Role of Physical Exercise, Fitness and Aerobic Training in Type I Diabetic and Healthy Men in ... PDF
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KUOPION YLlOPISTON JULKAISUJA D. LAAKETIEDE 293 KUOPIO UNIVERSITY PUBLICATIONS D. MEDICAL SCIENCES 293 DAVID E. LAAKSONEN Role of Physical Exercise, Fitness and Aerobic Training in Type I Diabetic and Healthy Men in Relation to the Lipid Profile, Lipid Peroxidation and the Metabolic Syndrome Doctoral dissertation To be presented by permission ofthe Faculty of Medicine ofthe University of Kuopio for public examination in Auditorium LI, Canthia building, University of Kuopio, on Wednesday the 18th of December 2002, at 12 noon Department of Physiology Department ofMedicine Department ofClinical Nutrition Research Institute ofPublic Health University of Kuopio and Kuopio University Hospital KUOPION YLIOPISTO KUOPIO 2002 Distributor: Kuopio University Library P,O,Box 1627 FIN-7021 I KUOPIO FINLAND Tel. +358 17 163 430 Fax+358 17 163410 Series Editors: Professor Esko Alhava, MD" PhD, Department ofSurgery Professor Martti Hakumaki, MD" PhD, Department ofPhysiology Professor Raimo Sulkava, MD" PhD, Department of Public Health and General Practice Author's address: Department ofPhysiology University ofKuopio P,O,Box 1627 FIN-7021 I Kuopio FINLAND Tel, +358 17 163 180 Fax +358 I7 I63 I I2 Supervisors: Docent Chandan K, Sen, PhD, Department ofSurgery Ohio State University Medical Center, Columbus, Ohio, USA Professor Leo Niskanen, MD, Department ofMedicine Professor Matti Uusitupa, MD, Department ofClinical Nutrition Professor Osmo Hanninen, MD" PhD, Department ofPhysiology Docent Timo A. Lakka, MD, Pennington Biomedical Research Center Lousiana State University, Baton Rouge, Louisiana, USA Reviewers: Professor Scott Powers, PhD, Department ofExercise and Sport Sciences Physiology, University ofFlorida, Gainesville, USA Docent Sari Makimattila, MD, Department ofEndocrinology Malmo University Hospital, Malmo, Sweden Opponent: DocentJohan Eriksson, MD, Department ofEpidemiology and Health Promotion National Public Health Institute, Helsinki ISBN 951-781-893-9 ISSN 1235-0303 Kuopio University Printing Office Kuopio 2002 Finland Laaksonen,DavidE. RoleofPhysicalExercise,FitnessandAerobicTraininginType 1Diabeticand HealthyMeninRelationtotheLipidProfile,LipidPeroxidationandtheMetabolicSyndrome KuopioUniversityPublicationsD.MedicalSciences293.2002. 90p. ISBN951-781-893-9 ISSN 1235-0303 ABSTRACT Dyslipidemia andpossibly lipid peroxidationplay importantroles in the development ofmacro- and microvascular disease in type 1 diabetes mellitus. Little is known, however, ofthe role ofaerobic exercise in dyslipidemia and resting and exercise-induced lipid peroxidation in type 1 diabetes. Despite the well-known effect of leisure-time physical activity (LTPA) on components of the metabolicsyndrome,littleisknownoftheassociationofLTPAandcardiorespiratoryfitness (maximal oxygen consumption, V02max) with development of the metabolic syndrome itself. A randomized controlledtrial assessingthe effectofa 12-16weekaerobic exerciseprogramonV0 andthe lipid 2max profile was carried out in otherwise healthy young men with type 1 diabetes. The effect of acute physical exercise onoxidative stress and antioxidantdefenses andthe relationto V0 inmenwith 2max type 1diabetes was also evaluated. To test four recently proposed definitions by the World Health Organization (WHO) and National Cholesterol Education Program (NCEP) of the metabolic syndrome, the sensitivity and specificity ofthe definitions for prevalent and incident diabetes were assessedinapopulation-basedcohortofmiddle-agedmen. We also studiedthe associations ofLTPA and cardiorespiratory fitness with prevalent and incident cases ofthe metabolic syndrome. A 12-16 week endurance exercise program produced antiatherogenic changes in lipid, lipoprotein and apolipoproteinlevelsin20type 1diabeticmenwhoforthemostpartwerealreadyphysicallyactiveat baseline. The most favorable training-induced changes in the high-density lipoprotein cholesterol (HDL)/Iow-densitylipoproteincholesterol(LDL)andapolipoproteinA-I/apolipoproteinBratioswere inpatientswithlowbaselineHDLILDLlevels, likelythe group withthe mostbenefittobegainedby such changes. Plasma thiobarbituric acid reactive substances (TBARS), a measure of lipid peroxidation,was higherinnine healthy young menwithtype 1diabetes than incontrolmenbothat rest and after exercise, suggesting increased oxidative stress. An inverse correlationbetweenresting plasma TBARS and V0 was found inthe diabetic men, which couldimply a protective effectof 2max physical fitness against lipid peroxidation. The nine young diabetic men also had lower erythrocyte Cu,Zn-superoxide dismutase and catalase activity, but higher glutathione reductase activity. Coupled with increased plasma TBARS and bloodtotal glutathione levels in the diabetic men, these changes may reflect increased susceptibility to oxidative stress and compensatory adaptations ofglutathione homeostasis in response to increased oxidative stress. The WHO and NCEP definitions of the metabolicsyndromeappearvalid,identifyingindividualsofapopulation-basedcohortofmiddle-aged men (n=1005) with a 5-9 -fold increased likelihood ofdeveloping diabetes during follow up. The modifiedWHO definitionbasedonwaist-hip ratio >0.9 was the mostsensitive indetectingprevalent and incidentdiabetesandhadgoodspecificity. TheNCEP definitionofthe metabolic syndrome with adiposity defined as waist girth >102 cm was the most specific, but did not detect most cases of incident diabetes. In a subset ofmen without diabetes or the metabolic syndrome at baseline, those whoengagedinmoreLTPA,especiallyvigorous,orwhoweremorefitwerelesslikelyto developthe metabolic syndrome during the four-year follow up. These findings support promotion ofmoderate and vigorous leisure-time physical activity in otherwise healthy type 1 diabetic men to improve dyslipidemia and cardiorespiratory fitness and possibly decrease lipid peroxidation, and in middle aged non-diabetic men, to decrease the risk for development ofthe metabolic syndrome and thereby chronicandprogressivediseasessuchasdiabetesandatherosclerosis. NationalLibraryofMedicineClassification:WK810,QU85,QT255 MedicalSubjectHeadings: diabetes, insulin-dependent;diabetes,non-insulin-dependent;metabolic syndromeX;exercise;physicalfitness; oxidativestress;lipidperoxidation;antioxidants; glutathione; obesity;hyperinsulinemia;apolipoproteins,lipoproteins;triglycerides;hypertension;randomized controlledtrials;prospectivestudies;riskfactors; male. ACKNOVVLEDGMENTS This workwas carriedoutinthe DepartmentofPhysiologyandthe DepartmentofMedicine, University ofKuopio, in 1994-2001. These studies were realized with the help of a large numberofindividuals,towhomIwouldliketoexpressmygratitude: DocentChandanK. Sen, PhD, headofthe LaboratoryofMolecularMedicine, Departmentof Surgery and Molecular and CellularBiochemistry, Davis Heart and Lung Research Institute, the Ohio State University Medical Center, is my main supervisor. Chandan has an infectious enthusiasm for science and an intellect, drive and other personal qualities that have led to a masteryofawide range oftechniques in microbiologyand genetics that make myhead spin. Itwas indiscussionswithChandanin 1994thatthe ideato studyoxidative stress andexercise intype 1diabetesarose. ProfessorLeoNiskanen, MD, PhD,DepartmentofMedicine,KuopioUniversityHospital, has providedtheclosestsupervisionandcollaborationthroughoutthese studies. Leo's enthusiasm and energy for research on wide-ranging topics and study designs and ability to combine research and clinical work have been an inspirationto me. Through Leo I have been able to become involved in a major clinical trial and in projects in epidemiology and nutrition, with the metabolic syndrome or insulin and glucose metabolism as the thread tying them all together. Professor Matti Uusitupa, Rector of the University of Kuopio, has also played a critical supervisory role in this thesis. Matti's clear common-sense approach to problems in science hasbeenimportantin manyphases ofthis thesis. Matti insistedonmaintaining arandomized controlleddesign inPublication 1, eventhough Iwas readyto shiftto an uncontrolleddesign because of worries about statistical power. This insistence was an important lesson in methodologyandstudydesign. ProfessorOsmo Hanninen, head ofthe Department ofPhysiology, UniversityofKuopio, has a sometimes idiosyncratic enthusiasm for an impressively wide range oftopics in science. Osmo gave me the opportunity to become involved in research. Without his sometimes idiosyncratic and always unprejudiced qualities, I would probably never have gotten that chance. The founding ofthe TULES Graduate School was for the most part conceived and realizedbyOsmo. Docent Timo Lakka, visiting scientist at the Pennington Biomedical Research Center, Louisiana State University, has also played a critical role in supervision and collaboration. Our early discussions aboutphysical activity and fitness atthe cafeteriatable eventually lead to concretecollaborationintheKuopio IschaemicHeartDiseaseRiskFactorStudy. Timoand Hanna Lakkas' collaboration and supervision have allowed the epidemiologist in me to express itselfand develop. Their collaboration and friendship have lead to exciting projects beyondthisthesis. Professor Scott Powers, PhD, head ofthe Department ofExercise and Sport Sciences and Physiology, University ofFlorida, and Docent Sari Makimattila, MD, PhD, Department of Endocrinology, Malmo University Hospital, Sweden, made insightful and constructive comments andimportantsuggestions forimprovementwhileundertakingthe time-consuming taskofreviewingthisthesis. Professor Jukka T. Salonen, MD, PhD, MScPH, head ofthe Research Institute of Public Health, has kindly allowed me to participate in projects in the Kuopio Ischaemic Heart Disease Risk Factor Study, and has also played an important role as co-author in several of mypapers. Mustafa Atalay, MD, PhD, MPH, ofthe Department ofPhysiology, played a critical role in Studies 1-3. Without his laboratory and organizational skills, these studies could never have beencarriedout. IappreciatethesacrificesbothheandSavitaKhanna, PhD,madein Study 1, whichalsoinvolvedweekendsofworkinJoensuu. Iwould like to acknowledge myotherco-authors for their contributions, including Professor Rainer Rauramaa, MD, PhD, head ofthe Kuopio Research Institute ofExercise Medicine; Juha Mustonen, MD, PhD, head of the Department of Medicine, North Kare1ia Central Hospital; and George A. Kaplan, PhD, ofthe DepartmentofEpidemiology, School ofPublic Health, UniversityofMichigan. The staffand colleagues at the Department ofPhysiology have provided important support throughout this study. Ms. Eeva-Liisa Palkispaa and Ms. Riitta Venalainen provided important assistance to Mustafa in the laboratory. Ms. Kaija Kettunen skillfully carried out the lipid, lipoprotein and apolipoprotein measurements ofStudy 1. Ms. Raija Holopainen has alsogivenimportantassistance. This studywas supportedbythe TULES Graduate School, the FinnishMinistryofEducation, the Academy ofFinland, the National Heart, Lung and Blood Institute, the City ofKuopio, the Ida Montin Foundation, the Yrjo Jahnsson Foundation, the North Savo Culural FoundationandtheJuhoVainioFoundation. Special thanks go to Riitta Paajanen, for her understanding and support over all these years. Also special thanks to my parents, G. Donald (Laaksonen) Larson, MD, and Alisa (Happonen) Larson, for their fostering of a respect for learning without ever applying pressure, and for their support, financial and otherwise, over my many years of higher education(16inall-I'maslowlearner). Kuopio,November2002 DavidLaaksonen ABBREVIAnONS ACSM AmericanCollegeofSportsMedicine AGE advancedglycationendproducts apoA-I apolipoproteinA-I apoB apolipoproteinB BMI bodymassindex CDC CenterforDiseaseControl CHD coronaryheartdisease CVD cardiovasculardisease CRP C-reactiveprotein DM diabetesmellitus E% energypercent EC extracellular EGIR EuropeanGroupfortheStudyofInsulinResistance GADA glutamicaciddecarboxylaseantibodies GLUT glucosetransporterptotein GPX glutathioneperoxidase GRD glutathionereductase GSH reducedglutathione GSSG glutathionedisulfide GST glutathione-S-transferase HbAle hemoglobinAle HDL high-densitylipoprotein. HOMA homeostasismodelassessment ICA isletcellantibodies IFG impairedfasting glycemia IGT impairedglucosetolerance ISH International SocietyofHypertension KIHD KuopioIschaemicHeartDiseaseRiskFactorStudy LADA latentautoimmunediabetes inadults LDL low-densitylipoprotein LTPA leisure-timephysicalactivity MDA malondialdehyde METs metabolicequivalents MODY maturity-onsetdiabetesoftheyoung MSy metabolic syndrome. N/A notapplicable NCEP NationalCholesterolEducationProgram OR oddsratio QUICKI quantitativeinsulinsensitivitycheckindex ROS reactiveoxygenspecies SOD superoxidedismutase TBARS thiobarbituricacidreactivesubstances TGSH totalglutathione TRAP totalperoxylradicaltrappingpotential VLDL very-Iow-densitylipoprotein. VO maximaloxygenconsumption Zmax W maximalexercisecapacity(inWattsperkg) max WHO WorldHealthOrganization WHR waist-hipratio LIST OFPUBLICATIONS This dissertation is based onthe following original publications, which will be referred to in thetextas Studies 1-5. 1. Laaksonen DE, Atalay M, Niskanen LK, Mustonen J, Sen CK, Lakka TA, Uusitupa ML Aerobic exercise and the lipid profile in type 1diabetic men: a randomized controlled trial. MedSci SportsExerc2000;32:1541-1548. 2. Laaksonen DE, Atalay M, Niskanen L, Uusitupa M, Hanninen 0, Sen CK. Increased resting and exercise-induced oxidative stress in young IDDM men. Diabetes Care 1996;19:569-574. 3. Atalay M, Laaksonen DE, Niskanen L, Uusitupa M, Hanninen 0, Sen CK. Altered antioxidant enzyme defences in insulin-dependent diabetic men with increased resting and exercise-inducedoxidative stress.ActaPhysiolScand1997;61:195-201. 4. LaaksonenDE, LakkaH-M, NiskanenLK, Kaplan GA, SalonenJT, LakkaTA. Metabolic syndrome and development of diabetes mellitus: application and validation of recently suggested definitions of the metabolic syndrome in a prospective cohort study. Am J Epidemio12002;156:l070-1077. 5. LaaksonenDE,LakkaH-M, SalonenJT,NiskanenLK, RauramaaR,LakkaTA. Low LevelsofLeisure-TimePhysicalActivityandCardiorespiratoryFitnessPredictDevelopment oftheMetabolic Syndrome. DiabetesCare2002;25:1612-1618.
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