions compared to normal weight subjects. Epidemiological studies also indicate that obesity is associated with a higher risk of developing depression and anxiety, and vice versa. These associations between pathologies that presumably have different etiologies suggest shared pathological mechanisms. Gut microbiota is a mediating factor between the environmental pressures (e.g., diet, lifestyle) and host physiology, and its alteration could partly explain the cross-link between those pathologies. Westernized dietary patterns are known to be a major cause of the obesity epidemic, which also promotes a dysbiotic drift in the gut microbiota; this, in turn, seems to contribute to obesity-related complications. Experimental studies in animal models and, to a lesser extent, in humans suggest that the obesity-associated microbiota may contribute to the endocrine, neurochemical and inflammatory alterations underlying obesity and its comorbidities. These include dysregulation of the HPA-axis with overproduction of glucocorticoids, alterations in levels of neuroactive metabolites (e.g., neurotransmitters, short-chain fatty acids) and activation of a pro-inflammatory milieu that can cause neuro-inflammation. This review updates current knowledge about the role and mode of action of the gut microbiota in the cross-link between energy metabolism, mood and cognitive function.
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Affiliation(s)
- Ana Agustí
- Microbial Ecology and Nutrition Research Unit, Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia, Spain
| | - Maria P García-Pardo
- Microbial Ecology and Nutrition Research Unit, Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia, Spain
| | - Inmaculada López-Almela
- Microbial Ecology and Nutrition Research Unit, Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia, Spain
| | - Isabel Campillo
- Microbial Ecology and Nutrition Research Unit, Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia, Spain
| | - Michael Maes
- IMPACT Strategic Research Centre, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - Marina Romaní-Pérez
- Microbial Ecology and Nutrition Research Unit, Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia, Spain
| | - Yolanda Sanz
- Microbial Ecology and Nutrition Research Unit, Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia, Spain
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Lee Y, Pamungkas AD, Medriano CAD, Park J, Hong S, Jee SH, Park YH. High-resolution metabolomics determines the mode of onset of type 2 diabetes in a 3-year prospective cohort study. Int J Mol Med 2017; 41:1069-1077. [PMID: 29207196 DOI: 10.3892/ijmm.2017.3275] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 11/07/2017] [Indexed: 11/06/2022] Open
Abstract
Type 2 diabetes mellitus (DM) is a progressive disease and the rate of progression from non-diabetes to DM varies considerably between individuals, ranging from a few months to many years. It is important to understand the mechanisms underlying the progression of diabetes. In the present study, a high-resolution metabolomics (HRM) analysis was performed to detect potential biomarkers and pathways regulating the mode of onset by comparing subjects who developed and did not develop type 2 DM at the second year in a 3-year prospective cohort study. Metabolic profiles correlated with progression to DM were examined. The subjects (n=98) were classified into four groups: Control (did not develop DM for 3 years), DM (diagnosed with DM at the start of the study), DM onset at the third year and DM onset at the second year. The focus was on the comparison of serum samples of the DM groups with onset at the second and third year from the first year, where these two groups had not developed DM, yet. Analyses involved sample examination using liquid chromatography-mass spectrometry-based HRM and multivariate statistical analysis of the data. Metabolic differences were identified across all analyses with the affected pathways involved in metabolism associated with steroid biosynthesis and bile acid biosynthesis. In the first year, higher levels of cholesterol {mass-to charge ratio (m/z) 369.35, (M+H-H2O)+}, 25-hydroxycholesterol [m/z 403.36, (M+H)+], 3α,7α-dihydroxy-5β-cholestane [m/z 443.33, (M+K)+], 4α-methylzymosterol-4-carboxylate [m/z 425.34, (M+H‑H2O)+], and lower levels of 24,25-dihydrolanosterol [m/z 429.40, (M+H)+] were evident in the group with DM onset at the second year compared with those in the group with DM onset at the third year. These results, with a focus on the cholesterol biosynthesis pathway, point to important aspects in the development of DM and may aid in the development of more effective means of treatment and prevention.
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Affiliation(s)
- Yeseung Lee
- Metabolomics Laboratory, College of Pharmacy, Korea University, Sejong City 30019, Republic of Korea
| | - Aryo Dimas Pamungkas
- Metabolomics Laboratory, College of Pharmacy, Korea University, Sejong City 30019, Republic of Korea
| | - Carl Angelo D Medriano
- Metabolomics Laboratory, College of Pharmacy, Korea University, Sejong City 30019, Republic of Korea
| | - Jinsung Park
- Department of Control and Instrumentation on Engineering, Korea University, Sejong City 30019, Republic of Korea
| | - Seri Hong
- Department of Epidemiology and Health Promotion and Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul 03722, Republic of Korea
| | - Sun Ha Jee
- Department of Epidemiology and Health Promotion and Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul 03722, Republic of Korea
| | - Youngja H Park
- Metabolomics Laboratory, College of Pharmacy, Korea University, Sejong City 30019, Republic of Korea
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Abstract
Premature atherosclerosis in diabetes accounts for much of the decreased life span. New treatments have reduced this risk considerably. This review explores the relationship among the disturbances in glucose, lipid, and bile salt metabolic pathways that occur in diabetes. In particular, excess nutrient intake and starvation have major metabolic effects, which have allowed us new insights into the disturbance that occurs in diabetes. Metabolic regulators such as the forkhead transcription factors, the farnesyl X transcription factors, and the fibroblast growth factors have become important players in our understanding of the dysregulation of metabolism in diabetes and overnutrition. The disturbed regulation of lipoprotein metabolism in both the intestine and the liver has been more clearly defined over the past few years, and the atherogenicity of the triglyceride-rich lipoproteins, and - in tandem - low levels of high-density lipoproteins, is seen now as very important. New information on the apolipoproteins that control lipoprotein lipase activity has been obtained. This is an exciting time in the battle to defeat diabetic atherosclerosis.
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Affiliation(s)
- GH Tomkin
- Diabetes Institute of Ireland, Beacon Hospital
- Trinity College, University of Dublin, Dublin, Ireland
- Correspondence: GH Tomkin, Diabetes Institute of Ireland, Beacon Hospital, Clontra, Quinns Road, Shankill, Dublin 18, Ireland, Email
| | - D Owens
- Diabetes Institute of Ireland, Beacon Hospital
- Trinity College, University of Dublin, Dublin, Ireland
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