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OBJECTIVE--To quantify the relation of fitness to mortality among men with diabetes, adjusted for BMI and within levels of BMI.

RESEARCH DESIGN AND METHODS--In this observational cohort study, we calculated all cause death rates in men with diabetes across quartiles of fitness and BMI categories. Study participants were 2,196 men with diabetes (average age 49.3 years, SD 9.5) who underwent a medical examination, including a maximal exercise test, during 1970 to 1995, with mortality follow-up to 31 December 1996.

RESULTS--We identified 275 deaths during 32,161 person-years of observation. Risk of all-cause mortality was inversely related to fitness. For example, in the fully adjusted model, the risk of mortality was 4.5 (2.6-7.6), 2.8 (1.6-4.7), and 1.6 (0.93-2.76) for the first, second, and third fitness quartiles, respectively, with the fourth quartile (highest fitness level) as the referent (P for trend <0.0001) There was no significant trend across BMI categories for mortality after adjustment for fitness. Similar results were found when the fitness mortality relation was examined within levels of body composition. In normal-weight men with diabetes, the relative risks of mortality were 6.6 (2.8-15.0), 3.2 (1.4-7.0), and 2.2 (1.1-4.6) for the first, second, and third quartiles of fitness, respectively, as compared with the fourth quartile (P for trend < 0.0001). We found similar results in the overweight and obese weight categories.

CONCLUSIONS--There was a steep inverse gradient between fitness and mortality, in this cohort of men with documented diabetes, and this association was independent of BMI.

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While the importance of physical activity and weight loss in the prevention of diabetes is now well established by randomized clinical trials, few studies have examined the relative contribution of weight and physical activity on morbidity and mortality in individuals with diabetes (1,2). A better understanding of the relative contributions of weight control and physical activity to mortality may guide clinical recommendations.

We previously reported that low car diorespiratory fitness and physical inactivity are independent predictors of all-cause and cardiovascular disease (CVD) mortality in men with type 2 diabetes (3). However, this study examined these exposures in multivariable models and, thus, did not allow for evaluation of the relative values of physical activity, fitness, or weight as mortality predictors. We have performed additional follow-up and can now extend our previous work by examining the relation of fitness and mortality within BMI categories.

The primary aims of this study of men with diabetes were to examine 1) the risk of mortality associated with fitness and BMI when examined as continuous and categorical variables and 2) the dose-response relationship between fitness and mortality both with adjustment for BMI and within levels of BMI.

RESEARCH DESIGN AND METHODS--The Aerobics Center Longitudinal Study (ACLS) is a prospective epidemiologic investigation, Participants for the analyses reported here are 2,196 men with diabetes examined at least once during 1970 to 1995 and who completed at least 1 year of follow-up. Diabetes case subjects were defined as men who reported use of insulin (n = 47), a physician-diagnosed history of diabetes, or a fasting plasma glucose level [greater than or equal to] 7.0 mmol/l ([greater than or equal to] 126 mg/dl) at baseline (4). The men were predominantly non-Hispanic whites, well educated, and either currently or previously employed in professional or executive positions. All participants were U.S. residents and ranged in age from 23 to 79 years (average 49.3 [+ or -] 9.5). All men gave informed consent for participation in the examination and registration in the follow-up study. The study protocol was approved annually by The Cooper Institute Institutional Review Board.

Mortality surveillance

We followed study participants for mortality from their baseline examination until their death or until 31 December 1996. The primary method of mortality surveillance has been accomplished by use of the National Death Index.

Clinical examination

The evaluation consisted of a physical examination by a clinic physician, obtaining blood by venipuncture from an antecubital vein, measurement of blood pressure, anthropometry, maximal exercise test on a treadmill, and completion of an extensive questionnaire on demographic characteristics, health history, family medical history, and a health habit inventory. Blood chemistry analyses were performed in the laboratory of the Cooper Clinic, which participates in and meets quality control standards of the Centers for Disease Control and Prevention (CDC) Lipid Standardization Program. Height and weight were measured on a standard physician's balance beam scale and stadiometer. We calculated BMI and assigned men to categories of normal weight (BMI 18.5-24.9 kg/[m.sup.2]), overweight (BMI 25.0-29.9 kg/[m.sup.2]), and obese (BMI [greater than or equal to] 30.0 kg/[m.sup.2]) (5). Body composition was assessed by hydrostatic weighing (n = 1,051), by skinfold thickness (n = 989), or both (n = 402). Because not all participants underwent hydrostatic weighing, we standardized the body fat measurement using methods previously described, resulting in 2,040 men (242 decedents) with body fat percentages available for analysis (6).

Blood pressure measurements were obtained using mercury manometers following the American Heart Association protocol (7). Men who reported a history of physician-diagnosed hypertension were classified as hypertensive. Individuals were classified as never, past, or current smokers based on self-report questionnaire. We defined baseline CVD as history of heart attack, stroke, abnormal resting or exercise electrocardiogram, and parental history of premature CVD as reporting a parent who had a stroke or myocardial infarction before the age of 50. Participation in regular physical activity was defined as reporting regular walking, jogging, cycling, or participation in a racket sport.

We measured fitness by a maximal exercise test following a modified Balke protocol (8). Patients began walking on a treadmill at 88 m/min (3.3 mph) with no elevation. After tire first minute, the in cline was increased to 2% and was increased 1% each minute thereafter until the 25th minute. For the few men still able to continue the test beyond 25 min, the elevation was maintained at 25% and the speed increased by 5.4 m/min (0.2 mph) each minute until the end of the test. The test was terminated when the men were exhausted or if the physician stopped the test for medical reasons. Time on the treadmill test with this protocol is highly correlated (R = 0.92) with measured maximal oxygen uptake (V[O.sub.2max]) (9). We express fitness as maximal metabolic equivalents (METs = work metabolic rate/resting metabolic rate = 3.5 ml * [kg.sup.-1] * [min.sup.-1]) attained during the treadmill test. We calculated METs from estimated V[O.sub.2max] for the Balke protocol using the formula V[O.sub.2max] = 1.44 * (minutes on treadmill) + 14.99 (9).

Statistical analyses

We calculated the mean and SD of each variable with participants categorized as survivors or decedents. To assess the in dependent association of fitness and BMI as continuous variables as well as to evaluate the contributions of traditional CVD risk factors, we used log-linear proportional hazard models.

We calculated MET quartiles and evaluated risk of mortality by four log-linear proportional hazards models --first adjusting only for age and year of examination, second by adding nonmodifiable risk factors (history of cancer or CVD events or family history of CVD), third by adding modifiable risk factors (smoking, systolic blood pressure, cholesterol, and glucose), and fourth by adding BMI. In a similar fashion, we evaluated the risk of mortality across BMI categories with the fourth model adjusting for fitness. To further assess the body composition-mortality relation, we also evaluated thirds of body fat percent instead of BMI categories.

We examined the association of fitness to mortality within levels of BMI by cross tabulated MET and BMI categories to create 12 fitness BMI categories (MET quartile 1, normal weight: MET quartile 2, overweight; MET quartile 4, obese). Due to a small number of deaths in the MET quartile 4 obese cell, we combined this group with the MET quartile 3 obese group, resulting in a final total of 11 categories. Log-linear proportional hazard models were used to estimate adjusted relative risks for mortality for each fitness-BMI category. We used the continuous variables of METs and BMI to test linear trends. We repeated the analyses using body fat percentage quartiles instead of BMI categories.

RESULTS--The study population included 2,196 diabetic men followed for 1-26 years; the average was 14.6 (7.1) years. We identified 275 deaths during 32,161 person-years of observation. The cohort characteristics, grouped by survival status, are shown in Table 1. At baseline, survivors were younger and fitter and had better metabolic profiles, in eluded fewer smokers, and had a lower prevalence of hypertension and previous CVD compared with decedents. 1-o verify our assumption that increased fitness is due primarily to physical activity, we examined the prevalence of self-reported regular physical activity across fitness quartiles. We observed a strong direct association with the prevalence of regular physical activity of 24.2, 33.6, 47.4, and 79.0 across the fitness quartiles (P for trend = 0.005). A total of 94% of participants achieved a maximal heart rate of [greater than or equal to] 85%, supporting the premise that the exercise test was a maximal effort for most.

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