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Ghazizadeh F, Afshari -Moez S, Alinaghian N, Torab M, Rahimi-Moghaddam P. Association of Adiponectin 45T/G (rs2241766) and Visfatin 4689G/T (rs2110385) Gene Polymorphisms with Susceptibility to Obesity. Int J Prev Med 2023; 14:115. [PMID: 38264564 PMCID: PMC10803681 DOI: 10.4103/ijpvm.ijpvm_79_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 02/16/2023] [Indexed: 01/25/2024] Open
Abstract
Background This study aimed to see whether the adiponectin 45T/G (rs2241766) and visfatin 4689G/T (rs2110385) gene polymorphisms in an Iranian population are linked to obesity and/or obesity-related traits in normal and obese individuals. Methods 230 obese individuals and 169 healthy controls had their genomic DNA taken. The alleles and genotypes of the rs2241766 and rs2110385 polymorphisms were determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Results Obese individuals had considerably greater frequencies of the G allele and GG genotypes of the rs2241766 polymorphism than healthy controls (35% vs 21%, Probability (P) <0.0001, odds ratios (OR): 1.99, 95% confidence intervals (CI): 1.45-2.75 and 21% vs 7%, P = 0.002, OR: 3.52, 95% CI: 1.81-6.85, respectively). In comparison to healthy controls, obesity patients had substantially lower frequencies of the T allele and TT genotype of the rs2241766 polymorphism (65% vs 79%, P < 0.0001, OR: 0.50, 95% CI: 0.36-0.69 and 51% vs 65%, P = 0.008, OR: 0.58, 95% CI: 0.39-0.87, respectively). Obese individuals had substantially higher frequencies of the G allele and GG genotype in the rs2110385 polymorphism than healthy controls (77% vs 69%, P = 0.01, OR: 1.47, 95% CI: 1.07-2.0 and 61% versus 51%, P = 0.047, OR: 1.5, 95% CI: 1.0-2.2, respectively). When compared to healthy controls, the frequency of the T allele in the rs2110385 polymorphism was considerably lower in obese individuals (23% vs 31%, P = 0.01, OR: 0.68, 95% CI: 0.5-0.93). Furthermore, these single nucleotide polymorphisms (SNPs) were shown to have a strong link to clinical data in obese individuals. In the case of adiponectin, 45T/G (rs2241766) genotypes, serum low-density lipoprotein, waist circumference, and diastolic blood pressure were substantially different among the rs2241766 genotypes (P = 0.007, P = 0.000, and P = 0.011, respectively). In the instance of the visfatin 4689G/T (rs2110385) gene polymorphism, serum triglycerides was substantially different among the rs2110385 genotypes (P = 0.039). Conclusions In the Iranian population, our findings revealed a strong link between adiponectin and visfatin gene polymorphisms and obesity and several obesity-related clinical characteristics. These SNPs might be used to identify those who are at risk of becoming obese.
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Affiliation(s)
- Foad Ghazizadeh
- Department of Pharmacology and Toxicology, School of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran
| | - Sepideh Afshari -Moez
- Department of Toxicology, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Nazila Alinaghian
- Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mansour Torab
- Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Parvaneh Rahimi-Moghaddam
- Department of Pharmacology and Physiology Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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Muli S, Brachem C, Alexy U, Schmid M, Oluwagbemigun K, Nöthlings U. Exploring the association of physical activity with the plasma and urine metabolome in adolescents and young adults. Nutr Metab (Lond) 2023; 20:23. [PMID: 37020289 PMCID: PMC10074825 DOI: 10.1186/s12986-023-00742-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 03/29/2023] [Indexed: 04/07/2023] Open
Abstract
BACKGROUND Regular physical activity elicits many health benefits. However, the underlying molecular mechanisms through which physical activity influences overall health are less understood. Untargeted metabolomics enables system-wide mapping of molecular perturbations which may lend insights into physiological responses to regular physical activity. In this study, we investigated the associations of habitual physical activity with plasma and urine metabolome in adolescents and young adults. METHODS This cross-sectional study included participants from the DONALD (DOrtmund Nutritional and Anthropometric Longitudinally Designed) study with plasma samples n = 365 (median age: 18.4 (18.1, 25.0) years, 58% females) and 24 h urine samples n = 215 (median age: 18.1 (17.1, 18.2) years, 51% females). Habitual physical activity was assessed using a validated Adolescent Physical Activity Recall Questionnaire. Plasma and urine metabolite concentrations were determined using ultra-high-performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) methods. In a sex-stratified analysis, we conducted principal component analysis (PCA) to reduce the dimensionality of metabolite data and to create metabolite patterns. Multivariable linear regression models were then applied to assess the associations between self-reported physical activity (metabolic equivalent of task (MET)-hours per week) with single metabolites and metabolite patterns, adjusted for potential confounders and controlling the false discovery rate (FDR) at 5% for each set of regressions. RESULTS Habitual physical activity was positively associated with the "lipid, amino acids and xenometabolite" pattern in the plasma samples of male participants only (β = 1.02; 95% CI: 1.01, 1.04, p = 0.001, adjusted p = 0.042). In both sexes, no association of physical activity with single metabolites in plasma and urine and metabolite patterns in urine was found (all adjusted p > 0.05). CONCLUSIONS Our explorative study suggests that habitual physical activity is associated with alterations of a group of metabolites reflected in the plasma metabolite pattern in males. These perturbations may lend insights into some of underlying mechanisms that modulate effects of physical activity.
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Affiliation(s)
- Samuel Muli
- Nutritional Epidemiology, Department of Nutrition and Food Sciences, University of Bonn, Friedrich-Hirzebruch- Allee 7, 53115, Bonn, Germany.
| | - Christian Brachem
- Nutritional Epidemiology, Department of Nutrition and Food Sciences, University of Bonn, Friedrich-Hirzebruch- Allee 7, 53115, Bonn, Germany
| | - Ute Alexy
- Nutritional Epidemiology, Department of Nutrition and Food Sciences, University of Bonn, Friedrich-Hirzebruch- Allee 7, 53115, Bonn, Germany
| | - Matthias Schmid
- Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), University Hospital Bonn, Venusberg Campus 1, 53127, Bonn, Germany
| | - Kolade Oluwagbemigun
- Nutritional Epidemiology, Department of Nutrition and Food Sciences, University of Bonn, Friedrich-Hirzebruch- Allee 7, 53115, Bonn, Germany
| | - Ute Nöthlings
- Nutritional Epidemiology, Department of Nutrition and Food Sciences, University of Bonn, Friedrich-Hirzebruch- Allee 7, 53115, Bonn, Germany
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SARZYNSKI MARKA, RICE TREVAK, DESPRÉS JEANPIERRE, PÉRUSSE LOUIS, TREMBLAY ANGELO, STANFORTH PHILIPR, TCHERNOF ANDRÉ, BARBER JACOBL, FALCIANI FRANCESCO, CLISH CLARY, ROBBINS JEREMYM, GHOSH SUJOY, GERSZTEN ROBERTE, LEON ARTHURS, SKINNER JAMESS, RAO DC, BOUCHARD CLAUDE. The HERITAGE Family Study: A Review of the Effects of Exercise Training on Cardiometabolic Health, with Insights into Molecular Transducers. Med Sci Sports Exerc 2022; 54:S1-S43. [PMID: 35611651 PMCID: PMC9012529 DOI: 10.1249/mss.0000000000002859] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The aim of the HERITAGE Family Study was to investigate individual differences in response to a standardized endurance exercise program, the role of familial aggregation, and the genetics of response levels of cardiorespiratory fitness and cardiovascular disease and diabetes risk factors. Here we summarize the findings and their potential implications for cardiometabolic health and cardiorespiratory fitness. It begins with overviews of background and planning, recruitment, testing and exercise program protocol, quality control measures, and other relevant organizational issues. A summary of findings is then provided on cardiorespiratory fitness, exercise hemodynamics, insulin and glucose metabolism, lipid and lipoprotein profiles, adiposity and abdominal visceral fat, blood levels of steroids and other hormones, markers of oxidative stress, skeletal muscle morphology and metabolic indicators, and resting metabolic rate. These summaries document the extent of the individual differences in response to a standardized and fully monitored endurance exercise program and document the importance of familial aggregation and heritability level for exercise response traits. Findings from genomic markers, muscle gene expression studies, and proteomic and metabolomics explorations are reviewed, along with lessons learned from a bioinformatics-driven analysis pipeline. The new opportunities being pursued in integrative -omics and physiology have extended considerably the expected life of HERITAGE and are being discussed in relation to the original conceptual model of the study.
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Affiliation(s)
- MARK A. SARZYNSKI
- Department of Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, SC
| | - TREVA K. RICE
- Division of Biostatistics, Washington University in St. Louis School of Medicine, St. Louis, MO
| | - JEAN-PIERRE DESPRÉS
- Department of Kinesiology, Faculty of Medicine, Laval University, Quebec, QC, CANADA
- Quebec Heart and Lung Institute Research Center, Laval University, Québec, QC, CANADA
| | - LOUIS PÉRUSSE
- Department of Kinesiology, Faculty of Medicine, Laval University, Quebec, QC, CANADA
- Institute of Nutrition and Functional Foods (INAF), Laval University, Quebec, QC, CANADA
| | - ANGELO TREMBLAY
- Department of Kinesiology, Faculty of Medicine, Laval University, Quebec, QC, CANADA
- Institute of Nutrition and Functional Foods (INAF), Laval University, Quebec, QC, CANADA
| | - PHILIP R. STANFORTH
- Department of Kinesiology and Health Education, University of Texas at Austin, Austin, TX
| | - ANDRÉ TCHERNOF
- Quebec Heart and Lung Institute Research Center, Laval University, Québec, QC, CANADA
- School of Nutrition, Laval University, Quebec, QC, CANADA
| | - JACOB L. BARBER
- Department of Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, SC
| | - FRANCESCO FALCIANI
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UNITED KINGDOM
| | - CLARY CLISH
- Metabolomics Platform, Broad Institute and Harvard Medical School, Boston, MA
| | - JEREMY M. ROBBINS
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA
- Cardiovascular Research Center, Beth Israel Deaconess Medical Center, Boston, MA
| | - SUJOY GHOSH
- Cardiovascular and Metabolic Disorders Program and Centre for Computational Biology, Duke-National University of Singapore Medical School, SINGAPORE
- Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA
| | - ROBERT E. GERSZTEN
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA
- Cardiovascular Research Center, Beth Israel Deaconess Medical Center, Boston, MA
| | - ARTHUR S. LEON
- School of Kinesiology, University of Minnesota, Minneapolis, MN
| | | | - D. C. RAO
- Division of Biostatistics, Washington University in St. Louis School of Medicine, St. Louis, MO
| | - CLAUDE BOUCHARD
- Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA
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Vettori A, Paolacci S, Maltese PE, Herbst KL, Cestari M, Michelini S, Michelini S, Samaja M, Bertelli M. Genetic Determinants of the Effects of Training on Muscle and Adipose Tissue Homeostasis in Obesity Associated with Lymphedema. Lymphat Res Biol 2020; 19:322-333. [PMID: 33373545 DOI: 10.1089/lrb.2020.0057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
It is widely accepted that metabolic changes associated with training are influenced by a person's genetic background. In this review, we explore the polymorphisms underlying interindividual variability in response to training of weight loss and muscle mass increase in obese individuals, with or without lymphedema, and in normal-weight subjects. We searched PubMed for articles in English published up to May 2019 using the following keywords: (((physical training[Title/Abstract] OR sport activity[Title/Abstract]) AND predisposition[Title/Abstract]) AND polymorphism [Title/Abstract]). We identified 38 single-nucleotide polymorphisms that may modulate the genetic adaptive response to training. The identification of genetic marker(s) that improve the beneficial effects of training may in perspective make it possible to assess training programs, which in combination with dietary intervention can optimize body weight reduction in obese subjects, with or without lymphedema. This is particularly important for patients with lymphedema because obesity can worsen the clinical status, and therefore, a personalized approach that could reduce obesity would be fundamental in the clinical management of lymphedema.
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Affiliation(s)
- Andrea Vettori
- Department of Biotechnology, University of Verona, Verona, Italy
| | | | | | - Karen L Herbst
- Department of Medicine, University of Arizona, Tucson, Arizona, USA.,Department of Pharmacy, University of Arizona, Tucson, Arizona, USA.,Department of Medical Imaging, University of Arizona, Tucson, Arizona, USA.,Department of Surgery, University of Arizona, Tucson, Arizona, USA
| | - Marina Cestari
- Study Centre Pianeta Linfedema, Terni, Italy.,Lymphology Sector of the Rehabilitation Service, USLUmbria2, Terni, Italy
| | - Sandro Michelini
- Department of Vascular Rehabilitation, San Giovanni Battista Hospital, Rome, Italy
| | - Serena Michelini
- Unit of Physical Medicine and Rehabilitation, Sant'Andrea Hospital, "Sapienza" University of Rome, Rome, Italy
| | - Michele Samaja
- Department of Health Science, University of Milan-San Paolo Hospital, Milan, Italy
| | - Matteo Bertelli
- MAGI'S Lab, Rovereto, Italy.,MAGI Euregio, Bolzano, Italy.,EBTNA-LAB, Rovereto, Italy
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Peña A, McNeish D, Ayers SL, Olson ML, Vander Wyst KB, Williams AN, Shaibi GQ. Response heterogeneity to lifestyle intervention among Latino adolescents. Pediatr Diabetes 2020; 21:1430-1436. [PMID: 32939893 PMCID: PMC8274397 DOI: 10.1111/pedi.13120] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 09/06/2020] [Accepted: 09/08/2020] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE To characterize the heterogeneity in response to lifestyle intervention among Latino adolescents with obesity. METHODS We conducted secondary data analysis of 90 Latino adolescents (age 15.4 ± 0.9 y, female 56.7%) with obesity (BMI% 98.1 ± 1.5%) that were enrolled in a 3 month lifestyle intervention and were followed for a year. Covariance pattern mixture models identified response phenotypes defined by changes in insulin sensitivity as measured using a 2 hour oral glucose tolerance test. Baseline characteristics were compared across response phenotypes using one-way ANOVA and chi-square test. RESULTS Three distinct response phenotypes (PH1, PH2, PH3) were identified. PH1 exhibited the most robust response defined by the greatest increase in insulin sensitivity over time (β ± SE, linear 0.52 ± 0.17, P < .001; quadratic -0.03 ± 0.01, P = .001). PH2 showed non-significant changes, while PH3 demonstrated modest short-term increases in insulin sensitivity which were not sustained over time (linear 0.08 ± 0.03, P = .002; quadratic -0.01 ± 0.002, P = .003). At baseline, PH3 (1.1 ± 0.4) was the most insulin resistant phenotype and exhibited the highest BMI% (98.5 ± 1.1%), 2 hours glucose concentrations (144.0 ± 27.5 mg/dL), and lowest beta-cell function as estimated by the oral disposition index (4.5 ± 2.8). CONCLUSION Response to lifestyle intervention varies among Latino youth with obesity and suggests that precision approaches are warranted to meet the prevention needs of high risk youth.
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Affiliation(s)
- Armando Peña
- Center for Health Promotion and Disease Prevention, Arizona State University, Phoenix, AZ,College of Health Solutions, Arizona State University, Phoenix, AZ
| | - Daniel McNeish
- Department of Psychology, Arizona State University, Tempe, AZ
| | - Stephanie L. Ayers
- Southwest Interdisciplinary Research Center, Arizona State University, Phoenix, AZ
| | - Micah L. Olson
- Center for Health Promotion and Disease Prevention, Arizona State University, Phoenix, AZ,College of Health Solutions, Arizona State University, Phoenix, AZ
| | - Kiley B. Vander Wyst
- Center for Health Promotion and Disease Prevention, Arizona State University, Phoenix, AZ
| | - Allison N. Williams
- Center for Health Promotion and Disease Prevention, Arizona State University, Phoenix, AZ
| | - Gabriel Q. Shaibi
- Center for Health Promotion and Disease Prevention, Arizona State University, Phoenix, AZ,College of Health Solutions, Arizona State University, Phoenix, AZ,Department of Pediatric Endocrinology and Diabetes, Phoenix Children’s Hospital, Phoenix, AZ
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Affiliation(s)
- Martijn Scherrenberg
- 1 Heart Centre Hasselt, Jessa Hospital, Belgium.,2 Faculty of Medicine & Life Sciences, Hasselt University, Belgium
| | - Paul Dendale
- 1 Heart Centre Hasselt, Jessa Hospital, Belgium.,2 Faculty of Medicine & Life Sciences, Hasselt University, Belgium
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Leońska-Duniec A, Jastrzębski Z, Jażdżewska A, Krzysztof F, Cięszczyk P. Leptin and Leptin Receptor Genes Are Associated With Obesity-Related Traits Changes in Response to Aerobic Training Program. J Strength Cond Res 2018; 32:1036-1044. [PMID: 29373433 DOI: 10.1519/jsc.0000000000002447] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Leońska-Duniec, A, Jastrzębski, Z, Jażdżewska, A, Krzysztof, F, and Cięszczyk, P. Leptin and leptin receptor genes are associated with obesity-related traits changes in response to aerobic training program. J Strength Cond Res 32(4): 1036-1044, 2018-Leptin (LEP) and leptin receptor (LEPR) genes have been studied for their potential association with development of human obesity and its related complications. Therefore, we have decided to check whether selected body mass, body composition, and metabolic variables observed in physically active participants will be modulated by the polymorphisms. The genotype distribution was examined in a group of 201 women measured for chosen traits before and after the completion of a 12-week aerobic training program. Our results revealed a significant interaction between training and LEP genotype for glucose level. A training-related decrease in plasma glucose concentration in the LEP AG heterozygotes differed significantly from the change in the homozygotes. The polymorphism was also associated with fat-free mass (FFM), total body water (TBW), total cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-C) levels. Another finding was a significant interaction between training and LEPR for LDL-C level. As opposed to AG and GG, AA homozygotes demonstrated a training-related decrease in LDL-C level. Our findings also showed that the LEPR G allele is connected with obesity-related traits. The participants with the GG genotype had higher body mass, body mass index (BMI), FFM, and TBW during the entire study period. This study provides evidence that polymorphisms in the LEP and LEPR genes are associated with the magnitude of the effects of regular physical activity on glucose and LDL-C levels, respectively. In addition, we found the association of the G allele of the LEPR polymorphism with body mass and BMI.
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Affiliation(s)
- Agata Leońska-Duniec
- Faculty of Physical Culture and Health Promotion, Department of Biological Basics of Physical Culture, University of Szczecin, Szczecin, Poland.,Faculty of Tourism and Recreation, Department of Health Promotion, Gdansk University of Physical Education and Sport, Gdańsk, Poland
| | - Zbigniew Jastrzębski
- Faculty of Tourism and Recreation, Department of Health Promotion, Gdansk University of Physical Education and Sport, Gdańsk, Poland
| | - Aleksandra Jażdżewska
- Faculty of Tourism and Recreation, Department of Health Promotion, Gdansk University of Physical Education and Sport, Gdańsk, Poland
| | - Ficek Krzysztof
- Faculty of Physiotherapy, Department of Physiotherapy Basics, The Jerzy Kukuczka Academy of Physical Education in Katowice, Katowice, Poland.,Galen-Orthopaedics, Bierun, Poland
| | - Paweł Cięszczyk
- Faculty of Physical Education, Department of Natural Sciences, Gdansk University of Physical Education and Sport, Gdańsk, Poland
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Solomon TPJ. Sources of Inter-individual Variability in the Therapeutic Response of Blood Glucose Control to Exercise in Type 2 Diabetes: Going Beyond Exercise Dose. Front Physiol 2018; 9:896. [PMID: 30061841 PMCID: PMC6055062 DOI: 10.3389/fphys.2018.00896] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 06/21/2018] [Indexed: 01/17/2023] Open
Abstract
In the context of type 2 diabetes, inter-individual variability in the therapeutic response of blood glucose control to exercise exists to the extent that some individuals, occasionally referred to as “non-responders,” may not experience therapeutic benefit to their blood glucose control. This narrative review examines the evidence and, more importantly, identifies the sources of such inter-individual variability. In doing so, this review highlights that no randomized controlled trial of exercise has yet prospectively measured inter-individual variability in blood glucose control in individuals with prediabetes or type 2 diabetes. Of the identified sources of inter-individual variability, neither has a prospective randomized controlled trial yet quantified the impact of exercise dose, exercise frequency, exercise type, behavioral/environmental barriers, exercise-meal timing, or anti-hyperglycemic drugs on changes in blood glucose control, in individuals with prediabetes or type 2 diabetes. In addition, there is also an urgent need for prospective trials to identify molecular or physiological predictors of inter-individual variability in the changes in blood glucose control following exercise. Therefore, the narrative identifies critical science gaps that must be filled if exercise scientists are to succeed in optimizing health care policy recommendations for type 2 diabetes, so that the therapeutic benefit of exercise may be maximized for all individuals with, or at risk of, diabetes.
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Affiliation(s)
- Thomas P J Solomon
- School of Sport, Exercise, and Rehabilitation Sciences, University of Birmingham, Birmingham, United Kingdom.,Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom
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Sparks LM. Exercise training response heterogeneity: physiological and molecular insights. Diabetologia 2017; 60:2329-2336. [PMID: 29032385 DOI: 10.1007/s00125-017-4461-6] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 08/18/2017] [Indexed: 12/17/2022]
Abstract
The overall beneficial effects of exercise are well studied, but why some people do not respond favourably to exercise is less understood. The National Institutes of Health Common Fund has recently launched the large-scale discovery project 'Molecular Transducers of Physical Activity in Humans' to examine the physiological and molecular (i.e. genetic, epigenetic, lipidomic, metabolomic, proteomic, etc.) responses to exercise training. A nationwide, multicentre clinical trial such as this one also provides a unique opportunity to robustly investigate the non-response to exercise in thousands of individuals that have undergone supervised aerobic- and resistance-based exercise training interventions. The term 'non-responder' is used here to address the lack of a response (to an exercise intervention) in an outcome specified a priori. Cardiorespiratory fitness ([Formula: see text]) as an exercise response variable was recently reviewed; thus, this review focuses on metabolic aspects of the non-response to exercise training. Integrated -omics platforms are discussed as an approach to disentangle the complicated relationships between endogenous and exogenous factors that drive the lack of a response to exercise in some individuals. Harnessing the power of combined -omics platforms with deep clinical phenotyping of human study participants will advance the field of exercise metabolism and shift the paradigm, allowing exercise interventions to be targeted at those most likely to benefit and identifying novel approaches to treat those who do not.
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Affiliation(s)
- Lauren M Sparks
- Translational Research Institute for Metabolism and Diabetes, Florida Hospital, 301 E Princeton Street, Orlando, FL, 32804, USA.
- Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL, USA.
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Böhm A, Hoffmann C, Irmler M, Schneeweiss P, Schnauder G, Sailer C, Schmid V, Hudemann J, Machann J, Schick F, Beckers J, Hrabě de Angelis M, Staiger H, Fritsche A, Stefan N, Nieß AM, Häring HU, Weigert C. TGF-β Contributes to Impaired Exercise Response by Suppression of Mitochondrial Key Regulators in Skeletal Muscle. Diabetes 2016; 65:2849-61. [PMID: 27358493 DOI: 10.2337/db15-1723] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 06/23/2016] [Indexed: 11/13/2022]
Abstract
A substantial number of people at risk of developing type 2 diabetes could not improve insulin sensitivity by physical training intervention. We studied the mechanisms of this impaired exercise response in 20 middle-aged individuals at high risk of developing type 2 diabetes who performed 8 weeks of controlled cycling and walking training at 80% individual Vo2 peak. Participants identified as nonresponders in insulin sensitivity (based on the Matsuda index) did not differ in preintervention parameters compared with high responders. The failure to increase insulin sensitivity after training correlates with impaired upregulation of mitochondrial fuel oxidation genes in skeletal muscle, and with the suppression of the upstream regulators PGC1α and AMPKα2. The muscle transcriptomes of the nonresponders are further characterized by the activation of transforming growth factor (TGF)-β and TGF-β target genes, which is associated with increases in inflammatory and macrophage markers. TGF-β1 as inhibitor of mitochondrial regulators and insulin signaling is validated in human skeletal muscle cells. Activated TGF-β1 signaling downregulates the abundance of PGC1α, AMPKα2, the mitochondrial transcription factor TFAM, and mitochondrial enzymes. Thus, the data suggest that increased TGF-β activity in skeletal muscle can attenuate the improvement of mitochondrial fuel oxidation after training and contribute to the failure to increase insulin sensitivity.
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Affiliation(s)
- Anja Böhm
- Division of Endocrinology, Diabetology, Angiology, Nephrology, Pathobiochemistry and Clinical Chemistry, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München, University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Christoph Hoffmann
- Division of Endocrinology, Diabetology, Angiology, Nephrology, Pathobiochemistry and Clinical Chemistry, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
| | - Martin Irmler
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Patrick Schneeweiss
- Department of Sports Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Günter Schnauder
- Division of Endocrinology, Diabetology, Angiology, Nephrology, Pathobiochemistry and Clinical Chemistry, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
| | - Corinna Sailer
- Division of Endocrinology, Diabetology, Angiology, Nephrology, Pathobiochemistry and Clinical Chemistry, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München, University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Vera Schmid
- Division of Endocrinology, Diabetology, Angiology, Nephrology, Pathobiochemistry and Clinical Chemistry, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
| | - Jens Hudemann
- Department of Sports Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Jürgen Machann
- German Center for Diabetes Research (DZD), Neuherberg, Germany Section on Experimental Radiology, Department of Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany
| | - Fritz Schick
- German Center for Diabetes Research (DZD), Neuherberg, Germany Section on Experimental Radiology, Department of Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany
| | - Johannes Beckers
- German Center for Diabetes Research (DZD), Neuherberg, Germany Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany Institute of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany
| | - Martin Hrabě de Angelis
- German Center for Diabetes Research (DZD), Neuherberg, Germany Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany Institute of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany
| | - Harald Staiger
- Division of Endocrinology, Diabetology, Angiology, Nephrology, Pathobiochemistry and Clinical Chemistry, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München, University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Andreas Fritsche
- Division of Endocrinology, Diabetology, Angiology, Nephrology, Pathobiochemistry and Clinical Chemistry, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München, University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Norbert Stefan
- Division of Endocrinology, Diabetology, Angiology, Nephrology, Pathobiochemistry and Clinical Chemistry, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München, University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Andreas M Nieß
- Department of Sports Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Hans-Ulrich Häring
- Division of Endocrinology, Diabetology, Angiology, Nephrology, Pathobiochemistry and Clinical Chemistry, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München, University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Cora Weigert
- Division of Endocrinology, Diabetology, Angiology, Nephrology, Pathobiochemistry and Clinical Chemistry, Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München, University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD), Neuherberg, Germany
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11
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Böhm A, Weigert C, Staiger H, Häring HU. Exercise and diabetes: relevance and causes for response variability. Endocrine 2016; 51:390-401. [PMID: 26643313 PMCID: PMC4762932 DOI: 10.1007/s12020-015-0792-6] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 10/28/2015] [Indexed: 12/31/2022]
Abstract
Exercise as a key prevention strategy for diabetes and obesity is commonly accepted and recommended throughout the world. Unfortunately, not all individuals profit to the same extent, some exhibit exercise resistance. This phenomenon of non-response to exercise is found for several endpoints, including glucose tolerance and insulin sensitivity. Since these non-responders are of notable quantity, there is the need to understand the underlying mechanisms and to identify predictors of response. This displays the basis to develop personalized training intervention regimes. In this review, we summarize the current knowledge on response variability, with focus on human studies and improvement of glucose homeostasis as outcome.
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Affiliation(s)
- Anja Böhm
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen, Eberhard Karls University Tübingen, 72076, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany
| | - Cora Weigert
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen, Eberhard Karls University Tübingen, 72076, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany
| | - Harald Staiger
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen, Eberhard Karls University Tübingen, 72076, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany
| | - Hans-Ulrich Häring
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen, Eberhard Karls University Tübingen, 72076, Tübingen, Germany.
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, Tübingen, Germany.
- German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany.
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12
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Wang G, Padmanabhan S, Wolfarth B, Fuku N, Lucia A, Ahmetov II, Cieszczyk P, Collins M, Eynon N, Klissouras V, Williams A, Pitsiladis Y. Genomics of elite sporting performance: what little we know and necessary advances. ADVANCES IN GENETICS 2013; 84:123-49. [PMID: 24262098 DOI: 10.1016/b978-0-12-407703-4.00004-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Numerous reports of genetic associations with performance- and injury-related phenotypes have been published over the past three decades; these studies have employed primarily the candidate gene approach to identify genes that associate with elite performance or with variation in performance-and/or injury-related traits. Although generally with small effect sizes and heavily prone to type I statistic error, the number of candidate genetic variants that can potentially explain elite athletic status, injury predisposition, or indeed response to training will be much higher than that examined by numerous biotechnology companies. Priority should therefore be given to applying whole genome technology to sufficiently large study cohorts of world-class athletes with adequately measured phenotypes where it is possible to increase statistical power. Some of the elite athlete cohorts described in the literature might suffice, and collectively, these cohorts could be used for replication purposes. Genome-wide association studies are ongoing in some of these cohorts (i.e., Genathlete, Russian, Spanish, Japanese, United States, and Jamaican cohorts), and preliminary findings include the identification of one single nucleotide polymorphism (SNP; among more than a million SNPs analyzed) that associates with sprint performance in Japanese, American (i.e., African American), and Jamaican cohorts with a combined effect size of ~2.6 (P-value <5×10(-7)) and good concordance with endurance performance between select cohorts. Further replications of these signals in independent cohorts will be required, and any replicated SNPs will be taken forward for fine-mapping/targeted resequencing and functional studies to uncover the underlying biological mechanisms. Only after this lengthy and costly process will the true potential of genetic testing in sport be determined.
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Affiliation(s)
- Guan Wang
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom
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13
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Hagberg JM, Jenkins NT, Spangenburg E. Exercise training, genetics and type 2 diabetes-related phenotypes. Acta Physiol (Oxf) 2012; 205:456-71. [PMID: 22672138 DOI: 10.1111/j.1748-1716.2012.02455.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is at virtually pandemic levels world-wide. Diabetes has been referred to as 'a geneticist's nightmare'. However, dramatic advances in our understanding of the genetics of T2DM have occurred in the past 5 years. While endurance exercise training and increased habitual physical activity levels have consistently been shown to improve or be associated with improved T2DM-related phenotypes, there is substantial interindividual variation in these responses. There is some evidence that T2DM-related phenotype responses to exercise training are heritable, indicating that they might have a genetic basis. Genome-wide linkage studies have not identified specific chromosomal loci that could account for these differences, and no genome-wide association studies have been performed relative to T2DM-related phenotype responses to exercise training. From candidate gene studies, there are relatively strong and replicated data supporting a role for the PPARγ Pro12Ala variant in the interindividual differences in T2DM-related phenotype responses to training. This is a potentially important candidate locus because it affects T2DM susceptibility, has high biological plausibility and is the target for the primary pharmaceutical method for treating T2DM. Is it time to conduct a hypothesis-driven large-scale exercise training intervention trial based on PPARγ Pro12Ala genotype with T2DM-related phenotypes as the primary outcome measures, while also assessing potential mechanistic changes in skeletal muscle and adipose tissue? Or would it be more appropriate to propose a smaller trial to address the specific skeletal muscle and adipose tissue mechanisms affected by the interaction between the PPARγ Pro12Ala genotype and exercise training?
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Affiliation(s)
- J. M. Hagberg
- Department of Kinesiology; School of Public Health; University of Maryland; College Park; MD; USA
| | - N. T. Jenkins
- Department of Kinesiology; School of Public Health; University of Maryland; College Park; MD; USA
| | - E. Spangenburg
- Department of Kinesiology; School of Public Health; University of Maryland; College Park; MD; USA
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14
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Hagberg JM. Do genetic variations alter the effects of exercise training on cardiovascular disease and can we identify the candidate variants now or in the future? J Appl Physiol (1985) 2011; 111:916-28. [DOI: 10.1152/japplphysiol.00153.2011] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Cardiovascular disease (CVD) and CVD risk factors are highly heritable, and numerous lines of evidence indicate they have a strong genetic basis. While there is nothing known about the interactive effects of genetics and exercise training on CVD itself, there is at least some literature addressing their interactive effect on CVD risk factors. There is some evidence indicating that CVD risk factor responses to exercise training are also heritable and, thus, may have a genetic basis. While roughly 100 studies have reported significant effects of genetic variants on CVD risk factor responses to exercise training, no definitive conclusions can be generated at the present time, because of the lack of consistent and replicated results and the small sample sizes evident in most studies. There is some evidence supporting “possible” candidate genes that may affect these responses to exercise training: APO E and CETP for plasma lipoprotein-lipid profiles; eNOS, ACE, EDN1, and GNB3 for blood pressure; PPARG for type 2 diabetes phenotypes; and FTO and BAR genes for obesity-related phenotypes. However, while genotyping technologies and statistical methods are advancing rapidly, the primary limitation in this field is the need to generate what in terms of exercise intervention studies would be almost incomprehensible sample sizes. Most recent diabetes, obesity, and blood pressure genetic studies have utilized populations of 10,000–250,000 subjects, which result in the necessary statistical power to detect the magnitude of effects that would probably be expected for the impact of an individual gene on CVD risk factor responses to exercise training. Thus at this time it is difficult to see how this field will advance in the future to the point where robust, consistent, and replicated data are available to address these issues. However, the results of recent large-scale genomewide association studies for baseline CVD risk factors may drive future hypothesis-driven exercise training intervention studies in smaller populations addressing the impact of specific genetic variants on well-defined physiological phenotypes.
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Affiliation(s)
- James M. Hagberg
- Department of Kinesiology, School of Public Health, University of Maryland, College Park, Maryland
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15
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Nakamura H, Asai A, Maruyama M, Sugimoto M. Production of rat monoclonal antibodies against RNA-binding protein Hzf. Hybridoma (Larchmt) 2010; 29:7-11. [PMID: 20199145 DOI: 10.1089/hyb.2009.0057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
The hematopoietic zinc finger protein, Hzf, is induced in response to DNA damage or by Arf tumor suppressor in a p53-dependent manner. Recent studies have revealed that Hzf is an RNA-binding protein that regulates localization and translation of specific mRNA. The RNA-binding activity of Hzf is required for the functions of cerebellar purkinje cells and adipocytes, although their molecular mechanisms underlying the mRNA regulation largely remain unknown. To further investigate the molecular function of Hzf, we raised two rat monoclonal antibodies (MAb) against a peptide corresponding to the C-terminal region of the mouse/human Hzf protein. Both MAbs reacted with the native protein expressed in mammalian cells, and were highly efficient in detecting endogenous Hzf by immunoblotting, immunoprecipitation, and immunofluorescence. These MAbs should therefore be useful for further analysis of molecular functions of the Hzf protein and for identification of Hzf-binding proteins.
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Affiliation(s)
- Hideaki Nakamura
- Department of Mechanism of Aging, National Institute for Longevity Sciences, NCGG, Aichi, Japan.
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16
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Ruchat SM, Rankinen T, Weisnagel SJ, Rice T, Rao DC, Bergman RN, Bouchard C, Pérusse L. Improvements in glucose homeostasis in response to regular exercise are influenced by the PPARG Pro12Ala variant: results from the HERITAGE Family Study. Diabetologia 2010; 53:679-89. [PMID: 20043145 PMCID: PMC2840709 DOI: 10.1007/s00125-009-1630-2] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2009] [Accepted: 11/17/2009] [Indexed: 11/30/2022]
Abstract
AIMS/HYPOTHESIS Exercise training improves glucose homeostasis, but large inter-individual differences are reported, suggesting a role of genetic factors. We investigated whether variants either confirmed or newly identified as diabetes susceptibility variants through genome-wide association studies (GWAS) modulate changes in phenotypes derived from an IVGTT in response to an endurance training programme. METHODS We analysed eight polymorphisms in seven type 2 diabetes genes (CDKAL1 rs7756992; CDKN2A and CDKN2B rs10811661 and rs564398; HHEX rs7923837; IGF2BP2 rs4402960; KCNJ11 rs5215; PPARG rs1801282; and TCF7L2 rs7903146) in a maximum of 481 sedentary, non-diabetic white individuals, who participated in a 20-week endurance training programme. Associations were tested between the variants and changes in IVGTT-derived phenotypes. RESULTS The only evidence of association with training response was found with PPARG rs1801282 (Pro12Ala). We observed that Ala carriers experienced greater increase in overall glucose tolerance (Deltaglucose disappearance index Ala/Ala 0.22 +/- 0.22, Pro/Ala 0.14 +/- 0.06, Pro/Pro 0.004 +/- 0.03; p = 0.0008), glucose effectiveness (Ala/Ala 0.28 +/- 0.41, Pro/Ala 0.44 +/- 0.14, Pro/Pro 0.09 +/- 0.06; p = 0.004), acute insulin response to glucose (Ala/Ala 64.21 +/- 37.73, Pro/Ala -11.92 +/- 40.30, Pro/Pro -46.30 +/- 14.70; p = 0.03) and disposition index (Ala/Ala 551.8 +/- 448.5, Pro/Ala 534.6 +/- 218.3, Pro/Pro -7.44 +/- 88.18; p = 0.003). CONCLUSIONS/INTERPRETATION Compared with Pro/Pro individuals, PPARG Ala carriers experienced greater improvements in glucose and insulin metabolism in response to regular endurance training. However, we did not find evidence of association between type 2 diabetes susceptibility variants recently identified through GWAS and glucose homeostasis response to exercise. Our results extend those of previous studies showing that Ala carriers appear to be more responsive to beneficial health effects of lifestyle interventions.
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Affiliation(s)
- S.-M. Ruchat
- Department of Social and Preventive Medicine, PEPS - Laval University, 2300 rue de la Terrasse, Quebec, QC, Canada G1V 0A6
- Lipid Research Center, CHUL Research Center, Quebec, QC, Canada
| | - T. Rankinen
- Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - S. J. Weisnagel
- Department of Social and Preventive Medicine, PEPS - Laval University, 2300 rue de la Terrasse, Quebec, QC, Canada G1V 0A6
- Lipid Research Center, CHUL Research Center, Quebec, QC, Canada
| | - T. Rice
- Division of Biostatistics, Washington University, St Louis, MO, USA
| | - D. C. Rao
- Division of Biostatistics, Washington University, St Louis, MO, USA
| | - R. N. Bergman
- Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - C. Bouchard
- Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - L. Pérusse
- Department of Social and Preventive Medicine, PEPS - Laval University, 2300 rue de la Terrasse, Quebec, QC, Canada G1V 0A6
- Lipid Research Center, CHUL Research Center, Quebec, QC, Canada
- Nutraceuticals and Functional Foods Institute (INAF), Quebec, QC, Canada
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17
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Lillioja S, Wilton A. Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies. Diabetologia 2009; 52:1061-74. [PMID: 19296077 DOI: 10.1007/s00125-009-1324-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2008] [Accepted: 02/13/2009] [Indexed: 12/22/2022]
Abstract
AIMS/HYPOTHESIS Little of the genetic basis for type 2 diabetes has been explained, despite numerous genetic linkage studies and the discovery of multiple genes in genome-wide association (GWA) studies. To begin to resolve the genetic component of this disease, we searched for sites at which genetic results had been corroborated in different studies, in the expectation that replication among studies should direct us to the genomic locations of causative genes with more confidence than the results of individual studies. METHODS We have mapped the physical location of results from 83 linkage reports (for type 2 diabetes and diabetes precursor quantitative traits [QTs, e.g. plasma insulin levels]) and recent large GWA reports (for type 2 diabetes) onto the same human genome sequence to identify replicated results in diabetes genetic 'hot spots'. RESULTS Genetic linkage has been found at least ten times at 18 different locations, and at least five times in 56 locations. All replication clusters contained study populations from more than one ethnic background and most contained results for both diabetes and QTs. There is no close relationship between the GWA results and linkage clusters, and the nine best replication clusters have no nearby GWA result. CONCLUSIONS/INTERPRETATION Many of the genes for type 2 diabetes remain unidentified. This analysis identifies the broad location of yet to be identified genes on 6q, 1q, 18p, 2q, 20q, 17pq, 8p, 19q and 9q. The discrepancy between the linkage and GWA studies may be explained by the presence of multiple, uncommon, mildly deleterious polymorphisms scattered throughout the regulatory and coding regions of genes for type 2 diabetes.
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Affiliation(s)
- S Lillioja
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia.
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18
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Bray MS, Hagberg JM, Pérusse L, Rankinen T, Roth SM, Wolfarth B, Bouchard C. The human gene map for performance and health-related fitness phenotypes: the 2006-2007 update. Med Sci Sports Exerc 2009; 41:35-73. [PMID: 19123262 DOI: 10.1249/mss.0b013e3181844179] [Citation(s) in RCA: 306] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
This update of the human gene map for physical performance and health-related fitness phenotypes covers the research advances reported in 2006 and 2007. The genes and markers with evidence of association or linkage with a performance or a fitness phenotype in sedentary or active people, in responses to acute exercise, or for training-induced adaptations are positioned on the map of all autosomes and sex chromosomes. Negative studies are reviewed, but a gene or a locus must be supported by at least one positive study before being inserted on the map. A brief discussion on the nature of the evidence and on what to look for in assessing human genetic studies of relevance to fitness and performance is offered in the introduction, followed by a review of all studies published in 2006 and 2007. The findings from these new studies are added to the appropriate tables that are designed to serve as the cumulative summary of all publications with positive genetic associations available to date for a given phenotype and study design. The fitness and performance map now includes 214 autosomal gene entries and quantitative trait loci plus seven others on the X chromosome. Moreover, there are 18 mitochondrial genes that have been shown to influence fitness and performance phenotypes. Thus,the map is growing in complexity. Although the map is exhaustive for currently published accounts of genes and exercise associations and linkages, there are undoubtedly many more gene-exercise interaction effects that have not even been considered thus far. Finally, it should be appreciated that most studies reported to date are based on small sample sizes and cannot therefore provide definitive evidence that DNA sequence variants in a given gene are reliably associated with human variation in fitness and performance traits.
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Affiliation(s)
- Molly S Bray
- USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA
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19
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Hzf regulates adipogenesis through translational control of C/EBPalpha. EMBO J 2008; 27:1481-90. [PMID: 18418387 DOI: 10.1038/emboj.2008.76] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2007] [Accepted: 03/26/2008] [Indexed: 11/09/2022] Open
Abstract
Adipocyte differentiation requires a well-defined programme of gene expression in which the transcription factor C/EBPalpha (CCAAT/enhancer-binding protein) has a central function. Here, we show that Hzf (haematopoietic zinc-finger), a previously identified p53 transcriptional target, regulates C/EBPalpha expression. Hzf is induced during differentiation of preadipocyte cell lines, and its suppression by short hairpin RNA disrupts adipogenesis. In Hzf's absence, expression of C/EBPalpha is severely impaired because of reduced translation of its mRNA. Hzf physically interacts with the 3' untranslated region of C/EBPalpha mRNA to enhance its translation. Taken together, these findings underscore a critical role of Hzf in the adipogenesis regulatory cascade.
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20
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Speidel D, Salehi A, Obermueller S, Lundquist I, Brose N, Renström E, Rorsman P. CAPS1 and CAPS2 regulate stability and recruitment of insulin granules in mouse pancreatic beta cells. Cell Metab 2008; 7:57-67. [PMID: 18177725 DOI: 10.1016/j.cmet.2007.11.009] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2007] [Revised: 10/15/2007] [Accepted: 11/19/2007] [Indexed: 11/25/2022]
Abstract
CAPS1 and CAPS2 regulate dense-core vesicle release of transmitters and hormones in neuroendocrine cells, but their precise roles in the secretory process remain enigmatic. Here we show that CAPS2(-/-) and CAPS1(+/-);CAPS2(-/-) mice, despite having increased insulin sensitivity, are glucose intolerant and that this effect is attributable to a marked reduction of glucose-induced insulin secretion. This correlates with diminished Ca(2+)-dependent exocytosis, a reduction in the size of the morphologically docked pool, a decrease in the readily releasable pool of secretory vesicles, slowed granule priming, and suppression of second-phase (but not first-phase) insulin secretion. In beta cells of CAPS1(+/-);CAPS2(-/-) mice, the lowered insulin content and granule numbers were associated with an increase in lysosome numbers and lysosomal enzyme activity. We conclude that although CAPS proteins are not required for Ca(2+)-dependent exocytosis to proceed, they exert a modulatory effect on insulin granule priming, exocytosis, and stability.
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Affiliation(s)
- Dina Speidel
- Department of Clinical Sciences Malmö, Lund University, UMAS, Malmö, Sweden.
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21
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Hu G, Lakka TA, Kilpeläinen TO, Tuomilehto J. Epidemiological studies of exercise in diabetes prevention. Appl Physiol Nutr Metab 2007; 32:583-95. [PMID: 17510700 DOI: 10.1139/h07-030] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Type 2 diabetes is one of the fastest growing public health problems in both developed and developing countries. It is estimated that the number of people with diabetes in the world will double in coming years, from 171 million in 2000 to 366 million in 2030. Cardiovascular disease accounts for more than 70% of total mortality among patients with type 2 diabetes. The associations of physical activity, physical fitness, and changes in the lifestyle with the risk of type 2 diabetes have been assessed by a number of prospective studies and clinical trials in the past decade. Several studies have also evaluated the joint associations of physical activity, body mass index, and glucose levels with the risk of type 2 diabetes. Prospective studies and clinical trials have shown that moderate or high levels of physical activity or physical fitness and changes in the lifestyle (dietary modification and increase in physical activity) can prevent type 2 diabetes. Our review of the scientific evidence confirms that 30 min/d of moderate- or high-level physical activity is an effective and safe way to prevent type 2 diabetes in all populations.
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Affiliation(s)
- Gang Hu
- Diabetes Unit, Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland
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22
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Goodarzi MO, Lehman DM, Taylor KD, Guo X, Cui J, Quiñones MJ, Clee SM, Yandell BS, Blangero J, Hsueh WA, Attie AD, Stern MP, Rotter JI. SORCS1: a novel human type 2 diabetes susceptibility gene suggested by the mouse. Diabetes 2007; 56:1922-9. [PMID: 17426289 DOI: 10.2337/db06-1677] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE A small number of susceptibility genes for human type 2 diabetes have been identified by candidate gene analysis or positional cloning. Genes found to influence diabetes or related traits in mice are likely to be susceptibility genes in humans. SorCS1 is the gene identified as responsible for the mouse chromosome 19 T2dm2 quantitative trait locus for fasting insulin levels, acting via impaired insulin secretion and increased islet disruption in obese females. Genes that impair compensatory insulin secretion in response to obesity-induced insulin resistance may be particularly relevant to human diabetes. Thus, we sought to determine whether variation in the human SORCS1 gene was associated with diabetes-related traits. RESEARCH DESIGN AND METHODS We assessed the contribution of variation in SORCS1 to human insulin-related traits in two distinct Mexican-American cohorts. One cohort (the Mexican-American Coronary Artery Disease [MACAD] cohort) consisted of nondiabetic individuals, allowing assessment of genetic association with subclinical intermediate insulin-related traits; the second cohort (the San Antonio Family Diabetes Study [SAFADS]) contained individuals with diabetes, allowing association analyses with overt disease. RESULTS We first found association of SORCS1 single nucleotide polymorphisms and haplotypes with fasting insulin levels and insulin secretion in the MACAD cohort. Similar to our results in the mice, the genetic association was strongest in overweight women. We then observed association with diabetes risk and age at diagnosis in women of the SAFADS cohort. CONCLUSIONS Identification of SORCS1 as a novel gene affecting insulin secretion and diabetes risk is likely to provide important insight into the biology of obesity-induced type 2 diabetes.
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Affiliation(s)
- Mark O Goodarzi
- Cedars-Sinai Medical Center, Division of Endocrinology, Diabetes, and Metabolism, 8700 Beverly Blvd., Becker B-131, Los Angeles, CA 90048, USA.
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23
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Abstract
Inbred mouse strains provide genetic diversity comparable to that of the human population. Like humans, mice have a wide range of diabetes-related phenotypes. The inbred mouse strains differ in the response of their critical physiological functions, such as insulin sensitivity, insulin secretion, beta-cell proliferation and survival, and fuel partitioning, to diet and obesity. Most of the critical genes underlying these differences have not been identified, although many loci have been mapped. The dramatic improvements in genomic and bioinformatics resources are accelerating the pace of gene discovery. This review describes how mouse genetics can be used to discover diabetes-related genes, summarizes how the mouse strains differ in their diabetes-related phenotypes, and describes several examples of how loci identified in the mouse may directly relate to human diabetes.
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Affiliation(s)
- Susanne M Clee
- Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, Wisconsin 53706-1544, USA
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24
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Rankinen T, Bray MS, Hagberg JM, Pérusse L, Roth SM, Wolfarth B, Bouchard C. The human gene map for performance and health-related fitness phenotypes: the 2005 update. Med Sci Sports Exerc 2007; 38:1863-88. [PMID: 17095919 DOI: 10.1249/01.mss.0000233789.01164.4f] [Citation(s) in RCA: 125] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The current review presents the 2005 update of the human gene map for physical performance and health-related fitness phenotypes. It is based on peer-reviewed papers published by the end of 2005. The genes and markers with evidence of association or linkage with a performance or fitness phenotype in sedentary or active people, in adaptation to acute exercise, or for training-induced changes are positioned on the genetic map of all autosomes and the X chromosome. Negative studies are reviewed, but a gene or locus must be supported by at least one positive study before being inserted on the map. By the end of 2000, in the early version of the gene map, 29 loci were depicted. In contrast, the 2005 human gene map for physical performance and health-related phenotypes includes 165 autosomal gene entries and QTL, plus five others on the X chromosome. Moreover, there are 17 mitochondrial genes in which sequence variants have been shown to influence relevant fitness and performance phenotypes. Thus, the map is growing in complexity. Unfortunately, progress is slow in the field of genetics of fitness and performance, primarily because the number of laboratories and scientists focused on the role of genes and sequence variations in exercise-related traits continues to be quite limited.
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Affiliation(s)
- Tuomo Rankinen
- Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808-4124, USA
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North KE, Franceschini N, Borecki IB, Gu CC, Heiss G, Province MA, Arnett DK, Lewis CE, Miller MB, Myers RH, Hunt SC, Freedman BI. Genotype-by-sex interaction on fasting insulin concentration: the HyperGEN study. Diabetes 2007; 56:137-42. [PMID: 17192475 DOI: 10.2337/db06-0624] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Recent studies have demonstrated the importance of sex effects on the underlying genetic architecture of insulin-related traits. To explore sex-specific genetic effects on fasting insulin, we tested for genotype-by-sex interaction and conducted linkage analysis of fasting insulin in Hypertension Genetic Epidemiology Network families. Hypertensive siblings and their first-degree relatives were recruited from five field centers. We performed a genome scan for quantitative trait loci influencing fasting insulin among 1,505 European Americans and 1,616 African Americans without diabetes. Sex-stratified linear regression models, adjusted for race, center, and age, were explored. The Mammalian Genotyping Service typed 391 microsatellite markers, spaced roughly 9 cM. Variance component linkage analysis was performed in SOLAR using ethnic-specific marker allele frequencies and multipoint IBDs calculated in MERLIN. We detected a quantitative trait locus influencing fasting insulin in female subjects (logarithm of odds [LOD] = 3.4) on chromosome 2 at 95 cM (between GATA69E12 and GATA71G04) but not in male subjects (LOD = 0.0, P for interaction = 0.007). This sex-specific signal at 2p13.2 was detected in both European-American (LOD = 2.1) and African-American (LOD = 1.2) female subjects. Our findings overlap with several other linkage reports of insulin-related traits and demonstrate the importance of considering complex context-dependent interactions in the search for insulin-related genes.
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Affiliation(s)
- Kari E North
- Department of Epidemiology, University of North Carolina Chapel Hill, Bank of America Center, 137 E. Franklin St., Suite 306, Chapel Hill, NC 27514, USA.
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Hu G, Rico-Sanz J, Lakka TA, Tuomilehto J. Exercise, genetics and prevention of type 2 diabetes. Essays Biochem 2006; 42:177-92. [PMID: 17144888 DOI: 10.1042/bse0420177] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Type 2 diabetes is one of the fastest growing public health problems in both developed and developing countries. Cardiovascular disease is the most prevalent complication of type 2 diabetes. In the past decade, the associations of physical activity, physical fitness and changes in the lifestyle with the risk of type 2 diabetes have been assessed by a number of prospective studies and clinical trials. A few studies have also evaluated the joint associations of physical activity, body mass index and glucose levels with the risk of type~2 diabetes. The results based on prospective studies and clinical trials have shown that moderate or high levels of physical activity or physical fitness and changes in the lifestyle (dietary modification and increase in physical activity) can prevent type 2 diabetes.
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Affiliation(s)
- Gang Hu
- Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland.
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Imperatore G, Cheng YJ, Williams DE, Fulton J, Gregg EW. Physical activity, cardiovascular fitness, and insulin sensitivity among U.S. adolescents: the National Health and Nutrition Examination Survey, 1999-2002. Diabetes Care 2006; 29:1567-72. [PMID: 16801580 DOI: 10.2337/dc06-0426] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The purpose of this study was to examine the association of physical activity and cardiovascular fitness (CVF) with insulin sensitivity in a nationally representative sample of U.S. youth. RESEARCH DESIGN AND METHODS The study included 1,783 U.S. adolescents (11% Mexican American, 14% non-Hispanic black, 63% non-Hispanic white, and 12% other) aged 12-19 years who were examined in the 1999-2002 National Health and Nutrition Examination Survey. Physical activity was assessed by questionnaire and expressed in units of MET hours per week. Predicted maximal oxygen uptake (Vo(2max), expressed in milliliters per kilogram of body weight per minute), a measure of CVF, was determined by a submaximal multistage treadmill test. Insulin sensitivity was defined by the Quantitative Insulin Sensitivity Check Index. RESULTS Boys were more likely than girls to be highly active (>or=30 MET h/week; 51 vs. 37%, P < 0.001) and had higher levels of CVF (mean Vo(2max) 47 vs. 39 ml x kg(-1) x min(-1), P < 0.001). Sex-specific multiple regression models controlled for age, race/ethnicity, and BMI showed that in boys, high levels of physical activity and high levels of CVF were significantly and positively associated with insulin sensitivity (beta = 0.84, P < 0.001 and beta = 0.82, P = 0.01, respectively). Among girls, insulin sensitivity was not significantly associated with physical activity or with CVF but was inversely and significantly associated with BMI. CONCLUSIONS Increasing physical activity and CVF may have an independent effect of improving insulin sensitivity among boys. For girls, the primary role of physical activity may be in weight maintenance.
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Affiliation(s)
- Giuseppina Imperatore
- Division of Diabetes Translation, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, 4770 Buford Highway, NE MS-K10, Atlanta, GA 30341, USA.
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Brutsaert TD, Parra EJ. What makes a champion? Respir Physiol Neurobiol 2006; 151:109-23. [PMID: 16448865 DOI: 10.1016/j.resp.2005.12.013] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2005] [Revised: 12/12/2005] [Accepted: 12/21/2005] [Indexed: 01/18/2023]
Abstract
Variation in human athletic performance is determined by a complex interaction of socio-cultural, psychological, and proximate physiological factors. Human physiological trait variance has both an environmental and genetic basis, although the classic gene-environment dichotomy is clearly too simplistic to understand the full range of variation for most proximate determinants of athletic performance, e.g., body composition. In other words, gene and environment interact, not just over the short term, but also over the lifetime of an individual with permanent effects on the adult phenotype. To further complicate matters, gene and environment may also be correlated. That is, genetically gifted individuals may be identified as children and begin training pulmonary, cardiovascular, and muscle systems at an early critical age. This review covers evidence in support of a genetic basis to human athletic performance, with some emphasis on the recent explosion of candidate gene studies. In addition, the review covers environmental influences on athletic performance with an emphasis on irreversible environmental effects, i.e., developmental effects that may accrue during critical periods of development either before conception (epigenetic effects), during fetal life (fetal programming), or during childhood and adolescence. Throughout, we emphasize the importance of gene-environment interaction (G x E) as a means of understanding variation in human physiological performance and we promote studies that integrate genomics with developmental biology.
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Affiliation(s)
- Tom D Brutsaert
- Department of Anthropology, 1400 Washington Ave., The University at Albany, SUNY, Albany, NY 12222, USA.
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An P, Teran-Garcia M, Rice T, Rankinen T, Weisnagel SJ, Bergman RN, Boston RC, Mandel S, Stefanovski D, Leon AS, Skinner JS, Rao DC, Bouchard C. Genome-wide linkage scans for prediabetes phenotypes in response to 20 weeks of endurance exercise training in non-diabetic whites and blacks: the HERITAGE Family Study. Diabetologia 2005; 48:1142-9. [PMID: 15868134 DOI: 10.1007/s00125-005-1769-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2004] [Accepted: 01/27/2005] [Indexed: 10/25/2022]
Abstract
AIMS/HYPOTHESIS Impaired insulin secretion, insulin action, insulin-independent glucose effectiveness, glucose tolerance and the associated abnormalities in insulin and glucose metabolism phenotypes are precursors of type 2 diabetes. Genome-wide multipoint variance component linkage scans were carried out using 654 markers to identify quantitative trait loci for insulin sensitivity, acute insulin response to glucose, disposition index and glucose effectiveness training responses in whites and blacks in the HERITAGE Family Study. METHODS These phenotypes were obtained from an IVGTT with the minimal model. The distributions of insulin sensitivity, acute insulin response to glucose and disposition index training responses (post-training minus baseline) were approximately normalised using a square-root transformation. All phenotypes were adjusted for the effects of age, BMI and their respective baseline values within sex and generation by race prior to linkage scans. RESULTS In blacks, a promising linkage with a maximum lod score of 3.1 on 19q (54-62 Mb) for glucose effectiveness training response was found. Six interesting linkages with lod scores of at least 1.0 were found for disposition index training response in whites. They included 1p (30 Mb), 3q (152 Mb), 6p (23-42 Mb), 7q (95-96 Mb), 10p (15 Mb) and 12q (119-126 Mb). CONCLUSIONS/INTERPRETATION Quantitative trait loci for 20 weeks of endurance exercise training responses in insulin action and glucose metabolism phenotypes were found on chromosome 19q as well as 6p and 7q, with nominal (6p, 7q) but consistent (6p) linkages across the races.
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Affiliation(s)
- P An
- Division of Biostatistics, Washington University School of Medicine, Campus Box 8067, 660 South Euclid Avenue, St Louis, MO, 63110, USA.
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An P, Freedman BI, Hanis CL, Chen YDI, Weder AB, Schork NJ, Boerwinkle E, Province MA, Hsiung CA, Wu X, Quertermous T, Rao DC. Genome-wide linkage scans for fasting glucose, insulin, and insulin resistance in the National Heart, Lung, and Blood Institute Family Blood Pressure Program: evidence of linkages to chromosome 7q36 and 19q13 from meta-analysis. Diabetes 2005; 54:909-14. [PMID: 15734873 DOI: 10.2337/diabetes.54.3.909] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Genome-wide linkage analyses were performed using a multipoint variance components method in eight study groups from four multicenter networks (whites and blacks in GenNet; whites, blacks, and Mexican Americans in GENOA; whites and blacks in HyperGEN; and Asians in SAPPHIRe) that comprise the National Heart, Lung, and Blood Institute Family Blood Pressure Program (FBPP), in order to identify quantitative trait loci (QTLs) influencing fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR). These study populations were enriched with subjects who had elevated blood pressure. Participants fasting <8 h, those with a history of type 2 diabetes, or those on antidiabetic medications were excluded from the current investigation. These three phenotypes were suitably transformed to approximate normal distributions. Each phenotype was adjusted for the effects of age, BMI, and field center separately by sex within each of the eight network ethnicity groups before genetic analysis. A total of 8,664 subjects comprising 5,923 sibpairs from 4,043 families with 365 markers were available for conducting a meta-analysis using a modified Fisher's method of combining the P values from each of the eight scans. Evidence of linkages was found on chromosome 7q36 at 163 cM, with a logarithm of odds (LOD) score of 3.21 for HOMA-IR, and on chromosome 19q13 at 88 cM, with a LOD score of 3.33 for fasting glucose. We also found suggestive linkages (LOD score >/=2.2) on chromosome 7q36 at 163 cM, with LOD scores of 2.31 for fasting glucose and 2.26 for fasting insulin (versus the LOD score of 3.21 for HOMA-IR at this locus). In conclusion, QTLs were identified on chromosomes 7q36 and 19q13 for fasting glucose, insulin, and insulin resistance in large and multiple-ethnicity populations in the FBPP with good replications across several other independent studies for relevant traits. Follow-up dense mapping and association studies are warranted.
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Affiliation(s)
- Ping An
- Division of Biostatistics (Campus Box 8067), Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110-1093, USA.
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Boulé NG, Weisnagel SJ, Lakka TA, Tremblay A, Bergman RN, Rankinen T, Leon AS, Skinner JS, Wilmore JH, Rao DC, Bouchard C. Effects of exercise training on glucose homeostasis: the HERITAGE Family Study. Diabetes Care 2005; 28:108-14. [PMID: 15616242 DOI: 10.2337/diacare.28.1.108] [Citation(s) in RCA: 234] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To determine the effect of a 20-week endurance training program in healthy, previously sedentary participants on measures derived from an intravenous glucose tolerance test (i.v.GTT). RESEARCH DESIGN AND METHODS An i.v.GTT was performed before and after a standardized training program in 316 women and 280 men (173 blacks and 423 whites). Participants exercised on cycle ergometers 3 days per week for 60 sessions. The exercise intensity was progressively increased from 55% VO2max for 30 min per session to 75% VO2max for 50 min per session. RESULTS Mean insulin sensitivity increased by 10% (P < 0.001) following the intervention, but the variability in the changes was high. Men had larger improvements than women (P = 0.02). Improvements in fasting insulin were transitory, disappearing 72 h after the last bout of exercise. There were also significant mean increases in the glucose disappearance index (3%, P = 0.02) and in glucose effectiveness (11%, P < 0.001), measures of glucose tolerance and of the capacity of glucose to mediate its own disposal, respectively. The acute insulin response to glucose, a measure of insulin secretion, increased by 7% in the quartile with the lowest baseline glucose tolerance and decreased by 14% in the quartile with the highest baseline glucose tolerance (P < 0.001). The glucose area below fasting levels during the i.v.GTT was reduced by 7% (P = 0.02). CONCLUSIONS Although the effects of structured regular exercise were highly variable, there were improvements in virtually all i.v.GTT-derived variables. In the absence of substantial weight loss, regular exercise is required for sustained improvements in glucose homeostasis.
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Affiliation(s)
- Normand G Boulé
- Division of Kinesiology, Laval University, Sainte-Foy, Québec, Canada
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Rankinen T, Pérusse L, Rauramaa R, Rivera MA, Wolfarth B, Bouchard C. The human gene map for performance and health-related fitness phenotypes: the 2003 update. Med Sci Sports Exerc 2004; 36:1451-69. [PMID: 15354024 DOI: 10.1249/01.mss.0000139902.42385.5f] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
This review presents the 2003 update of the human gene map for physical performance and health-related fitness phenotypes. It is based on peer-reviewed papers published by the end of 2003 and includes association studies with candidate genes, genome-wide scans with polymorphic markers, and single-gene defects causing exercise intolerance to variable degrees. The genes and markers with evidence of association or linkage with a performance or fitness phenotype in sedentary or active people, in adaptation to acute exercise, or for training-induced changes are positioned on the genetic map of all autosomes and the X chromosome. Negative studies are reviewed but a gene or locus must be supported by at least one positive study before being inserted on the map. By the end of 2000, 29 loci were depicted on the first edition of the map. In contrast, the 2003 human gene map for physical performance and health-related phenotypes includes 109 autosomal gene entries and QTL, plus two on the X chromosome. Moreover, there are 15 mitochondrial genes in which sequence variants have been shown to influence relevant fitness and performance phenotypes.
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Affiliation(s)
- Tuomo Rankinen
- Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808-4124, USA.
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Liu Z, Sun HX, Zhang YW, Li YF, Zuo J, Meng Y, Fang FD. Effect of SNPs in protein kinase Cz gene on gene expression in the reporter gene detection system. World J Gastroenterol 2004; 10:2357-60. [PMID: 15285019 PMCID: PMC4576288 DOI: 10.3748/wjg.v10.i16.2357] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To investigated the effects of the SNPs (rs411021, rs436045, rs427811, rs385039 and rs809912) on gene expression and further identify the susceptibility genes of type 2 diabetes.
METHODS: Ten allele fragments (49 bp each) were synthesized according to the 5 SNPs mentioned above. These fragments were cloned into luciferase reporter gene vector and then transfected into HepG2 cells. The activity of the luciferase was assayed. Effects of the SNPs on RNA splicing were analyzed by bioinformatics.
RESULTS: rs427811T allele and rs809912G allele enhanced the activity of the reporter gene expression. None of the 5 SNPs affected RNA splicing.
CONCLUSION: SNPs in protein kinase Cz (PKCZ) gene probably play a role in the susceptibility to type 2 diabetes by affecting the expression level of the relevant genes.
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Affiliation(s)
- Zhuo Liu
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
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Lakka TA, Rankinen T, Weisnagel SJ, Chagnon YC, Lakka HM, Ukkola O, Boulé N, Rice T, Leon AS, Skinner JS, Wilmore JH, Rao DC, Bergman R, Bouchard C. Leptin and leptin receptor gene polymorphisms and changes in glucose homeostasis in response to regular exercise in nondiabetic individuals: the HERITAGE family study. Diabetes 2004; 53:1603-8. [PMID: 15161768 DOI: 10.2337/diabetes.53.6.1603] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
We recently reported that a genomic region close to the leptin locus was linked to fasting insulin response to exercise training in nondiabetic white subjects. We tested the hypothesis that common exonic variants in the leptin (LEP) and leptin receptor (LEPR) genes modify the effects of regular physical activity on glucose homeostasis in nondiabetic whites (n = 397) and blacks (n = 143). In whites, exercise increased insulin sensitivity index (P = 0.041) and disposition index (P = 0.046) in the LEPR 109R allele carriers but not in the K109K homozygotes, increased glucose disappearance index more in the R109R homozygotes than in the K109 allele carriers (P = 0.039), and decreased fasting glucose only in the 109R allele carriers (P = 0.018). We also found an interaction between the LEP A19G and LEPR K109R polymorphisms on the change in fasting insulin in whites (P = 0.010). The association between the LEP A19G polymorphism and the change in insulin was evident only in the LEPR 109R carriers (P = 0.019). The decrease in insulin was strongest in the LEP A19A homozygotes who carried the LEPR 109R allele. Similar interaction was observed in blacks (P = 0.046). Variations in the LEP and LEPR genes are associated with the magnitude of the effects of regular exercise on glucose homeostasis in nondiabetic individuals.
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Affiliation(s)
- Timo A Lakka
- Human Genomics Laboratory, Pennington Biomedical Research Center, 6400 Perkins Rd., Baton Rouge, LA 70808-4124, USA.
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Current literature in diabetes. Diabetes Metab Res Rev 2003; 19:421-8. [PMID: 12951651 DOI: 10.1002/dmrr.350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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