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Biyabani A, Ghorbani F, Koushki M, Nedaei K, Hemmati M, Mahdei Nasir Mahalleh N, Ghadimi D. Quercetin and calorie restriction improve leptin/adiponectin balance through reducing high-fat diet-induced oxidative stress in male BALB/c mice. Biochem Biophys Res Commun 2025; 742:151073. [PMID: 39637705 DOI: 10.1016/j.bbrc.2024.151073] [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: 08/13/2024] [Revised: 10/29/2024] [Accepted: 11/25/2024] [Indexed: 12/07/2024]
Abstract
Throughout the recent decades, obesity has become a serious health problem that raises the risk of several diseases, including cancer, diabetes, hypertension, heart disease, neurological musculoskeletal disorders, and Non-alcoholic fatty liver disease. Some strategies, such as dietary interventions, calorie restriction (CR), and the use of antioxidant compounds, have been proposed to improve quality of life in relation to obesity. The goal of this study was to characterize the effects of CR and quercetin (QUER) on obesity-induced oxidative stress (OS). Thirty 8-week-old male BALB/c mice were divided into 5 groups of six mice each: normal diet, high-fat diet (HFD), HFD + CR, HFD + QUER (15 mg kg-1, IP), and HFD + QUER + CR. CR was applied as two fasting days with an interval of two days in a week. Catalase (CAT), Paraxonase 1 (PON1) and adiponectin (APN) were decreased in the HFD group, while the combination of QUER and CR increased these parameters. Treatment with QUER and CR improved Alanine transaminase and Alkaline Phosphatase enzyme activity and also the amount of leptin and insulin. Moreover, combined QUER and CR also reduced triacylglycerol (TAG), total cholesterol and TAG droplets in hepatocytes. Decreased OS was associated with the higher expression of NAD(P)H Quinone Oxidoreductase 1(NQO1) and reduced hepatic vacuoles in QUER and CR-HFD treated groups. In conclusion, these findings suggest that the combination of QUER and CR might exert protective impacts on obesity through alleviating OS and the regulation of metabolism.
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Affiliation(s)
- Arezou Biyabani
- Department of Clinical Biochemistry, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Fereshte Ghorbani
- Department of Clinical Biochemistry, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mehdi Koushki
- Department of Clinical Biochemistry, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Keivan Nedaei
- Department of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mina Hemmati
- Department of Clinical Biochemistry, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.
| | - Nima Mahdei Nasir Mahalleh
- Department of Clinical Biochemistry, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Darya Ghadimi
- Department of Clinical Biochemistry, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
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Tajima T, Kaga H, Ito N, Kogai T, Naito H, Kakehi S, Kadowaki S, Nishida Y, Kawamori R, Tamura Y, Watada H. Rationale and Design of the Study to Investigate the Metabolic Action of Imeglimin on Patients with Type 2 Diabetes Mellitus (SISIMAI). Diabetes Ther 2024; 15:2569-2580. [PMID: 39347897 PMCID: PMC11561198 DOI: 10.1007/s13300-024-01655-x] [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: 07/26/2024] [Accepted: 09/10/2024] [Indexed: 10/01/2024] Open
Abstract
INTRODUCTION Imeglimin is a first-in-class, novel, oral glucose-lowering agent for the treatment of type 2 diabetes mellitus. The efficacy and safety of imeglimin as an antidiabetic agent have been investigated in clinical trials. However, its metabolic effects in humans have not yet been fully elucidated. METHODS The Study to InveStIgate the Metabolic Action of Imeglimin on patients with type 2 diabetes mellitus (SISIMAI) is a single-arm intervention study. In this study, we have recruited 25 patients with type 2 diabetes to receive 2000 mg/day imeglimin for 20 weeks. We perform a 75-g oral glucose tolerance test (OGTT) with double-glucose tracers, a two-step hyperinsulinemic-euglycemic clamp with glucose tracer, ectopic fat measurement by proton magnetic resonance spectroscopy, visceral/subcutaneous fat area measurement by magnetic resonance imaging, muscle biopsy, and evaluation of fitness level by cycle ergometer before and after imeglimin administration. PLANNED OUTCOMES The primary outcome is the change in area under the curve of glucose levels during the OGTT after 20 weeks of imeglimin treatment. We also calculate the endogenous glucose production, rate of oral glucose appearance, and rate of glucose disappearance from the data during the 75-g OGTT and compare them between pre- and post-treatment. Additionally, we will compare other parameters, such as the changes in tissue-specific insulin sensitivity, ectopic fat accumulation, visceral/subcutaneous fat area accumulation, and fitness level between each point. This is the first study to investigate the organ-specific metabolic action of imeglimin in patients with type 2 diabetes mellitus using the 75-g OGTT with the double tracer method. The results of this study are expected to provide useful information for drug selection based on the pathophysiology of individual patients with type 2 diabetes mellitus. TRIAL REGISTRATION jRCTs031210600.
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Affiliation(s)
- Tsubasa Tajima
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Hideyoshi Kaga
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
| | - Naoaki Ito
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Toshiki Kogai
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Hitoshi Naito
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Saori Kakehi
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Satoshi Kadowaki
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Yuya Nishida
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Ryuzo Kawamori
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yoshifumi Tamura
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Sports Medicine and Sportology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hirotaka Watada
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
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Suzuki A, Hayashi A, Oda S, Fujishima R, Shimizu N, Matoba K, Taguchi T, Toki T, Miyatsuka T. Prolonged impacts of sodium glucose cotransporter-2 inhibitors on metabolic dysfunction-associated steatotic liver disease in type 2 diabetes: a retrospective analysis through magnetic resonance imaging. Endocr J 2024; 71:767-775. [PMID: 38811192 DOI: 10.1507/endocrj.ej24-0005] [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: 05/31/2024] Open
Abstract
The beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in people with type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD) have been suggested in several reports based on serological markers, imaging data, and histopathology associated with steatotic liver disease. However, evidence regarding their long-term effects is currently insufficient. In this retrospective observational study, 34 people with T2D and MASLD, treated with SGLT2 inhibitors, were examined by proton density fat fraction derived by magnetic resonance imaging (MRI-PDFF) and other clinical data before, one year after the treatment. Furthermore, 22 of 34 participants underwent MRI-PDFF five years after SGLT2 inhibitors were initiated. HbA1c decreased from 8.9 ± 1.8% to 7.8 ± 1.0% at 1 year (p = 0.006) and 8.0 ± 1.1% at 5 years (p = 0.122). Body weight and fat mass significantly reduced from baseline to 1 and 5 year(s), respectively. MRI-PDFF significantly decreased from 15.3 ± 7.8% at baseline to 11.9 ± 7.6% (p = 0.001) at 1 year and further decreased to 11.3 ± 5.7% (p = 0.013) at 5 years. Thus, a 5-year observation demonstrated that SGLT2 inhibitors have beneficial effects on liver steatosis in people with T2D and MASLD.
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Affiliation(s)
- Agena Suzuki
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Akinori Hayashi
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Satoshi Oda
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Rei Fujishima
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Naoya Shimizu
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Kenta Matoba
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Tomomi Taguchi
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Takuya Toki
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Takeshi Miyatsuka
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
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Rundle M, Fiamoncini J, Thomas EL, Wopereis S, Afman LA, Brennan L, Drevon CA, Gundersen TE, Daniel H, Perez IG, Posma JM, Ivanova DG, Bell JD, van Ommen B, Frost G. Diet-induced Weight Loss and Phenotypic Flexibility Among Healthy Overweight Adults: A Randomized Trial. Am J Clin Nutr 2023; 118:591-604. [PMID: 37661105 PMCID: PMC10517213 DOI: 10.1016/j.ajcnut.2023.07.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 06/28/2023] [Accepted: 07/03/2023] [Indexed: 09/05/2023] Open
Abstract
BACKGROUND The capacity of an individual to respond to changes in food intake so that postprandial metabolic perturbations are resolved, and metabolism returns to its pre-prandial state, is called phenotypic flexibility. This ability may be a more important indicator of current health status than metabolic markers in a fasting state. AIM In this parallel randomized controlled trial study, an energy-restricted healthy diet and 2 dietary challenges were used to assess the effect of weight loss on phenotypic flexibility. METHODS Seventy-two volunteers with overweight and obesity underwent a 12-wk dietary intervention. The participants were randomized to a weight loss group (WLG) with 20% less energy intake or a weight-maintenance group (WMG). At weeks 1 and 12, participants were assessed for body composition by MRI. Concurrently, markers of metabolism and insulin sensitivity were obtained from the analysis of plasma metabolome during 2 different dietary challenges-an oral glucose tolerance test (OGTT) and a mixed-meal tolerance test. RESULTS Intended weight loss was achieved in the WLG (-5.6 kg, P < 0.0001) and induced a significant reduction in total and regional adipose tissue as well as ectopic fat in the liver. Amino acid-based markers of insulin action and resistance such as leucine and glutamate were reduced in the postprandial phase of the OGTT in the WLG by 11.5% and 28%, respectively, after body weight reduction. Weight loss correlated with the magnitude of changes in metabolic responses to dietary challenges. Large interindividual variation in metabolic responses to weight loss was observed. CONCLUSION Application of dietary challenges increased sensitivity to detect metabolic response to weight loss intervention. Large interindividual variation was observed across a wide range of measurements allowing the identification of distinct responses to the weight loss intervention and mechanistic insight into the metabolic response to weight loss.
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Affiliation(s)
- Milena Rundle
- Section of Nutrition, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Jarlei Fiamoncini
- Food Research Center, Department of Food Science and Experimental Nutrition, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - E Louise Thomas
- Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, United Kingdom
| | - Suzan Wopereis
- Department of Microbiology and Systems Biology, Netherlands Organization for Applied Scientific Research, Hague, The Netherlands
| | - Lydia A Afman
- Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands
| | - Lorraine Brennan
- UCD School of Agriculture and Food Science, Institute of Food and Health, University College Dublin, Belfield, Dublin, Ireland
| | - Christian A Drevon
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway; Vitas Ltd, Oslo Science Park, Oslo, Norway
| | | | - Hannelore Daniel
- Hannelore Daniel, Molecular Nutrition Unit, Technische Universität München, München, Germany
| | - Isabel Garcia Perez
- Section of Nutrition, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Joram M Posma
- Section of Bioinformatics, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Diana G Ivanova
- Department of Biochemistry, Molecular Medicine and Nutrigenomics, Faculty of Pharmacy, Medical University, Varna, Bulgaria
| | - Jimmy D Bell
- Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, United Kingdom
| | - Ben van Ommen
- Department of Microbiology and Systems Biology, Netherlands Organization for Applied Scientific Research, Hague, The Netherlands
| | - Gary Frost
- Section of Nutrition, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom.
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Kadowaki S, Tamura Y, Sugimoto D, Kaga H, Suzuki R, Someya Y, Yamasaki N, Sato M, Kakehi S, Kanazawa A, Kawamori R, Watada H. A Short-Term High-Fat Diet Worsens Insulin Sensitivity with Changes in Metabolic Parameters in Non-Obese Japanese Men. J Clin Med 2023; 12:4084. [PMID: 37373776 DOI: 10.3390/jcm12124084] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 06/10/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
A short-term high-calorie high-fat diet (HCHFD) impairs insulin sensitivity in non-obese South Asian but not Caucasian men; however, the effect of short-term HCHFD on insulin sensitivity in East Asians is unknown. We recruited 21 healthy non-obese Japanese men to evaluate metabolic parameters and gut microbiota before and after 6-day HCHFD consisting of a regular diet plus a 45% energy excess with dairy fat supplementation. We evaluated tissue-specific insulin sensitivity and metabolic clearance rate of insulin (MCRI) using a two-step hyperinsulinemic euglycemic clamp, glucose tolerance using the glucose tolerance test, and measured ectopic fat in muscle and the liver using ¹H-magnetic resonance spectroscopy. The primary outcome of this study was insulin sensitivity measured by the clamp study. The secondary/exploratory outcomes were other metabolic changes. After HCHFD, levels of circulating lipopolysaccharide binding protein (LBP), a marker of endotoxemia, increased by 14%. In addition, intramyocellular lipid levels in the tibialis anterior and soleus and intrahepatic lipid levels increased by 47%, 31%, and 200%, respectively. Insulin sensitivity decreased by 4% in muscle and 8% in liver. However, even with reduced insulin sensitivity, glucose metabolism was maintained by increased serum insulin concentrations due to lower MCRI and higher endogenous insulin secretion during the clamp. Glucose levels during the meal tolerance test were comparable before and after HCHFD. In conclusion, short-term HCHFD impaired insulin sensitivity in the muscle and livers of non-obese Japanese men with increased LBP and ectopic fat accumulation. Elevated insulin levels from modulated insulin secretion and clearance might contribute to the maintenance of normal glucose metabolism during the clamp and meal tolerance test.
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Affiliation(s)
- Satoshi Kadowaki
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Yoshifumi Tamura
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
- Sportology Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
- Sports Medicine & Sportology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Daisuke Sugimoto
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Hideyoshi Kaga
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Ruriko Suzuki
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Yuki Someya
- Sportology Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Nozomu Yamasaki
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Motonori Sato
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Saori Kakehi
- Sportology Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
- Sports Medicine & Sportology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Akio Kanazawa
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Ryuzo Kawamori
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
- Sportology Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
- Sports Medicine & Sportology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Hirotaka Watada
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
- Sportology Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
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Wang X, Zhao B, Sun H, You H, Qu S. Effects of sitagliptin on intrahepatic lipid content in patients with non-alcoholic fatty liver disease. Front Endocrinol (Lausanne) 2022; 13:866189. [PMID: 36072931 PMCID: PMC9441565 DOI: 10.3389/fendo.2022.866189] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 08/05/2022] [Indexed: 11/13/2022] Open
Abstract
PURPOSE Dipeptidyl peptidase-4 inhibitors (DPP-4I), key regulators of the actions of incretin hormones, exert anti-hyperglycemic effects in type 2 diabetes mellitus (T2DM) patients. A major unanswered question concerns the potential ability of DPP-4I to improve intrahepatic lipid (IHL) content in nonalcoholic fatty liver disease (NAFLD) patients. The aim of this study was to evaluate the effects of sitagliptin on IHL in NAFLD patients. METHODS A prospective, 24-week, single-center, open-label, comparative study enrolled 68 Chinese NAFLD patients with T2DM. Subjects were randomly divided into 4 groups: control group who did not take medicine (14 patients); sitagliptin group who received sitagliptin treatment (100mg per day) (17 patients); metformin group who received metformin (500mg three times per day) (17 patients); and sitagliptin plus metformin group who received sitagliptin (100mg per day) and metformin (500 mg three times per day) (20 patients). IHL, physical examination (waist circumstances, WC; body mass index, BMI), glucose-lipid metabolism (fasting plasma glucose, FPG; hemoglobin A1c, Hb1A1c; triglycerides; cholesterol; alanine aminotransferase, ALT; aspartate aminotransferase, AST) were measured at baseline and at 24 weeks. RESULTS 1) WC and BMI were decreased significantly in all groups except control group (all P<0.05). 2) There was no statistically significant difference in IHL among the sitagliptin, metformin, and sitagliptin plus metformin groups before and after treatment(all P>0.05). Only the metformin group showed a statistically significant difference in IHL before and after treatment(P<0.05). 3) Sitagliptin treatment led to a significant decrease in FBG and HbA1c when compared with the control group (all P<0.01). Additionally, HhA1c was significant decreased in the sitagliptin group when compared with the metformin group (P< 0.05). 4) HbA1c and FBG were decreased by 0.8% and 0.7 mmol/l respectively and the percentage of patients with HbA1c less than 7% was 65% with sitagliptin treatment. CONCLUSION Sitagliptin improves abnormalities in glucose metabolism, but not reduces the IHL in T2DM with NAFLD, indicating that sitagliptin might be a therapeutic option for treatment of NAFLD indirectly while not directly on IHL. Clinical Trial Registration: https://clinicaltrials.gov/, identifier CTR# NCT05480007.
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Affiliation(s)
- Xingchun Wang
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
- Shanghai Center of Thyroid Diseases, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Bangfeng Zhao
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
| | - Hang Sun
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
| | - Hui You
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
| | - Shen Qu
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
- Shanghai Center of Thyroid Diseases, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Shen Qu,
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Endurance Runners with Intramyocellular Lipid Accumulation and High Insulin Sensitivity Have Enhanced Expression of Genes Related to Lipid Metabolism in Muscle. J Clin Med 2020; 9:jcm9123951. [PMID: 33291227 PMCID: PMC7762159 DOI: 10.3390/jcm9123951] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 11/20/2020] [Accepted: 12/03/2020] [Indexed: 01/04/2023] Open
Abstract
Context: Endurance-trained athletes have high oxidative capacities, enhanced insulin sensitivities, and high intracellular lipid accumulation in muscle. These characteristics are likely due to altered gene expression levels in muscle. Design and setting: We compared intramyocellular lipid (IMCL), insulin sensitivity, and gene expression levels of the muscle in eight nonobese healthy men (control group) and seven male endurance athletes (athlete group). Their IMCL levels were measured by proton-magnetic resonance spectroscopy, and their insulin sensitivity was evaluated by glucose infusion rate (GIR) during a euglycemic–hyperinsulinemic clamp. Gene expression levels in the vastus lateralis were evaluated by quantitative RT-PCR (qRT-PCR) and microarray analysis. Results: IMCL levels in the tibialis anterior muscle were approximately 2.5 times higher in the athlete group compared to the control group, while the IMCL levels in the soleus muscle and GIR were comparable. In the microarray hierarchical clustering analysis, gene expression patterns were not clearly divided into control and athlete groups. In a gene set enrichment analysis with Gene Ontology gene sets, “RESPONSE TO LIPID” was significantly upregulated in the athlete group compared with the control group. Indeed, qRT-PCR analysis revealed that, compared to the control group, the athlete group had 2–3 times higher expressions of proliferator-activated receptor gamma coactivator-1 alpha (PGC1A), adiponectin receptors (AdipoRs), and fatty acid transporters including fatty acid transporter-1, plasma membrane-associated fatty acid binding protein, and lipoprotein lipase. Conclusions: Endurance runners with higher IMCL levels have higher expression levels of genes related to lipid metabolism such as PGC1A, AdipoRs, and fatty acid transporters in muscle.
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Someya Y, Tamura Y, Takeno K, Kakehi S, Funayama T, Furukawa Y, Eshima H, Watanabe K, Kurihara T, Yanagiya T, Kaga H, Suzuki R, Sugimoto D, Kadowaki S, Kawamori R, Watada H. Decreased Muscle Strength of Knee Flexors is Associated with Impaired Muscle Insulin Sensitivity in Non-Diabetic Middle-Aged Japanese Male Subjects. Diabetes Ther 2020; 11:2401-2410. [PMID: 32767276 PMCID: PMC7509026 DOI: 10.1007/s13300-020-00895-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Indexed: 11/29/2022] Open
Abstract
INTRODUCTION Reduced muscle strength is a high risk factor for type 2 diabetes mellitus, and this association is especially strong in non-obese male individuals. However, it remains unclear how reduced muscle strength affects susceptibility to diabetes. We have examined whether lower limb muscle strength is associated with insulin resistance in non-obese Japanese male subjects. METHODS Measurements from 64 non-diabetic, non-obese, middle-aged Japanese men were analyzed. Insulin sensitivity in muscle was measured using the hyperinsulinemic-euglycemic clamp. Isometric muscle strength of the knee extensor and flexor muscles was evaluated using a dynameter. RESULTS Lower muscle strength of knee flexors, but not knee extensors, was associated with impaired muscle insulin sensitivity (knee flexor muscles: low, medium, and high strength was 6.6 ± 2.2, 7.3 ± 2.0, and 8.8 ± 2.2 mg/kg per minute, respectively, p for trend < 0.05; knee extensor muscles: low, medium, and high strength was 7.3 ± 2.5, 7.5 ± 2.2, and 7.8 ± 2.3 mg/kg per minute, respectively, p for trend = 0.73). Knee flexor muscle strength was also identified as an independent determinant of insulin sensitivity in the multiple regression analysis (β = 0.274, p = 0.036). CONCLUSIONS Diminished strength of knee flexor muscles, but not knee extensor muscles, was associated with muscle insulin sensitivity in non-diabetic, non-obese Japanese male subjects.
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Affiliation(s)
- Yuki Someya
- Sportology Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
- Graduate School of Health and Sports Science, Juntendo University, 1-1 Hiraga-gakuendai, Inzai City, Chiba, 270-1695, Japan
| | - Yoshifumi Tamura
- Sportology Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
- Faculty of International Liberal Arts, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
| | - Kageumi Takeno
- Sportology Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Saori Kakehi
- Sportology Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Takashi Funayama
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Yasuhiko Furukawa
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Hiroaki Eshima
- Sportology Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Keisuke Watanabe
- Graduate School of Health and Sports Science, Juntendo University, 1-1 Hiraga-gakuendai, Inzai City, Chiba, 270-1695, Japan
| | - Toshiyuki Kurihara
- Graduate School of Health and Sports Science, Juntendo University, 1-1 Hiraga-gakuendai, Inzai City, Chiba, 270-1695, Japan
| | - Toshio Yanagiya
- Graduate School of Health and Sports Science, Juntendo University, 1-1 Hiraga-gakuendai, Inzai City, Chiba, 270-1695, Japan
| | - Hideyoshi Kaga
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Ruriko Suzuki
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Daisuke Sugimoto
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Satoshi Kadowaki
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Ryuzo Kawamori
- Sportology Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Hirotaka Watada
- Sportology Center, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
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10
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Fasting serum free glycerol concentration is a potential surrogate marker of visceral obesity and insulin sensitivity in middle-aged Japanese men. J Clin Lipidol 2020; 14:522-530. [PMID: 32654995 DOI: 10.1016/j.jacl.2020.06.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 06/03/2020] [Accepted: 06/03/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Triglyceride (TG) is a tri-ester composed of a glycerol and 3 fatty acids. Degradation of TG in adipose tissue is increased in the fasting state but inhibited in the postprandial state. Although insulin suppresses adipose TG degradation, patients with insulin resistance have high concentrations of insulin and free glycerol (FG) in the fasting state. OBJECTIVE We examined whether the fasting FG concentration reflects visceral obesity and insulin sensitivity in middle-aged Japanese men. METHODS We measured the fasting serum FG concentration in 72 males aged 30 to 50 years using a simple enzymatic method. The subjects were divided into tertiles according to their homeostasis model assessment of insulin resistance (HOMA-IR). Besides routine glucose- and lipid-related parameters, we determined insulin sensitivity as the rate of glucose disappearance in a 2-step hyperinsulinemic-euglycemic clamp and the abdominal visceral fat area (VFA) by magnetic resonance imaging. RESULTS The highest HOMA-IR tertile group had a higher fasting FG concentration than the middle- and lowest-tertile groups (0.077 ± 0.024 vs 0.063 ± 0.017 and 0.061 ± 0.016 mmol/L, P < .05 and P < .01). The FG concentration was positively correlated with VFA (rs = 0.36; P < .01) and the HOMA-IR score (rs = 0.26, P < .05) but negatively correlated with insulin sensitivity (rs = -0.26, P < .05). Multivariate regression analysis revealed that the FG concentration is independently associated with VFA and insulin sensitivity. CONCLUSION The fasting FG concentration reflects VFA and insulin sensitivity in middle-aged Japanese men. The fasting FG concentration may be a potential surrogate marker of visceral obesity and insulin resistance in outpatients.
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11
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Sato M, Tamura Y, Someya Y, Takeno K, Kaga H, Kadowaki S, Sugimoto D, Kakehi S, Funayama T, Furukawa Y, Suzuki R, Nakagata T, Nishitani-Yokoyama M, Shimada K, Daida H, Aoki S, Sato H, Kawamori R, Watada H. Characteristics associated with elevated 1-h plasma glucose levels during a 75-g oral glucose tolerance test in non-obese Japanese men. J Diabetes Investig 2020; 11:1520-1523. [PMID: 32129539 PMCID: PMC7610100 DOI: 10.1111/jdi.13245] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 02/08/2020] [Accepted: 03/01/2020] [Indexed: 12/27/2022] Open
Abstract
Elevated 1-h plasma glucose (1h-PG; ≥155 mg/dL) during an oral glucose tolerance test is a risk factor for type 2 diabetes. However, the metabolic characteristics of non-obese Asians with elevated 1h-PG are unknown. Thus, we studied 59 non-obese Japanese men with normal glucose tolerance. We divided study participants into the Low 1h-PG group (<155 mg/dL) and the High 1h-PG group (≥155 mg/dL). We compared the metabolic characteristics of the groups, including tissue-specific insulin sensitivity measured using a two-step hyperinsulinemic-euglycemic clamp. Insulinogenic index and adiponectin levels were significantly lower in the High 1h-PG group than in the Low 1h-PG group. Other characteristics, including insulin sensitivity, adiposity and ectopic fat accumulation, were similar between the groups. In conclusion, non-obese Japanese men with high 1h-PG have impaired early-phase insulin secretion and lower adiponectin levels. Insulin resistance and abnormal fat distribution were not evident in this population.
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Affiliation(s)
- Motonori Sato
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yoshifumi Tamura
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yuki Someya
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Kageumi Takeno
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hideyoshi Kaga
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Satoshi Kadowaki
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Daisuke Sugimoto
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Saori Kakehi
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Takashi Funayama
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yasuhiko Furukawa
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ruriko Suzuki
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Takashi Nakagata
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | | | - Kazunori Shimada
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Department of Cardiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hiroyuki Daida
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Department of Cardiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Shigeki Aoki
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Department of Radiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hiroaki Sato
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ryuzo Kawamori
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hirotaka Watada
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Center for Identification of Diabetic Therapeutic Targets, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Center for Molecular Diabetology, Juntendo University Graduate School of Medicine, Tokyo, Japan
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12
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Both higher fitness level and higher current physical activity level may be required for intramyocellular lipid accumulation in non-athlete men. Sci Rep 2020; 10:4102. [PMID: 32139784 PMCID: PMC7057967 DOI: 10.1038/s41598-020-61080-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 02/20/2020] [Indexed: 11/25/2022] Open
Abstract
Accumulation of intramyocellular lipid (IMCL) is observed in individuals with insulin resistance as well as insulin-sensitive endurance athletes with high peak oxygen consumption (VO2peak), which is called the athlete’s paradox. It remains unclear whether non-athletes with higher fitness levels have IMCL accumulation and higher insulin sensitivity in general. In this study, we investigated the association between IMCL accumulation and muscle insulin sensitivity (M-IS) in subjects with high or low VO2peak. We studied 61 nonobese (BMI, 23 to 25 kg/m2), non-athlete Japanese men. We divided the subjects into four groups based on the median value of VO2peak and IMCL in the soleus muscle. We evaluated M-IS using a two-step hyperinsulinemic-euglycemic clamp. Among subjects with higher VO2peak (n = 32), half of those (n = 16) had lower IMCL levels. Both High-VO2peak groups had higher M-IS than the Low-VO2peak groups. On the other hand, M-IS was comparable between the High-VO2peak/High-IMCL and High-VO2peak/Low-IMCL groups, whereas the High-VO2peak/High-IMCL group had IMCL levels that were twice as high as those in the High-VO2peak/Low-IMCL group. On the other hand, the High-VO2peak/High-IMCL group had significantly higher physical activity levels (approximately 1.8-fold) than the other three groups. In conclusion, in nonobese, non-athlete Japanese men, subjects with higher VO2peak and higher IMCL had higher physical activity levels. IMCL accumulation is not associated with insulin resistance in individuals with higher or lower fitness levels.
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13
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Cai R, Chao J, Li D, Zhang M, Kong L, Wang Y. Effect of community-based lifestyle interventions on weight loss and cardiometabolic risk factors in obese elderly in China: A randomized controlled trial. Exp Gerontol 2019; 128:110749. [PMID: 31644921 DOI: 10.1016/j.exger.2019.110749] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 09/29/2019] [Accepted: 10/04/2019] [Indexed: 02/07/2023]
Abstract
PURPOSE We aimed to assess the effect of community-based lifestyle interventions on weight loss and cardiometabolic risk factors among obese older adults, and to explore the potential factors that impede weight loss during lifestyle interventions. MATERIALS AND METHODS A 2-arm parallel randomized controlled trial was conducted from 2013 through 2016 in the community health service centers in Nanjing, China. Four hundred and eighty obese older adults were randomly assigned to receive a 24-month lifestyle intervention (242 participants) or usual care (238 participants). The intervention group received a community-based behavioral lifestyle intervention program, which targeted weight loss through dietary changes and increased physical activity, with a combination mode of intervention delivery. RESULTS Weight loss was statistically significant at the end of the intervention with a mean reduction of 0.03 ± 2.51 kg in the control group and 3.22 ± 3.43 kg in the intervention group (p < .001). In the intervention group, 41.1% of participants achieved the target of 5% weight loss significantly (p < .001). Participants in the intervention group had significantly greater improvements in cardiometabolic risk factors. Multivariable logistic regression showed that female, living alone, and having more comorbidities were barriers to weight loss during the intervention. CONCLUSIONS This study demonstrated that community-based lifestyle interventions are effective for managing weight and improving cardiometabolic risk factors in obese older adults.
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Affiliation(s)
- Ruixue Cai
- Key Laboratory of Environmental Medicine Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, China
| | - Jianqian Chao
- Key Laboratory of Environmental Medicine Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, China.
| | - Dan Li
- Key Laboratory of Environmental Medicine Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, China
| | - Man Zhang
- Key Laboratory of Environmental Medicine Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, China
| | - Lingyan Kong
- Key Laboratory of Environmental Medicine Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, China
| | - Yingpeng Wang
- Key Laboratory of Environmental Medicine Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, China
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14
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Someya Y, Tamura Y, Kaga H, Nojiri S, Shimada K, Daida H, Ishijima M, Kaneko K, Aoki S, Miida T, Hirayama S, Konishi S, Hattori N, Motoi Y, Naito H, Kawamori R, Watada H. Skeletal muscle function and need for long-term care of urban elderly people in Japan (the Bunkyo Health Study): a prospective cohort study. BMJ Open 2019; 9:e031584. [PMID: 31530621 PMCID: PMC6756356 DOI: 10.1136/bmjopen-2019-031584] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
PURPOSE The proportion of elderly individuals (age ≥65 years) in Japan reached 27.7% in 2017, the highest in the world. A serious social problem in a super-aged society is the rise in the number of elderly people who need long-term care (LTC), which is mainly due to cerebrovascular disease, dementia, age-related frailty, falls and fractures, and joint disease. We hypothesised that decreased muscle mass, muscle strength and insulin sensitivity are the common risk factors for these diseases related to needing LTC. We developed a prospective cohort study of elderly subjects in an urban community to test this hypothesis. The primary objective is to prospectively investigate associations between muscle mass, muscle strength, and insulin sensitivity and incidence of main disease and risk factors of needing LTC. The primary outcomes are the incidence of cerebrovascular disease and cognitive decline. PARTICIPANTS Participants were 1629 people aged 65-84 years living in 13 communities in an urban area (Bunkyo-ku, Tokyo, Japan). Average age was 73.1±5.4 years. FINDINGS TO DATE We obtained baseline data on cognitive function, cerebral small vessel disease (SVD) determined by brain MRI, body composition, bone mineral density, arteriosclerosis, physical function, muscle mass, muscle strength and insulin sensitivity. Mild cognitive impairment and dementia were observed in 18.1% and 3.3% of participants, respectively. The prevalence of cerebral SVD was 24.8%. These characteristics are similar to those previously reported in elderly Japanese subjects. FUTURE PLANS We will ask participants about their health status, including incidence of cerebrovascular disease, falls, fractures and other diseases every year by mail. We plan to re-evaluate cognitive function, brain MRI parameters and other parameters at 5 and 10 years after the baseline evaluation. We will evaluate whether low muscle function (muscle mass, muscle strength or insulin sensitivity) is a risk factor for cognitive decline or cerebrovascular disease.
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Affiliation(s)
- Yuki Someya
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Juntendo University Graduate School of Health and Sports Science, Chiba, Japan
| | - Yoshifumi Tamura
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hideyoshi Kaga
- Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Shuko Nojiri
- Clinical Research Support Center, Juntendo University, Tokyo, Japan
| | - Kazunori Shimada
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hiroyuki Daida
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Muneaki Ishijima
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Medicine for Orthtopaedics and Motor Organ, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Kazuo Kaneko
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Medicine for Orthtopaedics and Motor Organ, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Shigeki Aoki
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Radiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Takashi Miida
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Satoshi Hirayama
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Seiki Konishi
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Nobutaka Hattori
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Neurology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yumiko Motoi
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Diagnosis, Prevention and Treatment of Dementia, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hisashi Naito
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Juntendo University Graduate School of Health and Sports Science, Chiba, Japan
| | - Ryuzo Kawamori
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hirotaka Watada
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
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15
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Kaga H, Tamura Y, Takeno K, Kakehi S, Someya Y, Funayama T, Furukawa Y, Suzuki R, Sugimoto D, Kadowaki S, Nishitani-Yokoyama M, Shimada K, Daida H, Aoki S, Giacca A, Kanazawa A, Kawamori R, Watada H. Higher C-Peptide Level During Glucose Clamp Is Associated With Muscle Insulin Resistance in Nonobese Japanese Men. J Endocr Soc 2019; 3:1847-1857. [PMID: 31555755 PMCID: PMC6753586 DOI: 10.1210/js.2019-00167] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 07/17/2019] [Indexed: 11/19/2022] Open
Abstract
Context Circulating C-peptide is generally suppressed by exogenous insulin infusion. However, steady-state serum C-peptide (SSSC) levels during hyperinsulinemic-euglycemic clamp in obese subjects are higher than in healthy subjects, which may contribute to hyperinsulinemia to compensate for insulin resistance. Even in healthy subjects, interindividual variations in SSSC levels are present; however, the characteristics of subjects with high SSSC levels in those populations have not been fully elucidated. Objective To investigate the clinical parameters associated with interindividual variations in SSSC levels in apparently healthy, nonobese Japanese men. Design and Participants We studied 49 nonobese (BMI < 25 kg/m2), healthy Japanese men. We evaluated SSSC and insulin sensitivity using hyperinsulinemic-euglycemic clamp with tracer. Intrahepatic lipid (IHL) was measured using proton magnetic resonance spectroscopy. Results We divided subjects into high and low SSSC groups based on the median SSSC value and compared their clinical parameters. Compared with the low SSSC group, the high SSSC group had IHL accumulation, impaired muscle insulin sensitivity, reduced insulin clearance, and hyperinsulinemia during a 75-g oral glucose tolerance test (OGTT). All of these factors were significantly correlated with SSSC. Conclusions In healthy, nonobese men, higher SSSC was associated with impaired muscle insulin sensitivity, IHL accumulation, and hyperinsulinemia during OGTT. These findings suggest that higher endogenous insulin secretion during hyperinsulinemia, along with reduced insulin clearance, may be an early change to maintain metabolic status in the face of moderate muscle insulin resistance, even in healthy, nonobese men.
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Affiliation(s)
- Hideyoshi Kaga
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yoshifumi Tamura
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Kageumi Takeno
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Saori Kakehi
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yuki Someya
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Takashi Funayama
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yasuhiko Furukawa
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ruriko Suzuki
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Daisuke Sugimoto
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Satoshi Kadowaki
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | | | - Kazunori Shimada
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Department of Cardiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hiroyuki Daida
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Department of Cardiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Shigeki Aoki
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Department of Radiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Adria Giacca
- Departments of Physiology and Medicine, Institute of Medical Science and Banting and Best Diabetes Centre, University of Toronto, Toronto, Canada
| | - Akio Kanazawa
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ryuzo Kawamori
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hirotaka Watada
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Center for Identification of Diabetic Therapeutic Targets, Juntendo University Graduate School of Medicine, Tokyo, Japan
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16
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Inoue M, Hayashi A, Taguchi T, Arai R, Sasaki S, Takano K, Inoue Y, Shichiri M. Effects of canagliflozin on body composition and hepatic fat content in type 2 diabetes patients with non-alcoholic fatty liver disease. J Diabetes Investig 2019; 10:1004-1011. [PMID: 30461221 PMCID: PMC6626966 DOI: 10.1111/jdi.12980] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Revised: 10/22/2018] [Accepted: 11/16/2018] [Indexed: 12/19/2022] Open
Abstract
AIMS/INTRODUCTION Non-alcoholic fatty liver disease is frequently associated with type 2 diabetes, and constitutes an important risk factor for the development of hepatic fibrosis and hepatocellular carcinoma. Because there remains no effective drug therapy for non-alcoholic fatty liver disease associated with type 2 diabetes, we evaluated the efficacy of sodium-glucose cotransporter 2 inhibitor. METHODS AND MATERIALS In the present pilot, prospective, non-randomized, open-label, single-arm study, we evaluated the effect of 100 mg canagliflozin administered once daily for 12 months on serological markers, body composition measured by bioelectrical impedance analysis method and hepatic fat fraction measured by magnetic resonance imaging in type 2 diabetes patients with non-alcoholic fatty liver disease. RESULTS Canagliflozin significantly reduced body and fat mass, and induced a slight decrease in lean body or muscle mass that did not reach significance at 6 and 12 months. Reductions in fat mass in each body segment (trunk, arms and legs) were evident, whereas those in lean body mass were not. The hepatic fat fraction was reduced from a baseline of 17.6 ± 7.5% to 12.0 ± 4.6% after 6 months and 12.1 ± 6.1% after 12 months (P < 0.0005 and P < 0.005), whereas serum liver enzymes and type IV collagen concentrations improved. From a mean baseline hemoglobin A1c of 8.7 ± 1.4%, canagliflozin significantly reduced hemoglobin A1c after 6 and 12 months to 7.3 ± 0.6% and 7.7 ± 0.7% (P < 0.0005 and P < 0.01). CONCLUSIONS Canagliflozin reduced body mass, fat mass and hepatic fat content without significantly reducing muscle mass.
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Affiliation(s)
- Mitsuko Inoue
- Department of Endocrinology, Diabetes and MetabolismKitasato University School of MedicineKanagawaJapan
| | - Akinori Hayashi
- Department of Endocrinology, Diabetes and MetabolismKitasato University School of MedicineKanagawaJapan
| | - Tomomi Taguchi
- Department of Endocrinology, Diabetes and MetabolismKitasato University School of MedicineKanagawaJapan
| | - Riina Arai
- Department of Endocrinology, Diabetes and MetabolismKitasato University School of MedicineKanagawaJapan
| | - Sayaka Sasaki
- Department of Endocrinology, Diabetes and MetabolismKitasato University School of MedicineKanagawaJapan
| | - Koji Takano
- Department of Endocrinology, Diabetes and MetabolismKitasato University School of MedicineKanagawaJapan
| | - Yusuke Inoue
- Department of Diagnostic RadiologyKitasato University School of MedicineKanagawaJapan
| | - Masayoshi Shichiri
- Department of Endocrinology, Diabetes and MetabolismKitasato University School of MedicineKanagawaJapan
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17
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Sugimoto D, Tamura Y, Takeno K, Kaga H, Someya Y, Kakehi S, Funayama T, Furukawa Y, Suzuki R, Kadowaki S, Nishitani-Yokoyama M, Shimada K, Daida H, Aoki S, Kanazawa A, Kawamori R, Watada H. Clinical Features of Nonobese, Apparently Healthy, Japanese Men With Reduced Adipose Tissue Insulin Sensitivity. J Clin Endocrinol Metab 2019; 104:2325-2333. [PMID: 30689902 DOI: 10.1210/jc.2018-02190] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 01/18/2019] [Indexed: 12/23/2022]
Abstract
CONTEXT Adipose tissue insulin resistance has been observed in obese subjects and is considered an early metabolic defect that precedes insulin resistance in muscle and liver. Although Asians can readily develop metabolic disease without obesity, the clinical features of nonobese, apparently healthy, Asians with reduced adipose tissue insulin sensitivity (ATIS) have not been elucidated. OBJECTIVE To investigate the clinical parameters associated with reduced ATIS in nonobese, apparently healthy (body mass index <25 kg/m2), Japanese men. METHODS We studied 52 nonobese Japanese men without cardiometabolic risk factors. Using a two-step hyperinsulinemic euglycemic clamp with a glucose tracer, we evaluated the insulin sensitivity in muscle, liver, and adipose tissue. ATIS was calculated as the percentage of free fatty acid (FFA) suppression/insulin concentration during the first step of the glucose clamp. RESULTS Using the median ATIS value, the subjects were divided into low- and high-FFA suppression groups. The low-FFA suppression group had moderate fat accumulation in the abdominal subcutaneous adipose tissue and liver. Compared with the high-FFA group, they also had a lower fitness level, decreased insulin clearance, impaired insulin sensitivity in muscle, moderately elevated triglycerides, and lowered high-density lipoprotein cholesterol levels. All these factors correlated significantly with ATIS. Hepatic insulin sensitivity was comparable between the two groups. CONCLUSIONS In nonobese, apparently healthy, Japanese men, reduced ATIS was associated with moderate fat accumulation in subcutaneous fat and liver, lower insulin clearance, muscle insulin resistance, and moderate lipedema. These data suggest that reduced ATIS can occur early in the development of the metabolic syndrome, even in nonobese, apparently healthy, men.
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Affiliation(s)
- Daisuke Sugimoto
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yoshifumi Tamura
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Kageumi Takeno
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hideyoshi Kaga
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yuki Someya
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Saori Kakehi
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Takashi Funayama
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yasuhiko Furukawa
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ruriko Suzuki
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Satoshi Kadowaki
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | | | - Kazunori Shimada
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Department of Cardiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hiroyuki Daida
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Department of Cardiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Shigeki Aoki
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Department of Radiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Akio Kanazawa
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ryuzo Kawamori
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hirotaka Watada
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Center for Identification of Diabetic Therapeutic Targets, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Center for Molecular Diabetology, Juntendo University Graduate School of Medicine, Tokyo, Japan
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18
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Haslacher H, Fallmann H, Waldhäusl C, Hartmann E, Wagner OF, Waldhäusl WK. Obesity: outcome of standardized life-style change in a rehabilitation clinic. An observational study. Diabetes Metab Syndr Obes 2019; 12:813-820. [PMID: 31213867 PMCID: PMC6549422 DOI: 10.2147/dmso.s197495] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Accepted: 04/10/2019] [Indexed: 12/29/2022] Open
Abstract
Purpose: To explore differences in baseline characteristics following three weeks of semi-standardized in-patient care between patients with obesity without and with type 2 diabetes (T2D). Patients and methods: Patients without or with T2D were matched according to age, sex, and BMI. Food intake was restricted to 1,200-1,600 kcal/d to which a 400-600 kcal/d exercise load was added, and data were compared using Student's t-test, general linear models, and Spearman-rank correlations. Results: At baseline, patients with obesity and T2D displayed, besides elevated blood glucose and HbA1c values, higher serum liver enzymes (p<0.001-0.05), triglycerides, and CRP (p<0.01) and a greater prevalence of treated hyperlipidemia (p<0.001) than those with plain obesity who showed only higher LDL and HDL cholesterol levels (+9.0% and +16.0%). In response to three-weeks of standardized life-style change, both groups improved their vital variables and risk scores (p<0.001). While improvement in cholesterol slightly favored patients with plain obesity, the need for anti-hyperlipidemics (+25%) rose in both groups, albeit that for anti-hypertensives (+50%) increased only in patients with obesity and add-on T2D. Conclusion: Moderate changes in lifestyle improve the clinical condition, including coronary heart disease and premature mortality risk scores (HARD-CHD and ABSI) in patients with obesity both in the absence and presence of T2D, with the latter seemingly increasing the risk of hepatic steatosis and systemic inflammation.
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Affiliation(s)
- Helmuth Haslacher
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Hannelore Fallmann
- Rehabilitation Clinic for Diabetes and Metabolic Diseases, Moorbad Neydhartig, Neydharting, Upper Austria, Austria
| | - Claudia Waldhäusl
- Department of Radiotherapy, Medical University of Vienna, Vienna, Austria
| | - Edith Hartmann
- Rehabilitation Clinic for Diabetes and Metabolic Diseases, Moorbad Neydhartig, Neydharting, Upper Austria, Austria
| | - Oswald F Wagner
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Werner K Waldhäusl
- Rehabilitation Clinic for Diabetes and Metabolic Diseases, Moorbad Neydhartig, Neydharting, Upper Austria, Austria
- Department of Medicine III, Medical University of Vienna, Vienna, Austria
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19
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Three days of a eucaloric, low-carbohydrate/high-fat diet increases insulin clearance in healthy non-obese Japanese men. Sci Rep 2019; 9:3857. [PMID: 30846785 PMCID: PMC6405898 DOI: 10.1038/s41598-019-40498-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 02/18/2019] [Indexed: 12/17/2022] Open
Abstract
Metabolic clearance rate of insulin (MCRI) is thought to help maintain glucose homeostasis even in healthy subjects. However, the effect of a low carbohydrate/high fat (LCHF) diet on MCRI in healthy subject remains unclear. To investigate the effect of a 3-day eucaloric LCHF diet on MCRI in healthy subjects, we studied 42 healthy non-obese Japanese men. Each subject consumed a eucaloric LCHF diet for 3 days. Before and after the LCHF diet, intramyocellular lipid (IMCL) levels were measured using 1H-magnetic resonance spectroscopy, and glucose infusion rate (GIR) and MCRI were evaluated with a euglycemic hyperinsulinemic clamp. The LCHF diet increased MCRI by 10% and decreased steady state serum insulin (SSSI) and GIR during glucose clamp by 10% and 6%, respectively. To further investigate the role of MCRI, we divided subjects into high-responder (HR) and low-responder (LR) groups based on the median %change in MCRI. The LCHF diet increased IMCL and decreased SSSI during glucose clamp in the HR group, while those were not altered in the LR group. Our results suggested that a 3-day eucaloric LCHF diet increases MCRI in healthy non-obese Japanese men. This change seemed to be beneficial in terms of maintaining euglycemia during low carbohydrate availability.
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20
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Svendstrup M, Allin KH, Ängquist L, Schnohr P, Jensen GB, Linneberg A, Thuesen B, Astrup A, Saris WHM, Vestergaard H, Sørensen TIA. Is abdominal obesity at baseline influencing weight changes in observational studies and during weight loss interventions? Am J Clin Nutr 2018; 108:913-921. [PMID: 30475965 DOI: 10.1093/ajcn/nqy187] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 07/02/2018] [Indexed: 11/14/2022] Open
Abstract
Background Body fat distribution is a marker of metabolic health independent of body size. Visceral fat accumulation has been suggested to result from a decreased expandability of the subcutaneous fat depots. Furthermore, the visceral fat may be easier to mobilize than the peripheral fat. We examined whether differences in abdominal obesity at baseline influenced prospective body-weight changes. Objective In this study we examined whether body-fat distribution at baseline was associated with long-term and short-term weight changes. Design We included 3 observational studies (ntotal = 7271) with mean follow-up times of 5-9 y and two 8-10-wk weight loss intervention studies (ntotal = 1091). We examined the association between baseline waist circumference and weight changes in a substitution regression model, where body weight, height, and fat-free mass were fixed so that a difference in waist circumference would reflect a difference in body fat distribution alone. The results were summarized in meta-analyses. Results In the observational studies, we found no associations between baseline waist circumference and subsequent weight change in men (β: 0.03 kg; 95% CI: -0.01, 0.08 kg; P = 0.19), but a negligible inverse association in women (β: -0.05 kg; 95% CI: -0.08, -0.01 kg; P = 0.01). There was no association between baseline waist circumference and weight loss in the intervention studies (men: β: -0.05 kg; 95% CI: -0.13, 0.03 kg; P = 0.25; women: β: -0.00 kg; 95% CI: -0.03, 0.03 kg; P = 0.84). However, in all studies, the SDs of the weight change residuals were greater, the greater the waist circumference at baseline. This trend was statistically significant in women in most studies as well as in men in 1 of the studies. Conclusions With narrow CIs in 3 observational studies and 2 weight loss interventions, we did not find any clinically or epidemiologically relevant association between baseline abdominal obesity and weight change. However, the present study suggests that a greater baseline abdominal obesity is a marker for greater weight fluctuations. The CCHS trial was registered at www.clinicaltrials.gov as NCT02993172. The Health2006 trial was registered at www.clinicaltrials.gov as NCT00316667. The ORG study was conducted before trial registration was required. The NUGENOB trial was registered at www.isrctn.com as ISRCTN25867281. The DiOGenes trial was registered atwww.clinicaltrials.gov as NCT00390637.
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Affiliation(s)
- Mathilde Svendstrup
- Section of Metabolic Genetics, Novo Nordisk Foundation Center for Basic Metabolic Research.,Danish Diabetes Academy, Odense, Demark.,Department of Clinical Epidemiology (former Institute of Preventive Medicine)
| | - Kristine Højgaard Allin
- Section of Metabolic Genetics, Novo Nordisk Foundation Center for Basic Metabolic Research.,Department of Clinical Epidemiology (former Institute of Preventive Medicine)
| | - Lars Ängquist
- Department of Clinical Epidemiology (former Institute of Preventive Medicine)
| | - Peter Schnohr
- The Copenhagen City Heart Study, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark
| | - Gorm Boje Jensen
- The Copenhagen City Heart Study, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark
| | - Allan Linneberg
- Departments of 2 Clinical Medicine.,Research Center for Prevention and Health, Center for Health, Capital Region of Denmark, Copenhagen, Denmark.,Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark
| | - Betina Thuesen
- Research Center for Prevention and Health, Center for Health, Capital Region of Denmark, Copenhagen, Denmark
| | | | - Wim H M Saris
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, Netherlands
| | - Henrik Vestergaard
- Section of Metabolic Genetics, Novo Nordisk Foundation Center for Basic Metabolic Research.,Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Thorkild I A Sørensen
- Section of Metabolic Genetics, Novo Nordisk Foundation Center for Basic Metabolic Research.,Section of Epidemiology, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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21
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Okura T, Nakamura R, Fujioka Y, Kawamoto-Kitao S, Ito Y, Matsumoto K, Shoji K, Sumi K, Matsuzawa K, Izawa S, Ueta E, Kato M, Imamura T, Taniguchi SI, Yamamoto K. Body mass index ≥23 is a risk factor for insulin resistance and diabetes in Japanese people: A brief report. PLoS One 2018; 13:e0201052. [PMID: 30028879 PMCID: PMC6054391 DOI: 10.1371/journal.pone.0201052] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 07/07/2018] [Indexed: 12/24/2022] Open
Abstract
Background Screening for undiagnosed type 2 diabetes mellitus is recommended for Asian Americans with a body mass index ≥23. However, the optimal body mass index cut-off score for predicting the risk of diabetes mellitus in Japanese people is not well known. The aim of this study was to determine the best body mass index cut-off score for predicting insulin resistance and diabetes mellitus in the Japanese population. Methods This study had two parts, a clinical investigation and a retrospective observational investigation. In the clinical part of the study, 58 participants (26 with type 2 diabetes mellitus and 32 non-diabetics) underwent a hyperinsulinemic-euglycemic clamp from which their glucose disposal rate was measured. For the retrospective part of the study, medical check-up data from 88,305 people in the Tottori Prefecture were analyzed for clinical evidence of diabetes mellitus. The optimal BMI cut-off scores for prediction of insulin resistance and diabetes mellitus were determined. Results In the clamp study, the optimal body mass index cut-off score to predict insulin resistance in non-diabetic patients was 22.7. All participants with type 2 diabetes mellitus were insulin resistant, and the optimal body mass index cut-off score for prediction of severe insulin resistance was 26.2. When the data from the type 2 diabetic and the non-diabetic participants were combined, the optimal body mass index cut-off score for prediction of insulin resistance was 23.5. Analysis of 88,305 medical check-up records yielded an optimal body mass index cut-off score for prediction of diabetes mellitus of 23.6. Conclusions These results suggest that having a body mass index ≥23 is a risk factor for insulin resistance and diabetes mellitus in the Japanese population.
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Affiliation(s)
- Tsuyoshi Okura
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
- * E-mail:
| | - Risa Nakamura
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Yohei Fujioka
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Sonoko Kawamoto-Kitao
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Yuichi Ito
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Kazuhisa Matsumoto
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Kyoko Shoji
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Keisuke Sumi
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Kazuhiko Matsuzawa
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Shoichiro Izawa
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Etsuko Ueta
- School of Health Science, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Masahiko Kato
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Takeshi Imamura
- Division of Molecular Pharmacology, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Shin-ichi Taniguchi
- Department of Regional Medicine, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Kazuhiro Yamamoto
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
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22
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Franch-Nadal J, Caballeria L, Mata-Cases M, Mauricio D, Giraldez-García C, Mancera J, Goday A, Mundet-Tudurí X, Regidor E. Fatty liver index is a predictor of incident diabetes in patients with prediabetes: The PREDAPS study. PLoS One 2018; 13:e0198327. [PMID: 29856820 PMCID: PMC5983533 DOI: 10.1371/journal.pone.0198327] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 05/17/2018] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES We evaluated the ability of the Fatty Liver Index (FLI), a surrogate marker of hepatic steatosis, to predict the development of type 2 diabetes (T2D) at 3 years follow-up in a Spanish cohort with prediabetes from a prospective observational study in primary care (PREDAPS). METHODS FLI was calculated at baseline for 1,142 adult subjects with prediabetes attending primary care centers, and classified into three categories: FLI <30 (no steatosis), FLI 30-60 (intermediate) and FLI ≥60 (hepatic steatosis). We estimated the incidence rate of T2D in each FLI category at 3 years of follow-up. The association between FLI and incident T2D was calculated using Cox regression models adjusted for age, sex, educational level, family history of diabetes, lifestyles, hypertension, lipid profile and transaminases. RESULTS The proportion of subjects with prediabetes and hepatic steatosis (FLI ≥60) at baseline was 55.7%. The incidence rate of T2D at 3 years follow-up was 1.3, 2.9 and 6.0 per 100 person-years for FLI<30, FLI 30->60 and FLI ≥60, respectively. The most significant variables increasing the risk of developing T2D were metabolic syndrome (hazard ratio [HR] = 3.02; 95% confidence interval [CI] = 2.14-4.26) and FLI ≥60 (HR = 4.52; 95%CI = 2.10-9.72). Moreover, FLI ≥60 was independently associated with T2D incidence: the HR was 4.97 (95% CI: 2.28-10.80) in the base regression model adjusted by sex, age and educational level, and 3.21 (95%CI: 1.45-7.09) in the fully adjusted model. CONCLUSIONS FLI may be considered an easy and valuable early indicator of high risk of incident T2D in patients with prediabetes attended in primary care, which could allow the adoption of effective measures needed to prevent and reduce the progression of the disease.
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Affiliation(s)
- Josep Franch-Nadal
- redGDPS Foundation, Madrid, Spain
- Unitat de Suport a la Recerca Barcelona Ciutat, Institut Universitari d'Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol), Barcelona, Spain
- Diabetes and Associated Metabolic Diseases Networking Biomedical Research Centre (CIBERDEM), Madrid, Spain
- Department of Medicine, University of Barcelona, Barcelona, Spain
| | - Llorenç Caballeria
- Department of Medicine, University of Barcelona, Barcelona, Spain
- Liver and Digestive Diseases Networking Biomedical Research Centre (CIBEREHD), Madrid, Spain
- Unitat de Suport a la Recerca Barcelonès Nord, Institut Universitari d'Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol), Barcelona, Spain
| | - Manel Mata-Cases
- redGDPS Foundation, Madrid, Spain
- Unitat de Suport a la Recerca Barcelona Ciutat, Institut Universitari d'Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol), Barcelona, Spain
- Diabetes and Associated Metabolic Diseases Networking Biomedical Research Centre (CIBERDEM), Madrid, Spain
| | - Didac Mauricio
- redGDPS Foundation, Madrid, Spain
- Unitat de Suport a la Recerca Barcelona Ciutat, Institut Universitari d'Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol), Barcelona, Spain
- Diabetes and Associated Metabolic Diseases Networking Biomedical Research Centre (CIBERDEM), Madrid, Spain
- Department of Endocrinology and Nutrition, Health Sciences Research Institute & University Hospital Germans Trias i Pujol, Badalona, Spain
| | - Carolina Giraldez-García
- redGDPS Foundation, Madrid, Spain
- Preventive Medicine Service, University Hospital Infanta Elena, Madrid, Spain
- Preventive Medicine, Public Health and History of Science Department, Complutense University of Madrid, Madrid, Spain
| | - José Mancera
- redGDPS Foundation, Madrid, Spain
- Health Center Ciudad Jardín, Málaga, Spain
| | - Albert Goday
- redGDPS Foundation, Madrid, Spain
- Endocrinology Service, Hospital del Mar, Barcelona, Spain
| | - Xavier Mundet-Tudurí
- redGDPS Foundation, Madrid, Spain
- Unitat de Suport a la Recerca Barcelona Ciutat, Institut Universitari d'Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol), Barcelona, Spain
- Autonomous University of Barcelona, Bellaterra, Spain
| | - Enrique Regidor
- redGDPS Foundation, Madrid, Spain
- Preventive Medicine, Public Health and History of Science Department, Complutense University of Madrid, Madrid, Spain
- Epidemiology and Public Health Networking Biomedical Research Centre (CIBERESP), Madrid, Spain
- Health Research Institute, Hospital Clínico San Carlos (IdISSC), Madrid, Spain
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23
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Okura T, Nakamura R, Fujioka Y, Kawamoto-Kitao S, Ito Y, Matsumoto K, Shoji K, Sumi K, Matsuzawa K, Izawa S, Ueta E, Kato M, Imamura T, Taniguchi SI, Yamamoto K. CPR-IR is an insulin resistance index that is minimally affected by hepatic insulin clearance-A preliminary research. PLoS One 2018; 13:e0197663. [PMID: 29791512 PMCID: PMC5965889 DOI: 10.1371/journal.pone.0197663] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 05/07/2018] [Indexed: 01/23/2023] Open
Abstract
Background Increased hepatic insulin clearance (HIC) is important in the pathophysiology of type 2 diabetes mellitus (T2DM). The aim of this study is to analyze an effective insulin resistance (IR) index that is minimally affected by HIC. Methods Our study involved 20 participants with T2DM and 21 healthy participants without diabetes (Non-DM). Participants underwent a meal tolerance test from which plasma glucose, insulin and serum C-peptide immunoreactivity (CPR) were measured, and HOMA-IR and HIC were calculated. Participants then underwent a hyperinsulinemic-euglycemic clamp from which the glucose disposal rate (GDR) was measured. Results The index CPR-IR = 20/(fasting CPR × fasting plasma glucose) was correlated more strongly with GDR, than was HOMA-IR, and CPR-IR could be used to estimate GDR. In T2DM participants with HIC below the median, HOMA-IR and CPR-IR were equally well correlated with GDR. In T2DM with high HIC, CPR-IR correlated with GDR while HOMA-IR did not. In Non-DM, CPR-IR and HOMA-IR were equally well correlated with GDR regardless of HIC. The mean HIC value in T2DM was significantly higher than that of Non-DM. Conclusions CPR-IR could be a simple and effective index of insulin resistance for patients with type 2 diabetes that is minimally affected by HIC.
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Affiliation(s)
- Tsuyoshi Okura
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
- * E-mail:
| | - Risa Nakamura
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Yohei Fujioka
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Sonoko Kawamoto-Kitao
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Yuichi Ito
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Kazuhisa Matsumoto
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Kyoko Shoji
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Keisuke Sumi
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Kazuhiko Matsuzawa
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Shoichiro Izawa
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Etsuko Ueta
- School of Health Science, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Masahiko Kato
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Takeshi Imamura
- Division of Molecular Pharmacology, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Shin-ichi Taniguchi
- Department of Regional Medicine, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Kazuhiro Yamamoto
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
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24
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Matsuba I, Matsuba R, Ishibashi S, Yamashita S, Arai H, Yokote K, Suganami H, Araki E. Effects of a novel selective peroxisome proliferator-activated receptor-α modulator, pemafibrate, on hepatic and peripheral glucose uptake in patients with hypertriglyceridemia and insulin resistance. J Diabetes Investig 2018; 9:1323-1332. [PMID: 29603684 PMCID: PMC6215940 DOI: 10.1111/jdi.12845] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 01/17/2018] [Accepted: 03/21/2018] [Indexed: 12/20/2022] Open
Abstract
AIMS/INTRODUCTION Pemafibrate is a novel selective peroxisome proliferator-activated receptor-α modulator with potent triglyceride-lowering and high-density lipoprotein cholesterol-raising effects. We showed that pemafibrate decreased the homeostatic model assessment for insulin resistance in patients with dyslipidemia. To investigate how pemafibrate improves insulin sensitivity, we used a hyperinsulinemic-euglycemic clamp technique to determine the splanchnic and peripheral glucose uptake in patients with hypertriglyceridemia and insulin resistance. MATERIALS AND METHODS A total of 27 patients with hypertriglyceridemia and insulin resistance were randomly assigned to receive pemafibrate (0.4 mg/day, b.i.d.) or placebo treatment for 12 weeks. The hyperinsulinemic-euglycemic clamp test combined with oral glucose loading was carried out at weeks 0 and 12 to evaluate the splanchnic and peripheral glucose uptake. RESULTS Pemafibrate, but not the placebo, significantly increased the splanchnic glucose uptake rate from baseline (19.6 ± 5.9% with P = 0.005 and 2.1 ± 7.4% with P = 0.78, respectively), although no significant difference between the groups was observed (P = 0.084). Conversely, peripheral glucose uptake rate was not significantly altered. Pemafibrate, compared with the placebo, significantly decreased plasma triglycerides (-61.4 ± 16.4% vs -2.5 ± 41.4%, P = 0.001), free fatty acids (-24.8 ± 23.2% vs 2.0 ± 26.8%, P = 0.016) and gamma-glutamyl transpeptidase (-30 ± 46 vs 10 ± 19 U/L, P = 0.009) levels, and significantly increased fibroblast growth factor 21 (457.7 ± 402.1 vs -41.7 ± 37.4 pg/mL, P = 0.007) levels. CONCLUSIONS Pemafibrate increased splanchnic glucose uptake from baseline in patients with hypertriglyceridemia.
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Affiliation(s)
| | - Ren Matsuba
- Department of Internal Medicine, Division of Metabolism and Endocrinology, St. Marianna University School of Medicine, Kanagawa, Japan
| | - Shun Ishibashi
- Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Shizuya Yamashita
- Department of Community Medicine and Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.,Rinku General Medical Center, Osaka, Japan
| | - Hidenori Arai
- National Center for Geriatrics and Gerontology, Aichi, Japan
| | - Koutaro Yokote
- Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Hideki Suganami
- Clinical Data Science Department, Kowa Company, Ltd., Tokyo, Japan
| | - Eiichi Araki
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
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25
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Someya Y, Tamura Y, Suzuki R, Kaga H, Kadowaki S, Sugimoto D, Kakehi S, Funayama T, Furukawa Y, Takeno K, Sato J, Kanazawa A, Kawamori R, Watada H. Characteristics of Glucose Metabolism in Underweight Japanese Women. J Endocr Soc 2018; 2:279-289. [PMID: 29600294 PMCID: PMC5838825 DOI: 10.1210/js.2017-00418] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 02/14/2018] [Indexed: 12/11/2022] Open
Abstract
Context Japanese women have substantially lower body mass index (BMI) than women in other developed countries. The BMI of Japanese women has steadily decreased over time. However, glucose metabolism in underweight Japanese women has not been fully characterized. Objective The aim of this study was to investigate glucose metabolism and the physical characteristics of underweight Japanese women. Design and Participants We recruited 31 young (20 to 29 years of age) and 30 postmenopausal (50 to 65 years of age) underweight women. We also recruited young normal-weight women (n = 13) and postmenopausal normal-weight women (n = 10) to serve as references. We administered an oral glucose tolerance test (OGTT) and evaluated intramyocellular lipid (IMCL) levels and body composition using 1H-magnetic resonance spectroscopy and dual-energy X-ray absorptiometry, respectively. Results Young underweight women had similar glucose tolerance as young normal-weight women. However, postmenopausal underweight women had a higher area under the curve (AUC) for glucose during OGTT than postmenopausal normal-weight women. In postmenopausal underweight women, 2-hour glucose levels during OGTT were negatively correlated with lean body mass (r = −0.55, P < 0.01) and insulinogenic index (r = −0.42, P = 0.02) and were positively correlated with IMCL levels (r = 0.40, P = 0.03). Compared with young underweight women, postmenopausal underweight women had a higher AUC for glucose during OGTT and a lower insulinogenic index and AUC for insulin during OGTT. Conclusions Postmenopausal underweight women had more impaired glucose tolerance than young underweight women. In postmenopausal underweight women, the degree of glucose tolerance impairment was associated with decreased lean body mass, increased IMCL accumulation, and impaired insulin secretion.
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Affiliation(s)
- Yuki Someya
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yoshifumi Tamura
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ruriko Suzuki
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hideyoshi Kaga
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Satoshi Kadowaki
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Daisuke Sugimoto
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Saori Kakehi
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Takashi Funayama
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yasuhiko Furukawa
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Kageumi Takeno
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Junko Sato
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Akio Kanazawa
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ryuzo Kawamori
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hirotaka Watada
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Center for Molecular Diabetology, Juntendo University Graduate School of Medicine, Tokyo, Japan
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26
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Furukawa Y, Tamura Y, Takeno K, Funayama T, Kaga H, Suzuki R, Watanabe T, Kakehi S, Kanazawa A, Kawamori R, Watada H. Impaired peripheral insulin sensitivity in non-obese Japanese patients with type 2 diabetes mellitus and fatty liver. J Diabetes Investig 2017; 9:529-535. [PMID: 28836350 PMCID: PMC5934256 DOI: 10.1111/jdi.12731] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 08/02/2017] [Accepted: 08/20/2017] [Indexed: 01/09/2023] Open
Abstract
AIMS/INTRODUCTION Type two diabetes mellitus and fatty liver (FL) are not uncommon in Asians with normal body mass index. Previous studies reported a link between FL and insulin resistance. Thus, FL could coexist with insulin resistance in Asian type two diabetes mellitus patients with a normal body mass index. However, the clinical and metabolic features of such patients have not been characterized yet. MATERIALS AND METHODS We recruited 29 non-obese (body mass index <25 kg/m2 ) Japanese patients with early type two diabetes mellitus. Based on intrahepatic lipid level measured by H-magnetic resonance spectroscopy, the participants were divided into the FL (intrahepatic lipid ≥5%, n = 7) and non-FL groups (intrahepatic lipid <5%, n = 22). RESULTS Peripheral insulin sensitivity measured by hyperinsulinemic euglycemic clamp was ~25% lower in the FL group than in the non-FL group, whereas hepatic insulin sensitivity was comparable between the two groups. The subcutaneous fat area was larger, free fatty acid level was higher, C-reactive protein was higher and high molecular weight adiponectin was lower in the FL group than the non-FL group. CONCLUSIONS The present study showed that the metabolic features of non-obese Japanese type two diabetes patients with FL include impaired peripheral (mainly muscle) insulin sensitivity, fat accumulation and related metabolic disorders, such as elevated free fatty acid, low high molecular weight adiponectin and low-grade inflammation.
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Affiliation(s)
| | - Yoshifumi Tamura
- Department of Metabolism & EndocrinologyTokyoJapan
- Sportology CenterTokyoJapan
| | | | | | | | | | | | - Saori Kakehi
- Department of Metabolism & EndocrinologyTokyoJapan
- Sportology CenterTokyoJapan
| | | | - Ryuzo Kawamori
- Department of Metabolism & EndocrinologyTokyoJapan
- Sportology CenterTokyoJapan
| | - Hirotaka Watada
- Department of Metabolism & EndocrinologyTokyoJapan
- Sportology CenterTokyoJapan
- Center for Therapeutic Innovations in DiabetesTokyoJapan
- Center for Molecular DiabetologyJuntendo UniversityGraduate School of MedicineTokyoJapan
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27
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Shigiyama F, Kumashiro N, Furukawa Y, Funayama T, Takeno K, Wakui N, Ikehara T, Nagai H, Taka H, Fujimura T, Uchino H, Tamura Y, Watada H, Nemoto T, Shiraga N, Sumino Y, Hirose T. Characteristics of hepatic insulin-sensitive nonalcoholic fatty liver disease. Hepatol Commun 2017; 1:634-647. [PMID: 29404483 PMCID: PMC5721442 DOI: 10.1002/hep4.1077] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 06/30/2017] [Accepted: 07/03/2017] [Indexed: 12/20/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) plays a crucial role in type 2 diabetes and hepatocellular carcinoma. The major underlying pathogenesis is hepatic insulin resistance. The aim of the present study was to characterize patients with NAFLD with paradoxically normal hepatic insulin sensitivity relative to patients with NAFLD with hepatic insulin resistance. We recruited 26 patients with NAFLD and divided them into three groups ranked by the level of hepatic insulin sensitivity (HIS; high‐HIS, mid‐HIS, low‐HIS), as assessed by the hyperinsulinemic‐euglycemic clamp studies using stable isotope. Hepatic insulin sensitivity of the high‐HIS group was identical to that of the non‐NAFLD lean control (clamped percent suppression of endogenous glucose production, 91.1% ± 5.2% versus 91.0% ± 8.5%, respectively) and was significantly higher than that of the low‐HIS group (66.6% ± 7.5%; P < 0.01). Adiposity (subcutaneous, visceral, intrahepatic, and muscular lipid content), hepatic histopathology, and expression levels of various genes by using liver biopsies, muscle, and adipose tissue insulin sensitivity, plasma metabolites by metabolomics analysis, putative biomarkers, and lifestyles were assessed and compared between the high‐HIS and low‐HIS groups. Among these, adipose tissue insulin sensitivity assessed by clamped percent suppression of free fatty acid, serum high molecular weight adiponectin, and plasma tricarboxylic acid cycle metabolites, such as citric acid and cis‐aconitic acid, were significantly higher in the high‐HIS group compared to the low‐HIS group. In contrast, there were no differences in adiposity, including intrahepatic lipid content assessed by proton magnetic resonance spectroscopy (28.3% ± 16.1% versus 20.4% ± 9.9%, respectively), hepatic histopathology, other putative biomarkers, and lifestyles. Conclusion: High levels of adipose tissue insulin sensitivity, serum high molecular weight adiponectin, and plasma tricarboxylic acid cycle metabolites are unique characteristics that define patients with hepatic insulin‐sensitive NAFLD regardless of intrahepatic lipid content. (Hepatology Communications 2017;1:634–647)
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Affiliation(s)
- Fumika Shigiyama
- Division of Diabetes Metabolism, and Endocrinology, Department of Medicine, Toho University Graduate School of Medicine Tokyo Japan
| | - Naoki Kumashiro
- Division of Diabetes Metabolism, and Endocrinology, Department of Medicine, Toho University Graduate School of Medicine Tokyo Japan
| | - Yasuhiko Furukawa
- Department of Metabolism and Endocrinology Juntendo University Graduate School of Medicine Tokyo Japan
| | - Takashi Funayama
- Department of Metabolism and Endocrinology Juntendo University Graduate School of Medicine Tokyo Japan
| | - Kageumi Takeno
- Department of Metabolism and Endocrinology Juntendo University Graduate School of Medicine Tokyo Japan
| | - Noritaka Wakui
- Division of Gastroenterology and Hepatology Department of Medicine, Toho University Graduate School of Medicine Tokyo Japan
| | - Takashi Ikehara
- Division of Gastroenterology and Hepatology Department of Medicine, Toho University Graduate School of Medicine Tokyo Japan
| | - Hidenari Nagai
- Division of Gastroenterology and Hepatology Department of Medicine, Toho University Graduate School of Medicine Tokyo Japan
| | - Hikari Taka
- Laboratory of Proteomics and Biomolecular Science Research Support Center, Juntendo University Graduate School of Medicine Tokyo Japan
| | - Tsutomu Fujimura
- Laboratory of Bioanalytical Chemistry Tohoku Medical and Pharmaceutical University Sendai Japan
| | - Hiroshi Uchino
- Division of Diabetes Metabolism, and Endocrinology, Department of Medicine, Toho University Graduate School of Medicine Tokyo Japan
| | - Yoshifumi Tamura
- Department of Metabolism and Endocrinology Juntendo University Graduate School of Medicine Tokyo Japan.,Sportology Center Juntendo University Graduate School of Medicine Tokyo Japan
| | - Hirotaka Watada
- Department of Metabolism and Endocrinology Juntendo University Graduate School of Medicine Tokyo Japan.,Sportology Center Juntendo University Graduate School of Medicine Tokyo Japan
| | - Tetsuo Nemoto
- Department of Surgical Pathology Toho University Graduate School of Medicine Tokyo Japan
| | - Nobuyuki Shiraga
- Department of Radiology Toho University Graduate School of Medicine Tokyo Japan
| | - Yasukiyo Sumino
- Division of Gastroenterology and Hepatology Department of Medicine, Toho University Graduate School of Medicine Tokyo Japan
| | - Takahisa Hirose
- Division of Diabetes Metabolism, and Endocrinology, Department of Medicine, Toho University Graduate School of Medicine Tokyo Japan
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28
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de Godoy MRC, McLeod KR, Harmon DL. Influence of feeding a fish oil-containing diet to mature, overweight dogs: Effects on lipid metabolites, postprandial glycaemia and body weight. J Anim Physiol Anim Nutr (Berl) 2017; 102:e155-e165. [PMID: 28503817 DOI: 10.1111/jpn.12723] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 03/02/2017] [Indexed: 12/24/2022]
Abstract
The objective of this study was to determine the effect of feeding a fish oil (FO)-containing diet on lipid and protein metabolism, postprandial glycaemia and body weight (BW) of mature, overweight dogs. Seven female dogs were randomly assigned to one of two isonitrogenous and isocaloric diets, control (CO) or FO (FO), in a crossover design. Experimental periods were 69 day, separated by a washout period of 30 day. At the beginning of the experiment, and at 30 and 60 day of feeding the experimental diets, the dogs were infused with D-glucose (2 g/kg BW) through an intravenous catheter. Blood samples were collected for 3 hr to perform a glucose tolerance test. Nitrogen balance measurements began at 06:30 on d 63 of each experimental period and ended at 06:30 on d 69. On d 66 of each period, a single dose (7.5 mg/kg) of 15 N-glycine was administered orally for determination of protein turnover. Incremental area under the curve and glucose concentration at peak did not differ between treatments or among sampling days within treatment. Glucose half-life tended to decrease (p < .10) in the FO treatment on day 30 when compared to baseline (day 0). β-hydroxybutyrate, non-esterified fatty acid (NEFA) and triglycerides did not differ within or between treatments. Cholesterol decreased (p < .05) on the FO treatment on day 30, 60 and 69 when compared to day 0. High-density lipoprotein (HDL) decreased (p < .05) in the FO treatment on day 69 when compared to day 0. Body weight, food intake, faecal excretion, DM and N digestibilities, N balance and protein turnover were not different between diets. Overall, FO-containing diet decreases cholesterol in mature overweight dogs; however, further research is warranted to verify the effects of FO on glucose metabolism.
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Affiliation(s)
- M R C de Godoy
- Department of Animal and Food Sciences, University of Kentucky, Lexington, KY, USA
| | - K R McLeod
- Department of Animal and Food Sciences, University of Kentucky, Lexington, KY, USA
| | - D L Harmon
- Department of Animal and Food Sciences, University of Kentucky, Lexington, KY, USA
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29
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Peters HPF, Schrauwen P, Verhoef P, Byrne CD, Mela DJ, Pfeiffer AFH, Risérus U, Rosendaal FR, Schrauwen-Hinderling V. Liver fat: a relevant target for dietary intervention? Summary of a Unilever workshop. J Nutr Sci 2017; 6:e15. [PMID: 28630692 PMCID: PMC5468740 DOI: 10.1017/jns.2017.13] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Accepted: 03/09/2017] [Indexed: 12/20/2022] Open
Abstract
Currently it is estimated that about 1 billion people globally have non-alcoholic fatty liver disease (NAFLD), a condition in which liver fat exceeds 5 % of liver weight in the absence of significant alcohol intake. Due to the central role of the liver in metabolism, the prevalence of NAFLD is increasing in parallel with the prevalence of obesity, insulin resistance and other risk factors of metabolic diseases. However, the contribution of liver fat to the risk of type 2 diabetes mellitus and CVD, relative to other ectopic fat depots and to other risk markers, is unclear. Various studies have suggested that the accumulation of liver fat can be reduced or prevented via dietary changes. However, the amount of liver fat reduction that would be physiologically relevant, and the timeframes and dose-effect relationships for achieving this through different diet-based approaches, are unclear. Also, it is still uncertain whether the changes in liver fat per se or the associated metabolic changes are relevant. Furthermore, the methods available to measure liver fat, or even individual fatty acids, differ in sensitivity and reliability. The present report summarises key messages of presentations from different experts and related discussions from a workshop intended to capture current views and research gaps relating to the points above.
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Affiliation(s)
- Harry P. F. Peters
- Unilever R&D Vlaardingen, Olivier van Noortlaan 120, Vlaardingen, The Netherlands
| | - Patrick Schrauwen
- Department of Human Biology, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Petra Verhoef
- Unilever R&D Vlaardingen, Olivier van Noortlaan 120, Vlaardingen, The Netherlands
| | - Christopher D. Byrne
- Nutrition and Metabolism, Faculty of Medicine, University of Southampton & Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton, UK
| | - David J. Mela
- Unilever R&D Vlaardingen, Olivier van Noortlaan 120, Vlaardingen, The Netherlands
| | - Andreas F. H. Pfeiffer
- Department of Endocrinology, Diabetes and Nutrition, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin
- Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam and German Center for Diabetes Research, DZD, Neuherberg, Germany
| | - Ulf Risérus
- Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism Unit, Uppsala University, Sweden
| | - Frits R. Rosendaal
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Vera Schrauwen-Hinderling
- Department of Human Biology, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
- Department of Radiology, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
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30
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Kaga H, Tamura Y, Takeno K, Kakehi S, Funayama T, Furukawa Y, Nishitani-Yokoyama M, Shimada K, Daida H, Aoki S, Giacca A, Kanazawa A, Kawamori R, Watada H. Correlates of insulin clearance in apparently healthy non-obese Japanese men. Sci Rep 2017; 7:1462. [PMID: 28469173 PMCID: PMC5431197 DOI: 10.1038/s41598-017-01469-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 03/30/2017] [Indexed: 01/13/2023] Open
Abstract
Hyperinsulinemia observed in obese subject is caused at least in part by low metabolic clearance rate of insulin (MCRI). However, the determinants of MCRI in non-obese subjects are not fully understood. To investigate the correlates of MCRI in healthy non-obese men (BMI <25 kg/m2), we studied 49 non-obese Japanese men free of cardiometabolic risk factors. Using a 2-step hyperinsulinemic euglycemic clamp, we evaluated MCRI and insulin sensitivity. We also calculated the rate of glucose disappearance (Rd) during the clamp and muscle insulin sensitivity was defined as Rd/steady state serum insulin (SSSI) at the second step. Based on the median value of MCRI, the subjects were divided into the low- and high-MCRI groups. Subjects of the low-MCRI group had significant impairment of muscle insulin sensitivity, although Rd levels were comparable between the two groups, probably due to elevated SSSI in the low-MCRI group. Subjects of the low-MCRI group had higher total body fat content and lower VO2peak and showed no deterioration of cardiometabolic risk factors. Our results suggest that low MCRI may be early change to maintain glucose uptake and metabolic status in the face of slight impairment of muscle insulin sensitivity caused by increased adiposity and lower fitness level.
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Affiliation(s)
- Hideyoshi Kaga
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yoshifumi Tamura
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
| | - Kageumi Takeno
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Saori Kakehi
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Takashi Funayama
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yasuhiko Furukawa
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | | | - Kazunori Shimada
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Department of Cardiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hiroyuki Daida
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Department of Cardiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Shigeki Aoki
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Department of Radiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Adria Giacca
- Departments of Physiology and Medicine, Institute of Medical Science and Banting and Best Diabetes Centre, University of Toronto, Toronto, Canada
| | - Akio Kanazawa
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ryuzo Kawamori
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hirotaka Watada
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Center for Identification of Diabetic Therapeutic Targets, Juntendo University Graduate School of Medicine, Tokyo, Japan
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31
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Effects of alcohol abstinence on glucose metabolism in Japanese men with elevated fasting glucose: A pilot study. Sci Rep 2017; 7:40277. [PMID: 28067302 PMCID: PMC5220444 DOI: 10.1038/srep40277] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 12/05/2016] [Indexed: 12/23/2022] Open
Abstract
It has been demonstrated that moderate alcohol consumption provides protection against the development of type 2 diabetes. However, several other reports suggested that moderate alcohol intake may increase the risk of type 2 diabetes in non-obese Japanese. The aim of present study was to investigate the effect of 1-week alcohol abstinence on hepatic insulin sensitivity and fasting plasma glucose (FPG) in non-obese Japanese men. We recruited 8 non-obese Japanese men with mildly elevated FPG and drinking habits alcohol (mean frequency; 5.6 ± 2.5 times/week, mean alcohol consumption; 32.1 ± 20.0 g/day). Before and after the 1-week alcohol abstinence, we used the 2-step hyperinsulinemic-euglycemic clamp to measure endogenous glucose production (EGP) and insulin sensitivity (IS) in muscle and liver. One-week alcohol abstinence significantly reduced both FPG by 7% (from 105.5 ± 11.7 to 98.2 ± 7.8 mg/dl, P < 0.01) and fasting EGP by 6% (from 84.1 ± 4.2 to 77.6 ± 1.6 mg/m2 per min, P < 0.01), respectively. Two–step clamp study showed that alcohol abstinence significantly improved hepatic-IS, but not muscle-IS. In conclusion, one week alcohol abstinence improved hepatic IS and FPG in non-obese Japanese men with mildly elevated FPG and drinking habits alcohol.
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32
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Okura T, Ueta E, Nakamura R, Fujioka Y, Sumi K, Matsumoto K, Shoji K, Matsuzawa K, Izawa S, Nomi Y, Mihara H, Otsuka Y, Kato M, Taniguchi SI, Yamamoto K. High Serum Advanced Glycation End Products Are Associated with Decreased Insulin Secretion in Patients with Type 2 Diabetes: A Brief Report. J Diabetes Res 2017; 2017:5139750. [PMID: 28695132 PMCID: PMC5485485 DOI: 10.1155/2017/5139750] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 03/24/2017] [Accepted: 04/12/2017] [Indexed: 01/11/2023] Open
Abstract
OBJECTIVE Advanced glycation end products (AGEs) are important in the pathophysiology of type 2 diabetes mellitus (T2DM). They directly cause insulin secretory defects in animal and cell culture models and may promote insulin resistance in nondiabetic subjects. We have developed a highly sensitive liquid chromatography-tandem mass spectrometry method for measuring AGEs in human serum. Here, we use this method to investigate the relationship between AGEs and insulin secretion and resistance in patients with T2DM. METHODS Our study involved 15 participants with T2DM not on medication and 20 nondiabetic healthy participants. We measured the AGE carboxyethyllysine (CEL), carboxymethyllysine (CML), and methyl-glyoxal-hydro-imidazolone (MG-H1). Plasma glucose and insulin were measured in these participants during a meal tolerance test, and the glucose disposal rate was measured during a euglycemic-hyperinsulinemic clamp. RESULTS CML and CEL levels were significantly higher in T2DM than non-DM participants. CML showed a significant negative correlation with insulin secretion, HOMA-%B, and a significant positive correlation with the insulin sensitivity index in T2DM participants. There was no correlation between any of the AGEs measured and glucose disposal rate. CONCLUSIONS These results suggest that AGE might play a role in the development or prediction of insulin secretory defects in type 2 diabetes.
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Affiliation(s)
- Tsuyoshi Okura
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
- *Tsuyoshi Okura:
| | - Etsuko Ueta
- School of Health Science, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Risa Nakamura
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Yohei Fujioka
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Keisuke Sumi
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Kazuhisa Matsumoto
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Kyoko Shoji
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Kazuhiko Matsuzawa
- Department of Regional Medicine, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Shoichiro Izawa
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Yuri Nomi
- Faculty of Applied Life Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan
| | - Hitomi Mihara
- Department of Food and Nutrition, Toita Women's College, Tokyo, Japan
| | - Yuzuru Otsuka
- Department of Food and Nutrition, Toita Women's College, Tokyo, Japan
| | - Masahiko Kato
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Shin-ichi Taniguchi
- Department of Regional Medicine, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Kazuhiro Yamamoto
- Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
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Abstract
Non-alcoholic fatty liver disease (NAFLD) comprises a disease spectrum ranging from benign hepatic steatosis to non-alcoholic steatohepatitis with inflammation (NASH) and liver cirrhosis. NAFLD is now recognised as the hepatic manifestation of the metabolic syndrome. Simple steatosis is benign, whereas NASH can progress to cirrhosis with its resultant complications. Liver biopsy remains the gold standard in the diagnosis of NAFLD/NASH. Lifestyle and dietary modifications to achieve sustained weight loss is the cornerstone of NAFLD/NASH treatment.
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Affiliation(s)
- Hui-Hui Tan
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
| | - Jason Pik-Eu Chang
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
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Kaliora AC, Kokkinos A, Diolintzi A, Stoupaki M, Gioxari A, Kanellos PT, Dedoussis GVZ, Vlachogiannakos J, Revenas C, Ladas SD, Karathanos VT. The effect of minimal dietary changes with raisins in NAFLD patients with non-significant fibrosis: a randomized controlled intervention. Food Funct 2016; 7:4533-4544. [PMID: 27714002 DOI: 10.1039/c6fo01040g] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Aiming at investigating the potential effect of minimal dietary changes in NAFLD patients with non-significant fibrosis, 55 patients with NAFLD were enrolled in a randomized controlled clinical trial. Patients were assigned into two isocaloric dietary treatment groups for 24 weeks: (a) nutritional counseling (Control arm, N = 27), (b) nutritional counseling with currants included (two fruit servings, 36 g per day), substituting snacks of similar caloric content (Currant arm, N = 28). Clinical tests, anthropometrics, inflammatory and oxidative stress markers were conducted pre- and post-intervention. A total of 50 patients completed the trial. Significant differences between the two arms post-intervention were observed in fasting glucose and in IL-6 levels, these being significantly decreased only in Currant patients. Body weight, BMI, HbA1c, CRP and EUS values decreased in both arms, differences being insignificant between the two arms post-intervention. Participants in the Currant arm had significantly reduced total body fat, WC and trunk fat. Ultrasound scanning improved significantly in patients snacking currants daily. Also, volunteers enrolled in the Currant arm showed a reduced intake of saturated fatty acids. Because BW regulation has been officially recognised as a treatment approach in NAFLD an additional analysis was repeated in patients adhering to this. Post-intervention, the decrease in IL-6 and in fasting glucose was significantly higher in Currant patients who lost BW compared to their counterparts in the Control arm. Conclusively, minimal modifications in snacking choices, such as the inclusion of dried grapes in diet, are beneficial in NAFLD patients with non-significant fibrosis.
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Affiliation(s)
- Andriana C Kaliora
- Department of Dietetics and Nutritional Science, School of Health Science and Education, Harokopio University, 70 El. Venizelou Ave., 17671, Athens, Greece.
| | - Alexander Kokkinos
- First Department of Propaedeutic and Internal Medicine, Laiko General Hospital, Athens University Medical School, 17 Agiou Thoma St., 11527, Athens, Greece
| | - Anastacia Diolintzi
- Department of Dietetics and Nutritional Science, School of Health Science and Education, Harokopio University, 70 El. Venizelou Ave., 17671, Athens, Greece.
| | - Maria Stoupaki
- First Department of Propaedeutic and Internal Medicine, Laiko General Hospital, Athens University Medical School, 17 Agiou Thoma St., 11527, Athens, Greece
| | - Aristea Gioxari
- Department of Dietetics and Nutritional Science, School of Health Science and Education, Harokopio University, 70 El. Venizelou Ave., 17671, Athens, Greece.
| | - Panagiotis T Kanellos
- Department of Dietetics and Nutritional Science, School of Health Science and Education, Harokopio University, 70 El. Venizelou Ave., 17671, Athens, Greece.
| | - George V Z Dedoussis
- Department of Dietetics and Nutritional Science, School of Health Science and Education, Harokopio University, 70 El. Venizelou Ave., 17671, Athens, Greece.
| | - Jiannis Vlachogiannakos
- Academic Department of Gastroenterology, Athens University Medical School, Laiko General Hospital, Athens, 11527, Greece
| | | | - Spiros D Ladas
- First Department of Propaedeutic and Internal Medicine, Laiko General Hospital, Athens University Medical School, 17 Agiou Thoma St., 11527, Athens, Greece
| | - Vaios T Karathanos
- Department of Dietetics and Nutritional Science, School of Health Science and Education, Harokopio University, 70 El. Venizelou Ave., 17671, Athens, Greece. and Agricultural Cooperatives Union Aeghion SA, Korinthou 201, 25 100, Aeghio, Greece
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Saracco GM, Evangelista A, Fagoonee S, Ciccone G, Bugianesi E, Caviglia GP, Abate ML, Rizzetto M, Pellicano R, Smedile A. Etiology of chronic liver diseases in the Northwest of Italy, 1998 through 2014. World J Gastroenterol 2016; 22:8187-8193. [PMID: 27688660 PMCID: PMC5037087 DOI: 10.3748/wjg.v22.i36.8187] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 08/08/2016] [Accepted: 08/30/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To assess the etiology of chronic liver diseases (CLD) from 1998 to 2014 at the outpatient clinic of Gastroenterology of the main hospital in Northwest of Italy among those dedicated to hepatology.
METHODS A random sample of charts of patients referred to for increased liver enzymes between January 1998 and December 2006, and between January 2012 and December 2014 were reviewed. Etiology search included testing for hepatitis B virus (HBV), hepatitis C virus (HCV), autoimmune hepatitis, primary biliary cirrhosis, Wilson’s disease and hereditary hemocromatosis. A risky alcohol consumption was also considered. Non-alcoholic fatty liver disease (NAFLD) was diagnosed in patients with histological and/or ultrasound evidence of steatosis/steatohepatitis, and without other causes of CLD.
RESULTS The number of patients included was 1163. Of them, 528 (45%) had positivity for HCV and 85 (7%) for HBV. Among the virus-free patients, 417 (36%) had metabolic disorders whereas the remaining had history of alcohol abuse, less prevalent causes of CLD or concomitant conditions. In comparison to 1998-2000 (41%), a reduction of HCV alone-related cases was detected during the periods 2001-2003 (35%, OR = 0.75, 95%CI: 0.53-1.06), 2004-2006 (33%, OR = 0.70, 95%CI: 0.50-0.97) and 2012-2014 (31%, OR = 0.64, 95%CI: 0.46-0.91). On the contrary, in comparison to 1998-2000 (31%), metabolic-alone disorders increased in the period 2004-2006 (39%, OR = 1.37, 95%CI: 0.99-1.91) and 2012-2014 (41%, OR = 1.53, 95%CI: 1.09-2.16). The other etiologies remained stable. The increase of incidence of metabolic-alone etiology during the period 2004-2006 and 2012-2014 tended to be higher in older patients (≥ 50 years) compared to younger (P = 0.058).
CONCLUSION In the Northwest of Italy, during this study period, the prevalence of HCV infection decreased notably whereas that of NAFLD increased.
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Miller M, Sorkin JD, Mastella L, Sutherland A, Rhyne J, Donnelly P, Simpson K, Goldberg AP. Poly is more effective than monounsaturated fat for dietary management in the metabolic syndrome: The muffin study. J Clin Lipidol 2016; 10:996-1003. [PMID: 27578132 PMCID: PMC5010036 DOI: 10.1016/j.jacl.2016.04.011] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 04/26/2016] [Indexed: 01/14/2023]
Abstract
BACKGROUND The metabolic syndrome (MetS) is highly prevalent and associated with an increased risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Lifestyle recommendations to treat MetS often include the replacement of saturated fats (SFAs) and monosaccharides with unsaturated fat. However, it is unclear whether metabolic parameters will improve more when the saturated fat in American Heart Association (AHA) diets is replaced with higher concentrations of monounsaturated or polyunsaturated fatty acids (MUFA or PUFA). OBJECTIVE To test the hypothesis that an AHA diet enriched in MUFA improves lipoprotein lipids, insulin resistance, inflammation, and endothelial function to a greater extent than a diet enriched in PUFA in middle-aged men and women with MetS. METHODS A prospective, open-label, parallel group design with randomization to a hypocaloric MUFA or PUFA-enriched diet after weight stabilization on an AHA step I diet. Participants consumed 3 MUFA-enriched or PUFA-enriched muffins daily with additional supplementation as required to ensure 25%-50% increases in dietary fat intake from these sources at the expense of SFA and the opposing unsaturated fat. Changes in MetS components were measured at baseline and after 6 months of dietary intervention. RESULTS Thirty-nine participants (mean age, 60.8 years; 79% African-American, 60% women) with MetS completed the 6-month study. Compared to baseline, assignment to either MUFA (n = 23) or PUFA (n = 16) both were associated with weight loss (MUFA: -2.3 ± 1 kg, P = .06; PUFA: -4.6 ± 2 kg; P = .002), but PUFA was also associated with reductions in triglycerides (TG) (-30 ± 18 mg/dL, P = .02), systolic blood pressure (BP) (-7 ± 3 mm Hg, P = .01), diastolic BP (DBP) (-4 ± 2 mm Hg, P = .01) and improved flow mediated dilation (FMD) (7.1% ± 1.8% vs 13.6% ± 2%, absolute increase; P = .0001). When compared to MUFA treatment, PUFA intervention was associated with reduced TG (P = .04) and DBP (P = .07) as well as increased FMD (P = .04) even after adjustment for changes in weight. There was no effect on total cholesterol, low-density lipoprotein cholesterol, glucose, high-sensitivity C-reactive protein (hs-CRP), or other inflammatory proteins. Overall, 25% (4 of 16) assigned to PUFA and 13% (3 of 23) to MUFA converted to non-MetS status. CONCLUSION Substitution of SFA with PUFA in patients with MetS is associated with greater reductions in TG and improvement in endothelial function than MUFA that is independent of weight loss. These preliminary findings raise the possibility that PUFA may be the unsaturated fat of choice to reduce cardiometabolic risk in patients with MetS.
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Affiliation(s)
- Michael Miller
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA; Division of Cardiology, University of Maryland School of Medicine, Baltimore, MD, USA; University of Maryland School of Medicine, Baltimore, MD, USA; Geriatric Research Education and Clinical Center, Veterans Affairs Medical Center, Baltimore, USA.
| | - John D Sorkin
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; University of Maryland School of Medicine, Baltimore, MD, USA; Geriatric Research Education and Clinical Center, Veterans Affairs Medical Center, Baltimore, USA; Division of Gerontology and Geriatric Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Laura Mastella
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; University of Maryland School of Medicine, Baltimore, MD, USA; Division of Gerontology and Geriatric Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | | | - Jeffrey Rhyne
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; Division of Cardiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Patrick Donnelly
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Kathy Simpson
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; Geriatric Research Education and Clinical Center, Veterans Affairs Medical Center, Baltimore, USA; Division of Gerontology and Geriatric Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Andrew P Goldberg
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; University of Maryland School of Medicine, Baltimore, MD, USA; Geriatric Research Education and Clinical Center, Veterans Affairs Medical Center, Baltimore, USA; Division of Gerontology and Geriatric Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
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37
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Kakehi S, Tamura Y, Takeno K, Sakurai Y, Kawaguchi M, Watanabe T, Funayama T, Sato F, Ikeda SI, Kanazawa A, Fujitani Y, Kawamori R, Watada H. Increased intramyocellular lipid/impaired insulin sensitivity is associated with altered lipid metabolic genes in muscle of high responders to a high-fat diet. Am J Physiol Endocrinol Metab 2016; 310:E32-40. [PMID: 26487001 DOI: 10.1152/ajpendo.00220.2015] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 10/16/2015] [Indexed: 01/07/2023]
Abstract
The accumulation of intramyocellular lipid (IMCL) is recognized as an important determinant of insulin resistance, and is increased by a high-fat diet (HFD). However, the effects of HFD on IMCL and insulin sensitivity are highly variable. The aim of this study was to identify the genes in muscle that are related to this inter-individual variation. Fifty healthy men were recruited for this study. Before and after HFD for 3 days, IMCL levels in the tibialis anterior were measured by (1)H magnetic resonance spectroscopy, and peripheral insulin sensitivity was evaluated by glucose infusion rate (GIR) during the euglycemic-hyperinsulinemic clamp. Subjects who showed a large increase in IMCL and a large decrease in GIR by HFD were classified as high responders (HRs), and subjects who showed a small increase in IMCL and a small decrease in GIR were classified as low responders (LRs). In five subjects from each group, the gene expression profile of the vastus lateralis muscle was analyzed by DNA microarray analysis. Before HFD, gene expression profiles related to lipid metabolism were comparable between the two groups. Gene Set Enrichment Analysis demonstrated that five gene sets related to lipid metabolism were upregulated by HFD in the HR group but not in the LR group. Changes in gene expression patterns were confirmed by qRT-PCR using more samples (LR, n = 9; HR, n = 11). These results suggest that IMCL accumulation/impaired insulin sensitivity after HFD is closely associated with changes in the expression of genes related to lipid metabolism in muscle.
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Affiliation(s)
- Saori Kakehi
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan; Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yoshifumi Tamura
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan; Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan;
| | - Kageumi Takeno
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yuko Sakurai
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Minako Kawaguchi
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Takahiro Watanabe
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Takashi Funayama
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Fumihiko Sato
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Shin-Ichi Ikeda
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan; Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Akio Kanazawa
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yoshio Fujitani
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ryuzo Kawamori
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan; Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hirotaka Watada
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan; Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan; Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate School of Medicine, Tokyo, Japan; and Center for Molecular Diabetology, Juntendo University Graduate School of Medicine, Tokyo, Japan
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38
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Fonvig CE, Chabanova E, Ohrt JD, Nielsen LA, Pedersen O, Hansen T, Thomsen HS, Holm JC. Multidisciplinary care of obese children and adolescents for one year reduces ectopic fat content in liver and skeletal muscle. BMC Pediatr 2015; 15:196. [PMID: 26714769 PMCID: PMC4696236 DOI: 10.1186/s12887-015-0513-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Accepted: 11/24/2015] [Indexed: 02/07/2023] Open
Abstract
Background Ectopic fat deposition in liver and skeletal muscle tissue is related to cardiovascular disease risk and is a common metabolic complication in obese children. We evaluated the hypotheses of ectopic fat in these organs could be diminished following 1 year of multidisciplinary care specialized in childhood obesity, and whether this reduction would associate with changes in other markers of metabolic function. Methods This observational longitudinal study evaluated 40 overweight children and adolescents enrolled in a multidisciplinary treatment protocol at the Children’s Obesity Clinic, Holbæk, Denmark. The participants were assessed by anthropometry, fasting blood samples (HbA1c, glucose, insulin, lipids, and biochemical variables of liver function), and liver and muscle fat content assessed by magnetic resonance spectroscopy at enrollment and following an average of 12.2 months of care. Univariate linear regression models adjusted for age, sex, treatment duration, baseline degree of obesity, and pubertal developmental stage were used for investigating possible associations. Results The standard deviation score (SDS) of baseline median body mass index (BMI) was 2.80 (range: 1.49–3.85) and the median age was 14 years (10–17). At the end of the observational period, the 40 children and adolescents (21 girls) significantly decreased their BMI SDS, liver fat, muscle fat, and visceral adipose tissue volume. The prevalence of hepatic steatosis changed from 28 to 20 % (p = 0.26) and the prevalence of muscular steatosis decreased from 75 to 45 % (p = 0.007). Changes in liver and muscle fat were independent of changes in BMI SDS, baseline degree of obesity, duration of treatment, age, sex, and pubertal developmental stage. Conclusions A 1-year multidisciplinary intervention program in the setting of a childhood obesity outpatient clinic confers a biologically important reduction in liver and muscle fat; metabolic improvements that are independent of the magnitude of concurrent weight loss. Trial registration ClinicalTrials.gov registration number: NCT00928473, the Danish Childhood Obesity Biobank. Registered June 25, 2009. Electronic supplementary material The online version of this article (doi:10.1186/s12887-015-0513-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Cilius Esmann Fonvig
- The Children's Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, 4300, Holbæk, Denmark. .,The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Medical and Health Sciences, University of Copenhagen, 2100, Copenhagen Ø, Denmark.
| | - Elizaveta Chabanova
- Department of Diagnostic Radiology, Copenhagen University Hospital Herlev, 2730, Herlev, Denmark.
| | - Johanne Dam Ohrt
- The Children's Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, 4300, Holbæk, Denmark.
| | - Louise Aas Nielsen
- The Children's Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, 4300, Holbæk, Denmark.
| | - Oluf Pedersen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Medical and Health Sciences, University of Copenhagen, 2100, Copenhagen Ø, Denmark.
| | - Torben Hansen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Medical and Health Sciences, University of Copenhagen, 2100, Copenhagen Ø, Denmark.
| | - Henrik S Thomsen
- Department of Diagnostic Radiology, Copenhagen University Hospital Herlev, 2730, Herlev, Denmark. .,University of Copenhagen, Faculty of Medical and Health Sciences, 2200, Copenhagen N, Denmark.
| | - Jens-Christian Holm
- The Children's Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, 4300, Holbæk, Denmark. .,University of Copenhagen, Faculty of Medical and Health Sciences, 2200, Copenhagen N, Denmark.
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39
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Lambert JE, Parnell JA, Eksteen B, Raman M, Bomhof MR, Rioux KP, Madsen KL, Reimer RA. Gut microbiota manipulation with prebiotics in patients with non-alcoholic fatty liver disease: a randomized controlled trial protocol. BMC Gastroenterol 2015; 15:169. [PMID: 26635079 PMCID: PMC4669628 DOI: 10.1186/s12876-015-0400-5] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 11/25/2015] [Indexed: 02/08/2023] Open
Abstract
Background Evidence for the role of the gut microbiome in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) is emerging. Strategies to manipulate the gut microbiota towards a healthier community structure are actively being investigated. Based on their ability to favorably modulate the gut microbiota, prebiotics may provide an inexpensive yet effective dietary treatment for NAFLD. Additionally, prebiotics have established benefits for glucose control and potentially weight control, both advantageous in managing fatty liver disease. Our objective is to evaluate the effects of prebiotic supplementation, adjunct to those achieved with diet-induced weight loss, on heptic injury and liver fat, the gut microbiota, inflammation, glucose tolerance, and satiety in patients with NAFLD. Methods/design In a double blind, placebo controlled, parallel group study, adults (BMI ≥25) with confirmed NAFLD will be randomized to either a 16 g/d prebiotic supplemented group or isocaloric placebo group for 24 weeks (n = 30/group). All participants will receive individualized dietary counseling sessions with a registered dietitian to achieve 10 % weight loss. Primary outcome measures include change in hepatic injury (fibrosis and inflammation) and liver fat. Secondary outcomes include change in body composition, appetite and dietary adherence, glycemic and insulinemic responses and inflammatory cytokines. Mechanisms related to prebiotic-induced changes in gut microbiota (shot-gun sequencing) and their metabolic by-products (volatile organic compounds) and de novo lipogenesis (using deuterium incorporation) will also be investigated. Discussion There are currently no medications or surgical procedures approved for the treatment of NAFLD and weight loss via lifestyle modification remains the cornerstone of current care recommendations. Given that prebiotics target multiple metabolic impairments associated with NAFLD, investigating their ability to modulate the gut microbiota and hepatic health in patients with NAFLD is warranted. Trial registration ClinicalTrials.gov (NCT02568605) Registered 30 September 2015
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Affiliation(s)
- Jennifer E Lambert
- Faculty of Kinesiology, University of Calgary, 2500 University Dr. NW, Calgary, AB, T2N 1N4, Canada.
| | - Jill A Parnell
- Health and Physical Education, Mount Royal University, 4825 Mount Royal Gate SW, Calgary, AB, T3E 6K6, Canada.
| | - Bertus Eksteen
- Snyder Institute for Chronic Diseases, Health Research and Innovation Center, University of Calgary, 3280 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada. .,Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.
| | - Maitreyi Raman
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.
| | - Marc R Bomhof
- Faculty of Kinesiology, University of Calgary, 2500 University Dr. NW, Calgary, AB, T2N 1N4, Canada.
| | - Kevin P Rioux
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada. .,Department of Microbiology and Infectious Diseases, University of Calgary, 1863 Health Sciences Centre, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.
| | - Karen L Madsen
- Division of Gastroenterology, Centre of Excellence for Gastrointestinal Inflammation and Immunity Research, 7-142 Katz Group-Rexall Centre, University of Alberta, Edmonton, AB, T6G 2C2, Canada.
| | - Raylene A Reimer
- Faculty of Kinesiology, University of Calgary, 2500 University Dr. NW, Calgary, AB, T2N 1N4, Canada. .,Department of Biochemistry & Molecular Biology, Cumming School of Medicine, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.
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40
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Shiwa M, Yoneda M, Okubo H, Ohno H, Kobuke K, Monzen Y, Kishimoto R, Nakatsu Y, Asano T, Kohno N. Distinct Time Course of the Decrease in Hepatic AMP-Activated Protein Kinase and Akt Phosphorylation in Mice Fed a High Fat Diet. PLoS One 2015; 10:e0135554. [PMID: 26266809 PMCID: PMC4534138 DOI: 10.1371/journal.pone.0135554] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 07/23/2015] [Indexed: 12/25/2022] Open
Abstract
AMP-activated protein kinase (AMPK) plays an important role in insulin resistance, which is characterized by the impairment of the insulin-Akt signaling pathway. However, the time course of the decrease in AMPK and Akt phosphorylation in the liver during the development of obesity and insulin resistance caused by feeding a high fat diet (HFD) remains controversial. Moreover, it is unclear whether the impairment of AMPK and Akt signaling pathways is reversible when changing from a HFD to a standard diet (SD). Male ddY mice were fed the SD or HFD for 3 to 28 days, or fed the HFD for 14 days, followed by the SD for 14 days. We examined the time course of the expression and phosphorylation levels of AMPK and Akt in the liver by immunoblotting. After 3 days of feeding on the HFD, mice gained body weight, resulting in an increased oil red O staining, indicative of hepatic lipid accumulation, and significantly decreased AMPK phosphorylation, in comparison with mice fed the SD. After 14 days on the HFD, systemic insulin resistance occurred and Akt phosphorylation significantly decreased. Subsequently, a change from the HFD to SD for 3 days, after 14 days on the HFD, ameliorated the impairment of AMPK and Akt phosphorylation and systemic insulin resistance. Our findings indicate that AMPK phosphorylation decreases early upon feeding a HFD and emphasizes the importance of prompt lifestyle modification for decreasing the risk of developing diabetes.
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Affiliation(s)
- Mami Shiwa
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masayasu Yoneda
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hirofumi Okubo
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Haruya Ohno
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuhiro Kobuke
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuko Monzen
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Rui Kishimoto
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yusuke Nakatsu
- Department of Biomedical Chemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomoichiro Asano
- Department of Biomedical Chemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Nobuoki Kohno
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Kato H, Nagai Y, Ohta A, Tenjin A, Nakamura Y, Tsukiyama H, Sasaki Y, Fukuda H, Ohshige T, Terashima Y, Sada Y, Kondo A, Sasaoka T, Tanaka Y. Effect of sitagliptin on intrahepatic lipid content and body fat in patients with type 2 diabetes. Diabetes Res Clin Pract 2015; 109:199-205. [PMID: 25934525 DOI: 10.1016/j.diabres.2015.04.008] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2014] [Revised: 02/07/2015] [Accepted: 04/12/2015] [Indexed: 12/18/2022]
Abstract
AIMS To evaluate the effect of the DPP-4 inhibitor sitagliptin on intrahepatic lipid (IHL) content and body fat in overweight Japanese patients with type 2 diabetes. METHODS A prospective, 24-week, single-center, open-label comparative study enrolled 20 Japanese patients with type 2 diabetes (male: 11, female: 9) with a BMI≥25 kg/m(2) or fatty liver. Subjects were randomly assigned to receive treatment with sitagliptin (25 mg titrated up to 50 mg: S) or glimepiride (0.5 mg titrated up to 1 mg: G). After starting each treatment, IHL and total fat mass were evaluated by (1)H-magnetic resonance spectroscopy ((1)H-MRS) and dual energy X-ray absorptiometry (DEXA), respectively at baseline and at 12 weeks and 24 weeks. RESULTS After 24 weeks, HbA1c levels showed a similar significant decrease in both groups from 7.2 (7.0, 7.5) to 6.6 (6.4, 6.8)%, (54 (53, 56) to 48(47, 49) mmol/mol) with S and 7.3(6.8, 7.4) to 6.6 (6.3, 6.7)%, (55 (51, 56) to 48 (46, 49) mmol/mol) with G, median (interquartile range), p<0.05 vs. baseline, with no significant differences between the two groups. The IHL and total body fat mass were decreased in S group from 24.5(18.9, 36.6) to 20.5 (14.6, 28.5)% (p=0.009) and 22.5 (20.6, 33.7) to 21.6 (19.7, 32.4)kg (p=0.028), respectively, but not in G group. CONCLUSIONS Our findings indicate that sitagliptin and glimepiride achieved similar glycemic control, but only sitagliptin reduced IHL and total body fat (UMIN: 000013356).
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Affiliation(s)
- Hiroyuki Kato
- Department of Internal Medicine, Division of Metabolism and Endocrinology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan
| | - Yoshio Nagai
- Department of Internal Medicine, Division of Metabolism and Endocrinology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
| | - Akio Ohta
- Department of Internal Medicine, Division of Metabolism and Endocrinology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan
| | - Ayumi Tenjin
- Department of Internal Medicine, Division of Metabolism and Endocrinology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan
| | - Yuta Nakamura
- Department of Internal Medicine, Division of Metabolism and Endocrinology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan
| | - Hidekazu Tsukiyama
- Department of Internal Medicine, Division of Metabolism and Endocrinology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan
| | - Yosuke Sasaki
- Department of Internal Medicine, Division of Metabolism and Endocrinology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan
| | - Hisashi Fukuda
- Department of Internal Medicine, Division of Metabolism and Endocrinology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan
| | - Toshihiko Ohshige
- Department of Internal Medicine, Division of Metabolism and Endocrinology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan
| | - Yuko Terashima
- Department of Internal Medicine, Division of Metabolism and Endocrinology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan
| | - Yukiyoshi Sada
- Department of Internal Medicine, Division of Metabolism and Endocrinology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan
| | - Akihiko Kondo
- Department of Internal Medicine, Division of Metabolism and Endocrinology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan
| | - Toshiyasu Sasaoka
- Department of Clinical Pharmacology, University School of Toyama, 930-0194 Sugitani, Toyama, Japan
| | - Yasushi Tanaka
- Department of Internal Medicine, Division of Metabolism and Endocrinology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan
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Yu X, Ye L, Zhang H, Zhao J, Wang G, Guo C, Shang W. Ginsenoside Rb1 ameliorates liver fat accumulation by upregulating perilipin expression in adipose tissue of db/db obese mice. J Ginseng Res 2014. [PMID: 26199550 PMCID: PMC4506369 DOI: 10.1016/j.jgr.2014.11.004] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background Ginsenoside Rb1 (G-Rb1), the major active constituent of ginseng, improves insulin sensitivity and exerts antidiabetic effects. We tested whether the insulin-sensitizing and antidiabetic effects of G-Rb1 results from a reduction in ectopic fat accumulation, mediated by inhibition of lipolysis in adipocytes. Methods Obese and diabetic db/db mice were treated with daily doses of 20 mg/kg G-Rb1 for 14 days. Hepatic fat accumulation was evaluated by measuring liver weight and triglyceride content. Levels of blood glucose and serum insulin were used to evaluate insulin sensitivity in db/db mice. Lipolysis in adipocytes was evaluated by measuring plasma-free fatty acids and glycerol release from 3T3-L1 adipocytes treated with G-Rb1. The expression of relevant genes was analyzed by western blotting, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay kit. Results G-Rb1 increased insulin sensitivity and alleviated hepatic fat accumulation in obese diabetic db/db mice, and these effects were accompanied by reduced liver weight and hepatic triglyceride content. Furthermore, G-Rb1 lowered the levels of free fatty acids in obese mice, which may contribute to a decline in hepatic lipid accumulation. Corresponding to these results, G-Rb1 significantly suppressed lipolysis in 3T3-L1 adipocytes and upregulated the perilipin expression in both 3T3-L1 adipocytes and mouse epididymal fat pads. Moreover, G-Rb1 increased the level of adiponectin and reduced that of tumor necrosis factor-α in obese mice, and these effects were confirmed in 3T3-L1 adipocytes. Conclusion G-Rb1 may improve insulin sensitivity in obese and diabetic db/db mice by reducing hepatic fat accumulation and suppressing adipocyte lipolysis; these effects may be mediated via the upregulation of perilipin expression in adipocytes.
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Affiliation(s)
- Xizhong Yu
- Medical Research Center, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Lifang Ye
- Department of Endocrinology, the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Hao Zhang
- Medical Research Center, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Juan Zhao
- Medical Research Center, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Guoqiang Wang
- Medical Research Center, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Chao Guo
- Medical Research Center, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenbin Shang
- Medical Research Center, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China ; Department of Endocrinology, the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
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Kawaguchi M, Tamura Y, Kakehi S, Takeno K, Sakurai Y, Watanabe T, Funayama T, Sato F, Ikeda S, Ogura Y, Saga N, Naito H, Fujitani Y, Kanazawa A, Kawamori R, Watada H. Association between expression of FABPpm in skeletal muscle and insulin sensitivity in intramyocellular lipid-accumulated nonobese men. J Clin Endocrinol Metab 2014; 99:3343-52. [PMID: 24937540 DOI: 10.1210/jc.2014-1896] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
CONTEXT Intramyocellular lipid (IMCL) accumulation is observed in both insulin-resistant subjects and insulin-sensitive endurance athletes (athlete's paradox). We hypothesized that the expression pattern of fatty acid transporters may influence oxidative capacity and determine the association between IMCL and insulin resistance. OBJECTIVE The objective of the study was to investigate the muscle expression of fatty acid transporters and their function related to insulin sensitivity in IMCL-accumulated subjects. DESIGN AND SETTING The study subjects were 36 nonobese healthy men. Their IMCL levels were measured by (1)H-magnetic resonance spectroscopy, and their insulin sensitivity was evaluated by steady-state glucose infusion rate (GIR) during a euglycemic-hyperinsulinemic clamp. Gene expression levels in the vastus lateralis were evaluated by quantitative RT-PCR. We compared the clinical phenotypes and the expression levels of genes involved in lipid metabolism in skeletal muscle between IMCL-accumulated high-GIR (H-GIR) subjects (n = 8) and low-GIR subjects (n = 9). The functions of candidate fatty acid transporters were determined by in vitro analyses. RESULTS Compared with the low-GIR group, body fat was lower and maximum oxygen uptake was higher in the H-GIR group. Several lipid oxidation genes in muscle were up-regulated in the H-GIR group, and this was associated with increased expression of higher plasma membrane-associated fatty acid-binding protein (FABPpm) and decreased expression of fatty acid transport protein (FATP)-1. Overexpression of FABPpm in C2C12 myotubes increased fatty acid oxidation coupled with the elevated expression of genes related to fatty acid oxidation. These changes were not observed in FATP1-overexpressed myotubes. CONCLUSIONS Differences in the gene expression of fatty acid transporters may, at least in part, affect insulin sensitivity in IMCL-accumulated nonobese men.
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Affiliation(s)
- Minako Kawaguchi
- Department of Metabolism and Endocrinology (M.K., Y.T., S.K., K.T., Y.S., T.W., T.F., F.S., S.I., Y.F., A.K., R.K., H.W.), Sportology Center (Y.T., S.K., S.I., R.K., H.W.), Center for Therapeutic Innovations in Diabetes (H.W.), and Center for Molecular Diabetology (H.W.), Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; and Institute of Health and Sports Science and Medicine (Y.O., N.S., H.N.) and Department of Exercise Physiology (Y.O., N.S., H.N.), Juntendo University Graduate School of Health and Sports Science, Chiba 270-1695, Japan
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Watanabe T, Tamura Y, Kakehi S, Funayama T, Gastaldelli A, Takeno K, Kawaguchi M, Yamamoto R, Sato F, Ikeda SI, Taka H, Fujimura T, Fujitani Y, Kawamori R, Watada H. Effects of sitagliptin on ectopic fat contents and glucose metabolism in type 2 diabetic patients with fatty liver: A pilot study. J Diabetes Investig 2014; 6:164-72. [PMID: 25802724 PMCID: PMC4364851 DOI: 10.1111/jdi.12262] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Revised: 05/27/2014] [Accepted: 06/08/2014] [Indexed: 01/13/2023] Open
Abstract
Aims/Introduction Recent data have shown that ectopic fat accumulation in the liver worsens hepatic glucose metabolism, suggesting that fatty liver in patients with type 2 diabetes is a therapeutic target. Glucagon-like peptide (GLP)-1 improves fatty liver, but the effect of dipeptidyl peptidase-4 inhibitor on fatty liver is still unclear. The present pilot study determined the effects of 12-week treatment with sitagliptin, a dipeptidyl peptidase-4 inhibitor, on liver fat content in type 2 diabetes with fatty liver. We also evaluated intramyocellular lipid (IMCL) and glucose kinetics during oral glucose tolerance test (OGTT) before and after the treatment. Materials and Methods The study participants were seven type 2 diabetes patients with fatty liver who were studied at baseline and 12 weeks after sitagliptin treatment. Intrahepatic lipid (IHL) and IMCL were assessed by 1H magnetic resonance spectroscopy. Glucose kinetics was assessed during double-tracer OGTT (U-[13C]-glucose orally and 6,6-[2H2]-glucose intravenously). Results Sitagliptin significantly reduced glycated hemoglobin (from 7.1 ± 0.2 to 6.5 ± 0.3%, P < 0.005), but had no effects on IHL and IMCL. The glucose level diminished, whereas GLP-1 concentration increased during OGTT at the end of treatment. These changes were not accompanied by significant changes in insulin or glucagon levels. However, long-term sitagliptin treatment partially decreased the rate of appearance of oral glucose during OGTT, but did not affect endogenous glucose production or the rate of disappearance. Conclusions It was found that 12-week sitagliptin treatment improved glycated hemoglobin and glucose excursion during OGTT in type 2 diabetes with fatty liver, independent of changes in lipid accumulation in the liver. This trial was registered with the Japan Clinical Trials Registry (UMIN-CTR000005666).
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Affiliation(s)
- Takahiro Watanabe
- Department of Metabolism & Endocrinology, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan
| | - Yoshifumi Tamura
- Department of Metabolism & Endocrinology, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan ; Sportology Center, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan
| | - Saori Kakehi
- Department of Metabolism & Endocrinology, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan ; Sportology Center, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan
| | - Takashi Funayama
- Department of Metabolism & Endocrinology, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan
| | - Amalia Gastaldelli
- National Research Council (CNR), Institute of Clinical Physiology Pisa, Italy
| | - Kageumi Takeno
- Department of Metabolism & Endocrinology, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan
| | - Minako Kawaguchi
- Department of Metabolism & Endocrinology, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan
| | - Risako Yamamoto
- Department of Metabolism & Endocrinology, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan ; Sportology Center, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan
| | - Fumihiko Sato
- Department of Metabolism & Endocrinology, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan
| | - Shin-Ichi Ikeda
- Department of Metabolism & Endocrinology, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan ; Sportology Center, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan
| | - Hikari Taka
- Laboratory of Proteomics and Biomolecular Science, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan
| | - Tsutomu Fujimura
- Laboratory of Proteomics and Biomolecular Science, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan
| | - Yoshio Fujitani
- Department of Metabolism & Endocrinology, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan ; Center for Therapeutic Innovations in Diabetes, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan
| | - Ryuzo Kawamori
- Department of Metabolism & Endocrinology, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan ; Sportology Center, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan
| | - Hirotaka Watada
- Department of Metabolism & Endocrinology, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan ; Sportology Center, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan ; Center for Therapeutic Innovations in Diabetes, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan ; Center for Molecular Diabetology, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan ; Center for Beta Cell Biology and Regeneration, Biomedical Research Center, Juntendo University Graduate School of Medicine Tokyo, Japan
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Sakurai Y, Tamura Y, Takeno K, Kumashiro N, Sato F, Kakehi S, Ikeda S, Ogura Y, Saga N, Naito H, Katamoto S, Fujitani Y, Hirose T, Kawamori R, Watada H. Determinants of intramyocellular lipid accumulation after dietary fat loading in non-obese men. J Diabetes Investig 2014; 2:310-7. [PMID: 24843504 PMCID: PMC4014973 DOI: 10.1111/j.2040-1124.2010.00091.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Aims/Introduction: Accumulation of intramyocellular lipid (IMCL) is associated with insulin resistance. However, the factors affecting the change in IMCL remain to be elucidated. The aim of the present study was to determine the factors that influence the change in IMCL level after high‐fat loading. Materials and Methods: The study subjects were 37 non‐obese men. Each subject consumed a high‐fat diet for 3 days after a normal‐fat diet for 3 days. After each diet program, IMCL levels in the tibialis anterior (TA‐IMCL) and soleus (SOL‐IMCL) were measured by proton magnetic resonance spectroscopy. Glucose infusion rate (GIR) was evaluated by euglycemic hyperinsulinemic clamp as an index of peripheral insulin sensitivity. Results: The high‐fat diet significantly increased TA‐IMCL and SOL‐IMCL by ∼30 and ∼20%, respectively (P < 0.05), whereas it did not significantly alter GIR. The increase in SOL‐IMCL, but not in TA‐IMCL, negatively correlated with serum high molecular weight (HMW)‐adiponectin (r = −0.36, P < 0.05) and HMW‐/total‐adiponectin ratio (r = −0.46, P < 0.05). Although high‐fat diet‐related changes in SOL‐IMCL showed high inter‐individual variations, in subjects doing exercise, changes in SOL‐IMCL (r = 0.55, P < 0.05) and TA‐IMCL (r = 0.61, P < 0.05) positively correlated with daily physical activity level. In contrast, in sedentary subjects, changes in SOL‐IMCL (r = −0.50, P < 0.01) and TA‐IMCL (r = −0.48, P < 0.05) negatively correlated with daily physical activity. Conclusions: HMW‐adiponectin and daily physical activity are determinants of IMCL accumulation by a high‐fat diet. Intriguingly, the effect of daily physical activity on the change in IMCL depends on the level of regular exercise. (J Diabetes Invest,doi: 10.1111/j.2040‐1124.2010.00091.x, 2011)
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Affiliation(s)
- Yuko Sakurai
- Department of Medicine, Metabolism and Endocrinology
| | - Yoshifumi Tamura
- Department of Medicine, Metabolism and Endocrinology ; Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo
| | | | | | - Fumihiko Sato
- Department of Medicine, Metabolism and Endocrinology
| | - Saori Kakehi
- Department of Medicine, Metabolism and Endocrinology ; Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo
| | - Shinichi Ikeda
- Department of Medicine, Metabolism and Endocrinology ; Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo
| | - Yuji Ogura
- Institute of Health and Sports Science and Medicine ; Department of Exercise Physiology, Graduate School of Health and Sports Science, Juntendo University, Chiba
| | - Norio Saga
- Institute of Health and Sports Science and Medicine ; Department of Exercise Physiology, Graduate School of Health and Sports Science, Juntendo University, Chiba
| | - Hisashi Naito
- Institute of Health and Sports Science and Medicine ; Department of Exercise Physiology, Graduate School of Health and Sports Science, Juntendo University, Chiba
| | - Shizuo Katamoto
- Institute of Health and Sports Science and Medicine ; Department of Exercise Physiology, Graduate School of Health and Sports Science, Juntendo University, Chiba
| | | | | | - Ryuzo Kawamori
- Department of Medicine, Metabolism and Endocrinology ; Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo ; Center for Therapeutic Innovations in Diabetes ; Center for Beta Cell Biology and Regeneration, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Hirotaka Watada
- Department of Medicine, Metabolism and Endocrinology ; Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo
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Sakurai Y, Tamura Y, Takeno K, Sato F, Fujitani Y, Hirose T, Kawamori R, Watada H. Association of T2 relaxation time determined by magnetic resonance imaging and intramyocellular lipid content of the soleus muscle in healthy subjects. J Diabetes Investig 2014; 2:356-8. [PMID: 24843513 PMCID: PMC4019302 DOI: 10.1111/j.2040-1124.2011.00108.x] [Citation(s) in RCA: 3] [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] [Indexed: 11/28/2022] Open
Abstract
The level of intramyocellular lipids (IMCL) is a physiological marker of skeletal muscle function. 1H‐magnetic resonance spectroscopy (MRS) is an established method to measure IMCL contents in vivo. However, all of the MR systems do not always contain measurement instruments for 1H‐MRS, thus in a clinical setting, alternative methods for estimation of IMCL content are needed. Here, we investigated the association between T1 and T2 relaxation times, determined by MR imaging, and IMCL measured by 1H‐MRS in the soleus and tibialis anterior muscles of 15 healthy male subjects. Intriguingly, in the soleus muscle, but not in the tibialis anterior muscle, T2 relaxation time correlated significantly with IMCL (r = 0.65, P < 0.05). The result suggests the possibility that T2 relaxation time of the soleus muscle can be used to estimate IMCL in a clinical setting. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00108.x, 2011)
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Affiliation(s)
- Yuko Sakurai
- Department of Medicine, Metabolism and Endocrinology, School of Medicine
| | - Yoshifumi Tamura
- Department of Medicine, Metabolism and Endocrinology, School of Medicine ; Sportology Center
| | - Kageumi Takeno
- Department of Medicine, Metabolism and Endocrinology, School of Medicine
| | - Fumihiko Sato
- Department of Medicine, Metabolism and Endocrinology, School of Medicine
| | - Yoshio Fujitani
- Department of Medicine, Metabolism and Endocrinology, School of Medicine ; Center for Therapeutic Innovations in Diabetes
| | - Takahisa Hirose
- Department of Medicine, Metabolism and Endocrinology, School of Medicine ; Center for Therapeutic Innovations in Diabetes
| | - Ryuzo Kawamori
- Department of Medicine, Metabolism and Endocrinology, School of Medicine ; Sportology Center ; Center for Therapeutic Innovations in Diabetes ; Center for Beta Cell Biology and Regeneration, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Hirotaka Watada
- Department of Medicine, Metabolism and Endocrinology, School of Medicine ; Sportology Center
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Evaluation of whole-abdominal fat volume by 700-slice CT scanning and comparison with the umbilical fat area anthropometric indices. Obes Res Clin Pract 2013; 4:e83-e162. [PMID: 24345649 DOI: 10.1016/j.orcp.2009.10.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2009] [Revised: 10/20/2009] [Accepted: 10/26/2009] [Indexed: 12/15/2022]
Abstract
SUMMARY BACKGROUND The fat area at the umbilical region on CT scans is widely used to identify visceral obesity. However, whether it precisely represents the abdominal visceral fat volume is uncertain, because of technical difficulty in evaluating whole-abdominal visceral fat volume. In this study, we compared the whole-abdominal visceral fat and subcutaneous fat volumes with the visceral fat area at the umbilical region and anthropometric indices. METHODS The study population consisted of 131 Japanese diabetic and non-diabetic subjects (72 males and 59 females) who underwent anthropometric measurements (height, weight, waist circumference, and hip circumference) and CT scanning from the top of the liver to the pelvic floor (about 700 slices) to analyze the whole-abdominal and umbilical contents of visceral and subcutaneous fat. RESULTS The visceral fat volume of the male group was 1.3-fold higher than that of the female group, while the subcutaneous fat volume of the female group was 1.3-fold higher than that of the male group. The visceral fat area at the umbilical region was strongly correlated with visceral fat volume (r = 0.921 in males and 0.931 in females). Both visceral and subcutaneous fat volumes were strongly correlated with the waist circumference (r = 0.768 and 0.809 in males and 0.744 and 0.803 in females), but not with the BMI or waist/hip ratio. CONCLUSION The visceral fat area at the umbilical region is an optimal indicator for whole-abdominal visceral fat volume, and the waist circumference is the anthropometric index that reflects visceral obesity more closely than BMI or the waist/hip ratio.
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Eckard C, Cole R, Lockwood J, Torres DM, Williams CD, Shaw JC, Harrison SA. Prospective histopathologic evaluation of lifestyle modification in nonalcoholic fatty liver disease: a randomized trial. Therap Adv Gastroenterol 2013; 6:249-59. [PMID: 23814606 PMCID: PMC3667474 DOI: 10.1177/1756283x13484078] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND AND AIMS Nonalcoholic fatty liver disease (NAFLD) is now recognized as part of the metabolic syndrome, and is specifically related to obesity and insulin resistance. Lifestyle modification is advocated for the treatment of NAFLD, but few studies have evaluated its impact on liver histology. The purpose of this study was to investigate which, if any, specific diet and exercise recommendations are associated with histopathologic changes. METHODS A total of 56 participants were randomly assigned to 1 of 4 lifestyle modification subgroups for 6 months: standard care, low-fat diet and moderate exercise, moderate-fat/low-processed-carbohydrate diet and moderate exercise, or moderate exercise only. All subjects had biopsy-proven NAFLD, to include nonalcoholic steatohepatitis (NASH), and received a repeat 6-month biopsy to detect histopathologic changes. Other measures included blood assay of liver enzymes (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase), fasting glucose, serum insulin, lipid panel, body weight, dietary intake, fat mass, and fitness level. RESULTS Among the 41 participants who completed the study (88% with NASH), a significant change was found in pre- to post-NAFLD activity score in the group as a whole (p < 0.001) with no difference detected between subgroups (p = 0.31). Our results confirm that lifestyle modification is effective in improving NAFLD and NASH. CONCLUSIONS Regardless of intervention group, lifestyle modification improved liver histology, as verified by repeat biopsy, after a 6-month intervention. This study reinforces the importance of lifestyle modification as the primary treatment strategy for patients with NAFLD.
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Affiliation(s)
- Carly Eckard
- Nutrition Care, US Army Medical Department-Vicenza Health Center, Vicenza, Italy
| | - Renee Cole
- US Military Dietetic Internship, Army Medical Department Center & School, Fort Sam Houston, TX, USA
| | - Joshua Lockwood
- Nutrition Care Division, Womack Army Medical Center, Fort Bragg, NC, USA
| | - Dawn M. Torres
- Hepatology Clinic, Gastroenterology Service, Department of Medicine, Walter Reed Army Medical Center, Washington, DC, USA
| | - Christopher D. Williams
- Gastroenterology Service, Department of Medicine, Brooke Army Medical Center, Fort Sam Houston, TX, USA
| | - Janet C. Shaw
- Anatomical Pathology, Wilford Hall Medical Center, Lackland AFB, TX, USA
| | - Stephen A. Harrison
- Division of Gastroenterology and Hepatology, Department of Medicine, Brooke Army Medical Center, Fort Sam Houston, TX 78234, USA
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Ryberg M, Sandberg S, Mellberg C, Stegle O, Lindahl B, Larsson C, Hauksson J, Olsson T. A Palaeolithic-type diet causes strong tissue-specific effects on ectopic fat deposition in obese postmenopausal women. J Intern Med 2013; 274:67-76. [PMID: 23414424 DOI: 10.1111/joim.12048] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Ectopic fat accumulation in liver and skeletal muscle may be an essential link between abdominal obesity, insulin resistance and increased risk of cardiovascular disease after menopause. We hypothesized that a diet containing a relatively high content of protein and unsaturated fat [mainly monounsaturated fatty acids (MUFAs)] but limited carbohydrates and saturated fat would reduce lipid content in liver and muscle and increase insulin sensitivity in postmenopausal women. SUBJECTS Ten healthy, nonsmoking postmenopausal women with a body mass index (BMI) >27 (28-35) kg m(-2) were included in the study. INTERVENTIONS Participants were instructed to consume an ad libitum Palaeolithic-type diet intended to provide approximately 30 energy percentage (E%) protein, 40 E% fat (mainly MUFAs) and 30 E% carbohydrate. Intramyocellular lipid (IMCL) levels in calf muscles and liver triglyceride levels were quantified using proton magnetic resonance spectroscopy ((1) H-MRS) before and 5 weeks after dietary intervention. Insulin sensitivity was estimated by homoeostasis model assessment (HOMA) indices and the euglycaemic hyperinsulinaemic clamp technique. RESULTS Mean energy intake decreased by 25% with a weight loss of 4.5 kg. BMI, waist and hip circumference, waist/hip ratio and abdominal sagittal diameter also decreased significantly, as did diastolic blood pressure (mean -7 mmHg), levels of fasting serum glucose, cholesterol, triglycerides, LDL/HDL cholesterol, apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1), urinary C-peptide and HOMA indices. Whole-body insulin sensitivity did not change. Liver triglyceride levels decreased by 49%, whereas IMCL levels in skeletal muscle were not significantly altered. CONCLUSIONS A modified Palaeolithic-type diet has strong and tissue-specific effects on ectopic lipid deposition in postmenopausal women.
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Affiliation(s)
- M Ryberg
- Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
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Waters DL, Ward AL, Villareal DT. Weight loss in obese adults 65years and older: a review of the controversy. Exp Gerontol 2013; 48:1054-61. [PMID: 23403042 DOI: 10.1016/j.exger.2013.02.005] [Citation(s) in RCA: 134] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2012] [Revised: 01/21/2013] [Accepted: 02/04/2013] [Indexed: 12/11/2022]
Abstract
Obesity in older adults is ubiquitous in many developed countries and is related to various negative health outcomes, making it an important public health target for intervention. However, treatment approaches for obesity in older adults remain controversial due to concerns surrounding the difficulty of behavior change with advancing age, exacerbating the age-related loss of skeletal muscle and bone, and the feasibility of long-term weight maintenance and related health consequences. This review serves to systematically examine the evidence regarding weight loss interventions with a focus on obese (body mass index 30kg/m(2) and above) older adults (aged 65years and older) and some proposed mechanisms associated with exercise and caloric restriction (lifestyle intervention). Our findings indicate that healthy weight loss in this age group can be achieved through lifestyle interventions of up to a one-year period. Most interventions reviewed reported a loss of lean body mass and bone mineral density with weight loss. Paradoxically muscle quality and physical function improved. Inflammatory molecules and metabolic markers also improved, although the independent and additive effects of exercise and weight loss on these pathways are poorly understood. Using our review inclusion criteria, only one small pilot study investigating long-term weight maintenance and associated health implications was found in the literature. Future research on lifestyle interventions for obese older adults should address the loss of bone and lean body mass, inflammatory mechanisms, and include sufficient follow-up to assess long-term weight maintenance and health outcomes.
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Affiliation(s)
- Debra L Waters
- Department of Preventive and Social Medicine, University of Otago, P.O. Box 913, Dunedin 9054, New Zealand.
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