Impact of type 2 diabetes on cardiorespiratory function and exercise performance

The aim of this study was to examine the impact of well-controlled uncomplicated type 2 diabetes (T2D) on exercise performance. Six obese sedentary men with T2D and 7 control participants without diabetes matched for age, sex and body mass index were recruited. Anthropometric characteristics, blood samples, resting cardiac and pulmonary functions and maximal oxygen uptake (VO2max) and ventilatory threshold were measured on a first visit. On the four subsequent visits, participants performed step transitions (6 min) of moderate-intensity exercise on an upright cycle ergometer from unloaded pedaling to 80 % of ventilatory threshold. VO2 (τVO2) and HR (τHR) kinetics were characterized with a mono-exponential model. VO2max (27.8±4.0 vs. 27.5±5.3 ml kg-1 min-1; p=0.95), τVO2 (43±6 vs. 43±10 s; p=0.73) and τHR (42±17 vs. 43±13 s; p=0.94) were similar between diabetics and controls respectively. The remaining variables were also similar between groups. These results suggest that well-controlled T2D is not associated with a reduction in VO2max or slower τVO2 and τHR.

Related papers:

title: Studies on the mechanism of improved glucose control during regular exercise in Type 2 (non-insulin-dependent) diabetes
abstract: SummaryThe effects of 6 weeks of thrice weekly training on glycaemic control were assessed in 20 sedentary Type 2 (non-insulin-dependent) diabetic patients and 11 control subjects matched for previous physical activity. Maximal oxygen uptake was lower in the diabetic patients than in control subjects before training (26.2±1.1 versus 32.6±1.7 ml·kg-1·min-1; p<0.001). Glycosylated haemoglobin levels decreased in the diabetic patients during the training programme (12.2±0.5 to 10.7±0.4%; p < 0.02). Oral and intravenous glucose tolerance determined 72 h after the last exercise period showed only minimal improvement. Plasma glucose levels were, however, significantly lower at 12 h than 72 h after exercise in eight subjects tested at both time points. These data suggest that an exercise programme can produce a significant decrease in glycosylated haemoglobin levels in Type 2 diabetic males probably due, in great measure, to the cumulative effect of transient improvements in glucose tolerance which follow each individual period of exercise.

title: Impaired stroke volume and aerobic capacity in female adolescents with type 1 and type 2 diabetes mellitus
abstract: hypothesisThis study was designed to determine whether type 2 diabetic adolescents have reduced aerobic capacity and to investigate the role of cardiac output and arteriovenous oxygen difference (a−vO2) in their exercise response.MethodsFemale adolescents (age 12–18 years) with type 2 diabetes mellitus (n = 8) and type 1 diabetes mellitus (n = 12) and obese (n = 10) and non-obese (n = 10) non-diabetic controls were recruited for this study. Baseline data included maximal aerobic capacity (cycle ergometer) and body composition. Cardiac output and a−vO2 were determined at rest and during submaximal exercise.ResultsDiabetic groups had lower aerobic capacity than non-diabetic groups (p < 0.05). Adolescents with type 2 diabetes had lower aerobic capacity than the type 1 diabetic group. Maximal heart rate was lower in the type 2 diabetic group (p < 0.05). Exercise stroke volume was 30–40% lower at 100 and 120 beats per min in the diabetic than in the non-diabetic groups (p < 0.05). The a−vO2 value was not different in any condition.Conclusions and interpretationType 2 diabetic adolescents have reduced aerobic capacity and reduced heart rate response to maximal exercise. Furthermore, type 2 and type 1 diabetic adolescent girls have a blunted exercise stroke volume response compared with non-diabetic controls. Central rather than peripheral mechanisms contribute to the reduced aerobic capacity in diabetic adolescents. Although of short duration, type 2 diabetes in adolescence is already affecting cardiovascular function in adolescents.

title: Glucoregulation and hormonal responses to maximal exercise in non-insulin-dependent diabetes.
abstract: Maximal dynamic exercise results in a postexercise hyperglycemia in healthy young subjects. We investigated the influence of maximal exercise on glucoregulation in non-insulin-dependent diabetic subjects (NIDDM). Seven NIDDM and seven healthy control males bicycled 7 min at 60% of their maximal O2 consumption (VO2max), 3 min at 100% VO2max, and 2 min at 110% VO2max. In both groups, glucose production (Ra) increased more with exercise than did glucose uptake (Rd) and, accordingly, plasma glucose increased. However, in NIDDM subjects the increase in Ra was hastened and Rd inhibited compared with controls, so the increase in glucose occurred earlier and was greater [147 +/- 21 to 169 +/- 19 (30 min postexercise) vs. 90 +/- 4 to 100 +/- 5 (SE) mg/dl (10 min postexercise), P less than 0.05]. Glucose levels remained elevated for greater than 60 min postexercise in both groups. Glucose clearance increased during exercise but decreased postexercise to or below (NIDDM, P less than 0.05) basal levels, despite increased insulin levels (P less than 0.05). Plasma epinephrine and glucagon responses to exercise were higher in NIDDM than in control subjects (P less than 0.05). By use of the insulin clamp technique at 40 microU.m-2.min-1 of insulin with plasma glucose maintained at basal levels, glucose disposal in NIDDM subjects, but not in controls, was enhanced 24 h after exercise. It is concluded that, because of exaggerated counter-regulatory hormonal responses, maximal dynamic exercise results in a 60-min period of postexercise hyperglycemia and hyperinsulinemia in NIDDM. However, this event is followed by a period of increased insulin effect on Rd that is present 24 h after exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

title: Effect of type 2 diabetes on the dynamic response characteristics of leg vascular conductance during exercise
abstract: In this study we tested the hypothesis that type 2 diabetes impairs the dynamic response of leg vascular conductance (LVC) during exercise. LVC (leg blood flow/mean arterial pressure) responses were studied during intermittent contractions of the calf muscle in subjects with type 2 diabetes (n = 9), heavy controls (n = 10) and lean controls (n = 8) using a biexponential function and an estimate of the mean response time (MRT). The time constant of the second phase of LVC was significantly greater in type 2 diabetes (66.4 ± 29.2 s) than the heavy (22.2 ± 13.4 s) and lean (21.8 ± 9.3 s) controls, resulting in a significantly greater MRT in the diabetic group (median [IQR] = 30.7 [24.6—46.5] s versus 16.3 [4.3—23.2] s and 18.4 [13.7—19.3] s). These data support the hypothesis and suggest that a slowed hyperaemic response in the exercising limb might contribute to exercise intolerance in diabetic subjects.

title: Reduced leg blood flow during submaximal exercise in type 2 diabetes.
abstract: It is unclear whether impaired cardiac and/or vascular function contribute to exercise intolerance in patients with type 2 diabetes.



Magnetic resonance imaging (MRI) was used to determine whether reductions in cardiac output and/or femoral arterial blood flow contribute to reduced aerobic capacity in patients with type 2 diabetes.



Cardiac and femoral arterial blood flow MRI scans were performed at rest and during low-intensity leg exercise in eight patients with type 2 diabetes and 11 healthy individuals. Maximal aerobic capacity VO(2 max) and maximal oxygen pulse were also determined in all participants.



V O(2 max) was 20% lower and maximal oxygen pulse was 16% lower in patients with type 2 diabetes (P < 0.05), whereas maximal heart rate was the same between groups. Low-intensity exercise induced a 20% increase in heart rate and cardiac output as well as a 60-70% increase in femoral blood flow in both groups (P < 0.05). Femoral arterial blood flow indexed to thigh lean mass was reduced during exercise in patients with type 2 diabetes compared with healthy individuals. Stroke volume indexed to fat-free mass was lower in patients with type 2 diabetes, but greater heart rate allowed cardiac output to be maintained during submaximal exercise.



These findings suggest that impaired femoral arterial blood flow, an indirect marker of muscle perfusion, affects low-intensity exercise performance in patients with type 2 diabetes. However, because of lower exercising stroke volume, we propose that femoral arterial blood flow and, possibly, cardiac output, limit V O(2 max) in patients with type 2 diabetes.

title: Insulin resistance in adolescents with type 2 diabetes is associated with impaired exercise capacity.
abstract: The incidence of pediatric type 2 diabetes (T2D) is rising, with unclear effects on the cardiovascular system. Cardiopulmonary fitness, a marker of morbidity and mortality, is abnormal in adults with T2D, yet the mechanisms are incompletely understood.



We hypothesized that cardiopulmonary fitness would be reduced in youth with T2D in association with insulin resistance (IR) and cardiovascular dysfunction.



We conducted a cross-sectional study at an academic hospital that included 14 adolescents (age range, 12-19 yr) with T2D, 13 equally obese adolescents and 12 lean adolescents similar in age, pubertal stage, and activity level.



Cardiopulmonary fitness was measured by peak oxygen consumption (VO(2)peak) and oxygen uptake kinetics (VO(2)kinetics), IR by hyperinsulinemic clamp, cardiac function by echocardiography, vascular function by venous occlusion plethysmography, body composition by dual-energy x-ray absorptiometry, intramyocellular lipid by magnetic resonance spectroscopy, and inflammation by serum markers.



Adolescents with T2D had significantly decreased VO(2)peak and insulin sensitivity, and increased soleus intramyocellular lipid, C-reactive protein, and IL-6 compared to obese or lean adolescents. Adolescents with T2D also had significantly prolonged VO(2)kinetics, decreased work rate, vascular reactivity, and adiponectin, and increased left ventricular mass and fatty acids compared to lean adolescents. In multivariate linear regression analysis, IR primarily, and fasting free fatty acids and forearm blood flow secondarily, were significant independent predictors of VO(2)peak.



Given the strong relationship between decreased cardiopulmonary fitness and increased mortality, these findings in children are especially concerning and represent early signs of impaired cardiac function.

title: Abnormal oxygen uptake kinetic responses in women with type II diabetes mellitus.
abstract: Persons with type II diabetes mellitus (DM), even without cardiovascular complications have a decreased maximal oxygen consumption (VO2 max) and submaximal oxygen consumption (VO2) during graded exercise compared with healthy controls. We evaluated the hypothesis that change in the rate of VO2 in response to the onset of constant-load exercise (measured by VO2-uptake kinetics) was slowed in persons with type II DM. Ten premenopausal women with uncomplicated type II DM, 10 overweight, nondiabetic women, and 10 lean, nondiabetic women had a VO2 max test. On two separate occasions, subjects performed 7-min bouts of constant-load bicycle exercise at workloads below and above the lactate threshold to enable measurements of VO2 kinetics and heart rate kinetics (measuring rate of heart rate rise). VO2 max was reduced in subjects with type II DM compared with both lean and overweight controls (P < 0.05). Subjects with type II DM had slower VO2 and heart rate kinetics than did controls at constant workloads below the lactate threshold. The data suggest a notable abnormality in the cardiopulmonary response at the onset of exercise in people with type II DM. The findings may reflect impaired cardiac responses to exercise, although an additional defect in skeletal muscle oxygen diffusion or mitochondrial oxygen utilization is also possible.

title: Cardiac dysfunction during exercise in uncomplicated type 2 diabetes.
abstract: Type 2 diabetes mellitus (T2DM) has been associated with reduced peak exercise capacity (VO(2peak)). The causes of this impairment are not clearly established, but evidence suggests that abnormalities in cardiac function play a significant role. We hypothesized that exercise would be associated with impaired cardiac function and hemodynamics in recently diagnosed T2DM, even in the absence of clinically evident cardiovascular complications.



After baseline normal echocardiography screening, 10 premenopausal women with uncomplicated T2DM (average duration of diagnosed T2DM, 3.6 yr) and 10 healthy nondiabetic women of similar age, weight, and activity levels performed a peak cardiopulmonary exercise test while instrumented with an indwelling pulmonary artery catheter for assessing cardiac function. On separate days, technetium-99m sestamibi (cardolite) imaging was performed to assess myocardial perfusion at rest and peak exercise in seven T2DM and seven control patients.



Resting measures of cardiac hemodynamics were similar in T2DM and control subjects. Absolute VO(2peak) (mL x min(-1)) and peak cardiac output (L x min(-1)) tended to be lower in T2DM than in control subjects but did not reach statistical significance. However, pulmonary capillary wedge pressure (PCWP) rose significantly more during exercise in T2DM than in controls (148% vs 109% increase at peak exercise, P < 0.01). Normalized myocardial perfusion index was lower in persons with diabetes than in controls (11.0 +/- 3.5 x e(-9) vs 17.5 +/- 8.1 x e(-9), respectively, P < 0.05) and inversely related to peak exercise PCWP (R = -0.56, P < 0.05).



Cardiac hemodynamics during graded exercise are altered in women with recently diagnosed T2DM as demonstrated by the disproportionate increase in PCWP at peak exercise compared with controls subjects. Cardiac abnormalities observed are potentially early signs of subclinical cardiac dysfunction associated with T2DM, which may precede the more greatly impaired cardiac function at rest and with exercise observed in longer established T2DM.

title: Older type 2 diabetic males do not exhibit abnormal pulmonary oxygen uptake and muscle oxygen utilization dynamics during submaximal cycling exercise.
abstract: There are reports of abnormal pulmonary oxygen uptake (Vo(2)) and deoxygenated hemoglobin ([HHb]) kinetics in individuals with Type 2 diabetes (T2D) below 50 yr of age with disease durations of <5 yr. We examined the Vo(2) and muscle [HHb] kinetics in 12 older T2D patients with extended disease durations (age: 65 ± 5 years; disease duration 9.3 ± 3.8 years) and 12 healthy age-matched control participants (CON; age: 62 ± 6 years). Maximal oxygen uptake (Vo(2max)) was determined via a ramp incremental cycle test and Vo(2) and [HHb] kinetics were determined during subsequent submaximal step exercise. The Vo(2max) was significantly reduced (P < 0.05) in individuals with T2D compared with CON (1.98 ± 0.43 vs. 2.72 ± 0.40 l/min, respectively) but, surprisingly, Vo(2) kinetics was not different in T2D compared with CON (phase II time constant: 43 ± 17 vs. 41 ± 12 s, respectively). The Δ[HHb]/ΔVo(2) was significantly higher in T2D compared with CON (235 ± 99 vs. 135 ± 33 AU·l(-1)·min(-1); P < 0.05). Despite a lower Vo(2max), Vo(2) kinetics is not different in older T2D compared with healthy age-matched control participants. The elevated Δ[HHb]/ΔVo(2) in T2D individuals possibly indicates a compromised muscle blood flow that mandates a greater O(2) extraction during exercise. Longer disease duration may result in adaptations in the O(2) extraction capabilities of individuals with T2D, thereby mitigating the expected age-related slowing of Vo(2) kinetics.

title: Similar level of impairment in exercise performance and oxygen uptake kinetics in middle-aged men and women with type 2 diabetes.
abstract: The present study tested the hypothesis that the magnitude of the type 2 diabetes-induced impairments in peak oxygen uptake (Vo(2)) and Vo(2) kinetics would be greater in females than males in middle-aged participants. Thirty-two individuals with type 2 diabetes (16 male, 16 female), and 32 age- and body mass index (BMI)-matched healthy individuals (16 male, 16 female) were recruited. Initially, the ventilatory threshold (VT) and peak Vo(2) were determined. On a separate day, subjects completed four 6-min bouts of constant-load cycling at 80% VT for the determination of Vo(2) kinetics using standard procedures. Cardiac output (CO) (inert gas rebreathing) was recorded at rest, 30, and 240 s during two additional bouts. Peak Vo(2) (ml·kg(-1)·min(-1)) was significantly reduced in men and women with type 2 diabetes compared with their respective nondiabetic counterparts (men, 27.8 ± 4.4 vs. 31.1 ± 6.2 ml·kg(-1)·min(-1); women, 19.4 ± 4.1 vs. 21.4 ± 2.9 ml·kg(-1)·min(-1)). The time constant (s) of phase 2 (τ(2)) and mean response time (s) of the Vo(2) response (MRT) were slowed in women with type 2 diabetes compared with healthy women (τ(2), 43.3 ± 9.8 vs. 33.6 ± 10.0 s; MRT, 51.7 ± 9.4 vs. 43.5 ± 11.4s) and in men with type 2 diabetes compared with nondiabetic men (τ(2), 43.8 ± 12.0 vs. 35.3 ± 9.5 s; MRT, 57.6 ± 8.3 vs. 47.3 ± 9.3 s). The magnitude of these impairments was not different between males and females. The steady-state CO responses or the dynamic responses of CO were not affected by type 2 diabetes among men or women. The results suggest that the type 2 diabetes-induced impairments in peak Vo(2) and Vo(2) kinetics are not affected by sex in middle aged participants.

title: Effects of non-insulin-dependent diabetes on oxygen consumption during treadmill exercise.
abstract: Persons with non-insulin-dependent diabetes mellitus (NIDDM), in the absence of complications, have a decreased exercise performance compared with nondiabetic subjects. However, degree of impairment and factors associated with reduced exercise performance have not been fully characterized. Maximal exercise performance using a graded treadmill protocol was assessed in 10 sedentary persons with uncomplicated NIDDM (aged 51 +/- 7) and 10 healthy age- and activity-matched controls. Potential correlates of exercise performance measured included fasting and post-exercise glucose concentrations and fasting insulin concentration, hemoglobin A1C, hematocrit, and whole blood viscosity. At maximal exercise, diabetic persons had a 24% lower maximal walking time and 20% lower maximal VO2 than controls (both P < 0.05), while hemodynamic measures did not differ between groups. During graded exercise, at work loads below the maximal one, the relationship between VO2 and work load was significantly lower in persons with NIDDM than controls by an average of 16%. No correlations were found between peak exercise performance and any of the potential correlates of exercise performance measured. We conclude that persons with NIDDM have an impaired peak exercise performance not associated with degree of glycemic control. The reduced rate of increase in oxygen consumption during increasing submaximal work loads in NIDDM suggests that limitations in oxygen delivery may impair exercise performance in otherwise healthy persons with diabetes.

title: Reduced exercise arteriovenous O2 difference in Type 2 diabetes.
abstract: Maximal O(2) consumption (Vo(2 max)) is lower in individuals with Type 2 diabetes than in sedentary nondiabetic individuals. This study aimed to determine whether the lower Vo(2 max) in diabetic patients was due to a reduction in maximal cardiac output (Q(max)) and/or peripheral O(2) extraction. After 11 Type 2 diabetic patients and 12 nondiabetic subjects, matched for age and body composition, who had not exercised for 2 yr, performed a bicycle ergometer exercise test to determine Vo(2 max), submaximal cardiac output, Q(max), and arterial-mixed venous O(2) (a-v O(2)) difference were assessed. Maximal workload, Vo(2 max), and maximal a-v O(2) difference were lower in Type 2 diabetic patients (P < 0.05). Q(max) was low in both groups but not significantly different: 11.2 and 10.0 l/min for controls and diabetic patients, respectively (P > 0.05). Submaximal O(2) uptake and heart rate were lower at several workloads in diabetic patients; respiratory exchange ratio was similar between groups at all workloads. Vo(2 max) was linearly correlated with a-v O(2) difference, but not Q(max) in diabetic patients. These data suggest that a reduction in maximal a-v O(2) difference contributes to a decreased Vo(2 max) in Type 2 diabetic patients.

title: The Association Between Diabetic Complications and Exercise Capacity in NIDDM Patients
abstract: Exercise capacity has been used as a noninvasive parameter for predicting cardiovascular events. It has been demonstrated previously in NIDDM patients that several risk factors (i.e., obesity, smoking, hypertension, and African-American race) are associated with an impaired exercise capacity. We studied 265 male and 154 female NIDDM patients who underwent graded exercise testing with expired gas analyses to determine the possible influences of diabetic neuropathy, nephropathy, and retinopathy on exercise capacity.  Univariate and multiple linear regression analyses were performed to determine the relationship between diabetic neuropathy, urinary albumin excretion (UAE), and retinopathy with respect to peak oxygen consumption (Vo2). Neuropathy was assessed by neurological symptom and disability scores, autonomic function testing, and quantitative sensory exams involving thermal and vibratory sensation. Three categories of UAE were used: normal albuminuria (<20 μg=min), microalbuminuria (20–200 μg/min), and overt albuminuria (>200 μg/min). Retinopathy was assessed by stereoscopic fundus photographs. Multiple linear regression analyses were then performed controlling for age, sex, length of diagnosed diabetes, duration of hypertension, race and ethnicity, GHb, BMI, and smoking to determine whether there was an independent effect of these diabetic complications on exercise capacity.  Univariate analyses revealed that the presence of diabetic retinopathy (P = 0.03), neuropathy (P = 0.002), microalbuminuria (P = 0.04), and overt albuminuria (P = 0.06) were associated with a lower peak Vo2. Multiple linear regression analyses were performed to determine independent relationships with peak Vo2. The results revealed that increasing retinopathy stage (Parameter estimate [PE] = −0.59 ± 0.3 ml · kg−1 · min−1; P = 0.026) and increasing UAE stage (PE = −0.62 ± 0.3 ml · kg−1 · min−1; P = 0.044) were associated with a decrease in peak Vo2.  In the present study of NIDDM subjects, a significant independent association was demonstrated between diabetic nephropathy and retinopathy with exercise capacity. These results were obtained controlling for age, sex, length of diagnosed diabetes, hypertension, race, and BMI. Thus the findings in this large NIDDM population without a history of coronary artery disease indicate a potential pathogenic relationship between microvascular disease and exercise capacity.

title: Determinants of exercise capacity in patients with type 2 diabetes.
abstract: Type 2 diabetes is associated with reduced exercise capacity, but the cause of this association is unclear. We sought the associations of impaired exercise capacity in type 2 diabetes.



Subclinical left ventricular (LV) dysfunction was sought from myocardial strain rate and the basal segmental diastolic velocity (Em) of each wall in 170 patients with type 2 diabetes (aged 56 +/- 10 years, 91 men), good quality echocardiographic images, and negative exercise echocardiograms. The same measurements were made in 56 control subjects (aged 53 +/- 10 years, 29 men). Exercise capacity was calculated in metabolic equivalents, and heart rate recovery (HRR) was measured as the heart rate difference between peak and 1 min after exercise. In subjects with type 2 diabetes, exercise capacity was correlated with clinical, therapeutic, biochemical, and echocardiographic variables, and significant independent associations were sought using a multiple linear regression model.



Exercise capacity, strain rate, Em, and HRR were significantly reduced in type 2 diabetes. Exercise capacity was associated with age (r = -0.37, P < 0.001), male sex (r = 0.26, P = 0.001), BMI (r = -0.19, P = 0.012), HbA(1c) (A1C; r = -0.22, P = 0.009), Em (r = 0.43, P < 0.001), HRR (r = 0.42, P < 0.001), diabetes duration (r = -0.18, P = 0.021), and hypertension history (r = -0.28, P < 0.001). Age (P < 0.001), male sex (P = 0.007), BMI (P = 0.001), Em (P = 0.032), HRR (P = 0.013), and A1C (P = 0.0007) were independent predictors of exercise capacity.



Reduced exercise capacity in patients with type 2 diabetes is associated with diabetes control, subclinical LV dysfunction, and impaired HRR.

title: Cardiovascular autonomic neuropathy due to diabetes mellitus: clinical manifestations, consequences, and treatment.
abstract: The aim of this article was to review the importance of the clinical identification of persons with cardiovascular autonomic neuropathy (CAN) and discuss potential treatment interventions.



A MEDLINE search was conducted for articles published during the last 20 yr. In addition, subsequent references of retrieved articles were reviewed. Search strategies included using key terms such as CAN, heart rate variability, orthostatic hypotension, and diabetes mellitus.



CAN is a common form of diabetic autonomic neuropathy and causes abnormalities in heart rate control as well as central and peripheral vascular dynamics. The clinical manifestations of CAN include exercise intolerance, intraoperative cardiovascular lability, orthostatic hypotension, painless myocardial ischemia, and increased risk of mortality. CAN contributes to morbidity, mortality, and reduced quality of life for persons with diabetes. 
Once CAN is identified in a patient with diabetes, healthcare providers may consider altering the prescribed exercise regimen, increasing surveillance for cardiac ischemia, carefully reexamining the list of prescribed medications, and aggressively treating cardiovascular risk factors (e.g. hypertension) that may be associated with the development of CAN.

title: The effect of type 2 diabetes on diastolic function.
abstract: This study aimed to determine whether sedentary overweight subjects with type 2 diabetes have impaired diastolic function compared with equally sedentary and overweight nondiabetic subjects.



Mitral valve pulsed Doppler echocardiography and tissue Doppler imaging (TDI) were used to assess left ventricular structure and diastolic function in 40- to 60-yr-old sedentary overweight subjects with type 2 diabetes (N = 13) and age- and body mass-matched sedentary nondiabetic subjects (N = 15). Pseudonormal filling was identified using preload reduction and TDI.



Traditional Doppler mitral inflow parameters were not different between groups; however, early diastolic relaxation, as measured by peak early mitral annular velocity (E') and the ratio of E' and peak late mitral annular velocity (E'/A'), was reduced in type 2 diabetic subjects (P < 0.05). The ratio of peak early mitral inflow (E) to E' (E/E'), an estimate of left ventricular filling pressure, was also higher in the type 2 diabetes group (P < 0.05). The proportions of diastolic impairment (69 vs 40%) and pseudonormal filling (39 vs 20%) were not different between groups (P = 0.18).



These findings suggest that type 2 diabetes has an effect on diastolic function that is independent of age and body composition.

title: Influence of glycemic control on pulmonary function and heart rate in response to exercise in subjects with type 2 diabetes mellitus.
abstract: Conflicting results exist regarding the impact of glycemic control on peak oxygen uptake (VO2peak) in subjects with type 2 diabetes mellitus. The influence of glycemic control on submaximal oxygen uptake (VO2) in these subjects is unknown. The aim of this study was to evaluate the impact of fasting blood glucose (FBG) (short-term glycemic control) and glycated hemoglobin (HbA1c) (long-term glycemic control) on submaximal VO2 and VO2peak during exercise in subjects with type 2 diabetes mellitus without cardiovascular disease. FBG and HbA1c levels and exercise tolerance in 30 sedentary men with type 2 diabetes mellitus treated with oral hypoglycemic agents and/or diet were evaluated. VO2, carbon dioxide production (VCO2), heart rate, pulmonary ventilation (VE), and the respiratory exchange ratio (RER) were measured throughout the exercise protocol. Subjects were separated into 2 groups of the same age, weight, and body mass index according to median FBG and HbA1c levels (6.5 mmol/L and 6.1%, respectively). Per protocol design, there was a significant difference in FBG and HbA1c levels (P < .001), but not for age, weight, or body mass index. There was no significant difference in peak exercise parameters between the 2 groups according to median FBG or median HbA1c levels. However, the subjects with elevated HbA1c level had lower submaximal V e throughout the exercise protocol (P < .03), and the subjects with elevated FBG concentration had a blunted heart rate pattern during submaximal exercise (P < .03). Although relatively small abnormalities in the control of glycemia do not affect VO2peak in subjects with type 2 diabetes mellitus without cardiovascular disease, they may influence pulmonary function and the chronotropic response during submaximal exercise in these subjects.

title: Heart rate variability and diastolic dysfunction in patients with type 2 diabetes mellitus
abstract: Cardiovascular autonomic neuropathy is a common form of autonomic dysfunction in diabetes mellitus (DM) and associates abnormalities in heart rate control and in vascular dynamics. This study evaluates the impact of diabetes mellitus on left ventricular diastolic dysfunction (LVDD) and heart rate variability in a group of type 2 diabetes mellitus without signs of cardiovascular disease. The study group consisted of 58 patients, aged 61 ± 8 years, diagnosed with type 2 DM. The subjects were selected from a series of 104 consecutive diabetic patients. All the subjects were on oral therapy or on diet for DM, and ECG was normal for all the subjects. The control group consisted of 45 healthy subjects, matched for age and sex. Heart rate variability was measured using a 24-h ECG monitoring system, and standard 2D and Doppler echocardiography was performed in all the subjects. There are significant differences between groups regarding disease duration, longer in patients with impaired relaxation (11.22 ± 9.17 vs. 8.31 ± 8.95 years), and disease control, worse in impaired relaxation group. Heart rate in impaired relaxation group is significantly higher than in controls, and higher, but not significantly, when compared with normal group (91 ± 10, vs. 88 ± 11 and 71 ± 11, respectively). Cardiac autonomic neuropathy was associated with LVDD in patients with type 2 DM, but without clinically manifest heart disease. Twenty-four-hour ECG monitoring and echocardiography can detect diabetic cardiomyopathy in early stages and should be performed in all subjects.

title: Impact of left ventricular diastolic dysfunction on maximal treadmill performance in normotensive subjects with well-controlled type 2 diabetes mellitus.
abstract: Patients with type 2 diabetes often have impaired exercise capacity compared with nondiabetic subjects. Left ventricular (LV) diastolic dysfunction has been shown to limit exercise performance in nondiabetic subjects. Men with well-controlled type 2 diabetes were divided into 2 groups: normal LV diastolic function (group 1, n = 9) or LV diastolic dysfunction (group 2, n = 10) based on standard echocardiographic criteria using pulmonary veins and transmitral flow recordings. They were matched for age and had no evidence of systemic hypertension, macroalbuminuria, coronary artery disease, congestive heart failure, clinical diabetic complications, and thyroid disease. Good metabolic control was demonstrated by glycated hemoglobin levels of 6.7+/-1.6% and 6.6+/-2.5% (means +/- SD) in patients with LV diastolic dysfunction and in controls, respectively. Each subject performed a symptom-limited modified Bruce protocol treadmill exercise test. Maximal treadmill performance was higher in subjects with normal diastolic function compared with subjects with LV diastolic dysfunction when expressed in time (803+/-29 vs. 662+/-44 seconds, respectively, p<0.02) or in METs (11.4+/-1.2 vs. 9.5+/-1.9 METs, respectively, p<0.02). Moreover, there was a correlation between E/A ratio and exercise duration (r = 0.64, p = 0.004) or E/A ratio and METs (r = 0.658, p = 0.003). There were no significant differences in maximal heart rate, maximal systolic and diastolic blood pressure, or maximal rate-pressure product attained during the exercise test. In conclusion, this study demonstrated that LV diastolic dysfunction influences maximal treadmill performance and could explain lower maximal performance observed in patients with type 2 diabetes.

title: Autonomic influence on cardiovascular performance in diabetic subjects.
abstract: Cardiomyopathy, coronary artery atherosclerosis, or autonomic neuropathy may affect the cardiovascular performance of the diabetic patient. To evaluate the role of parasympathetic nervous system activity on cardiovascular performance, 25 diabetic subjects who lacked symptoms, signs, or objective measurements of ischemia or cardiomyopathy were studied.



Diabetic subjects were classified according to their RR variation, an index of cardiac parasympathetic nervous system activity. Fourteen diabetic subjects had a normal RR variation of greater than 30 (D-NOR), and 11 diabetic patients had an abnormal RR variation of less than 20 (D-ABN). Fifteen age- and weight-matched, healthy, nondiabetic subjects (NOR) constituted the control group. All subjects had oxygen consumption, multigated acquisition determination of cardiac output, and work product measured before and during supine bicycle maximum exercise testing.



There was no difference in the resting cardiac output among the groups. Resting work product, however, was greatest in the D-ABN group when compared with performance in the other two groups (D-ABN: 11,500 +/- 800; D-NOR: 9,000 +/- 600; NOR: 8,700 +/- 400; p less than 0.0025). This was due to an increase in both heart rate (p less than 0.025) and systolic blood pressure (p less than 0.015). In the diabetic subjects, there was an inverse relationship between the RR variation and resting work product (r = 0.47, n = 25, p less than 0.005). In response to exercise, the percent increase in cardiac output at matched percent maximum oxygen uptake was greatest in the NOR, D-NOR, and D-ABN groups, respectively (analysis of variance, p less than 0.01). In the diabetic subjects, there was a significant relationship between the RR variation and the maximum percent change in cardiac output (r = 0.41, n = 25, p less than 0.02). Compared with the NOR group, the maximum increase in work product was impaired in diabetic subjects (p less than 0.002) and not different between the D-NOR and D-ABN groups.



The increase in resting work product and the poor cardiac output responses to exercise in the D-ABN group are due to a decrease in cardiac parasympathetic nervous system activity and can be suggested by an abnormal RR variation. This index of parasympathetic nervous system activity can help the physician identify that subset of diabetic patients that may need special consideration when exercise training is prescribed.

title: Preclinical diabetic cardiomyopathy: relation of left ventricular diastolic dysfunction to cardiac autonomic neuropathy in men with uncomplicated well-controlled type 2 diabetes.
abstract: Diabetic cardiomyopathy is an ill-defined entity. This study was designed to explore the possible association between left ventricular diastolic dysfunction (LVDD) and cardiac autonomic neuropathy (CAN) independently from metabolic control. Three groups of 10 age-matched men each with well-controlled type 2 diabetes were studied: (1) subjects with normal diastolic function, (2) subjects with LVDD characterized by impaired LV relaxation, and (3) subjects with a more severe form of LVDD characterized by a pseudonormalized pattern of LV filling. No subject had evidence of clinical diabetic complications, coronary artery disease (CAD), hypertension, congestive heart failure, or thyroid or overt renal disease, and all had a negative maximal exercise test. LVDD was evaluated by Doppler echocardiographic and CAN was evaluated using spectral analysis of heart rate variability (HRV; time and frequency domains) from 24-hour Holter recordings. Findings showed that the high frequency power (HF: 0.15 to 0.4 Hz) tends to decrease with worsening diastolic function; 5.0 +/- 0.2 ms(2) (mean +/- SE) in group 1, 4.2 +/- 0.3 ms(2) in group 2, and 3.9 +/- 0.4 ms(2) (P =.03) in group 3, respectively, whereas the low frequency power (LF: 0.04 to 0.15 Hz) was similar between groups. In the time domain, the mean squared differences of the successive RR intervals (rMSDD) also showed the same pattern, ie, 31.0 +/- 2.8 ms, 23.8 +/- 1.6 ms, and 21.5 +/- 2.9 ms in groups 1, 2, and 3, respectively (P =.03). The E/A ratio correlated significantly with indices of parasympathetic modulation (HF; r = 0.448, P =.013; rMSDD: r = 0.457, P =.011; pNN50: r = 0.425, P =.019). LVDD and CAN are associated in patients with otherwise uncomplicated well-controlled type 2 diabetes. The parameters defining these 2 abnormalities may serve to better define diabetic cardiomyopathy as a distinct entity and could eventually become useful prognostic indicators as it has been shown in nondiabetic populations.

title: The influence of lung function on exercise capacity in patients with type 2 diabetes.
abstract: Patients with type 2 diabetes have impaired exercise capacity. While numerous factors are known to contribute to impaired exercise capacity, the role of lung function remains unclear. We conducted the present study to investigate the influence of lung function on exercise capacity in patients with type 2 diabetes. Cardiopulmonary exercise testing was carried out in 31 male patients with type 2 diabetes without diabetic complications or cardiopulmonary diseases. Patients with abnormal spirometry results such as a percentage of predicted forced vital capacity (%FVC) < 80% and/or a ratio of forced expiratory volume in one second (FEV1) to FVC (FEV1/FVC) < 70% were excluded from the study. We used the percentage of predicted maximal oxygen uptake (%VO2max) as an index of exercise capacity. The correlations between %VO2max and lung function and other factors known to be associated with impaired exercise capacity were then assessed. Univariate analysis revealed %VO2max correlated significantly with percentage of predicted FEV1 (%FEV1), duration of type 2 diabetes, regular exercise habits, and systolic and diastolic blood pressures. In a multivariate analysis, %FEV1 and regular exercise habits were found to be independent determinants of %VO2max. A mild reduction in %FEV1, which may be a complication of diabetes, is associated with impaired exercise capacity in patients with type 2 diabetes. When evaluating spirometric values in patients with type 2 diabetes, a reduction in %FEV1 should be noted even when both %FVC and FEV1/FVC are within normal limits.

title: Exercise and gene expression: physiological regulation of the human genome through physical activity
abstract: The current human genome was moulded and refined through generations of time. We propose that the basic framework for physiologic gene regulation was selected during an era of obligatory physical activity, as the survival of our Late Palaeolithic (50 000–10 000 BC) ancestors depended on hunting and gathering. A sedentary lifestyle in such an environment probably meant elimination of that individual organism. The phenotype of the present day Homo sapiens genome is much different from that of our ancient ancestors, primarily as a consequence of expressing evolutionarily programmed Late Palaeolithic genes in an environment that is predominantly sedentary. In this sense, our current genome is maladapted, resulting in abnormal gene expression, which in turn frequently manifests itself as clinically overt disease. We speculate that some of these genes still play a role in survival by causing premature death from chronic diseases produced by physical inactivity. We also contend that the current scientific evidence supports the notion that disruptions in cellular homeostasis are diminished in magnitude in physically active individuals compared with sedentary individuals due to the natural selection of gene expression that supports the physically active lifestyle displayed by our ancestors. We speculate that genes evolved with the expectation of requiring a certain threshold of physical activity for normal physiologic gene expression, and thus habitual exercise in sedentary cultures restores perturbed homeostatic mechanisms towards the normal physiological range of the Palaeolithic Homo sapiens. This hypothesis allows us to ask the question of whether normal physiological values change as a result of becoming sedentary. In summary, in sedentary cultures, daily physical activity normalizes gene expression towards patterns established to maintain the survival in the Late Palaeolithic era.

title: The effects of aging and physical activity on Doppler measures of diastolic function.
abstract: Healthy aging results in changes in Doppler measures of diastolic function. It is unclear whether these alterations are a specific manifestation of the aging process or reflect a cardiac adaptation to a more sedentary lifestyle. It was hypothesized that healthy, but sedentary, aging would result in slowing of diastolic filling and myocardial relaxation, whereas lifelong endurance training would prevent such changes. Doppler data were measured in young subjects and sedentary and fit seniors across a broad range of loading conditions. Thirteen sedentary healthy (70+/-4 years) and 12 fit Masters athlete (68+/-3 years) seniors were recruited. Twelve young healthy (32+/-9 years) subjects were used for comparison. Pulmonary capillary wedge pressure and Doppler variables were measured at the 6 loading conditions of baseline (twice), -15 and -30 mm Hg lower body negative pressure, and 2 levels of saline solution infusion. Doppler variables consisted of early and late mitral inflow velocity (E/A) ratio, isovolumetric relaxation time (IVRT), tissue Doppler velocities (TDI Emean), and propagation velocity of mitral inflow. Aging resulted in a decrease in E/A ratio (p<0.001), TDI Emean (p<0.001), and propagation velocity of mitral inflow (p<0.001) and an increase in IVRT (p=0.001). Lifelong endurance training did not completely prevent the changes in E/A ratio (p=0.212), IVRT (p=0.546), or propagation velocity of mitral inflow (p=1.00). Fit seniors were able to achieve E/A ratios of 1.0 during baseline and saline solution infusion. TDI Emean was higher in fit versus sedentary seniors at baseline (p=0.012) and during maximal lower body negative pressure (p=0.036), but not during saline solution infusion (p=0.493). In conclusion, age-associated abnormalities in Doppler measures of myocardial filling and relaxation are only partially minimized by lifelong endurance training and therefore may be more specific to the aging process than secondary to years of deconditioning.

title: Diagnosis and classification of diabetes mellitus.
abstract: Diabetes is characterized by chronic hyperglycemia associated with long term microvascular and macrovascular complications such as blindness, kidney failure, lower limbs amputations, myocardial infarction and stroke.

title: Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.
abstract: A method for estimating the cholesterol content of the serum low-density lipoprotein fraction (Sf0-20) is presented. The method involves measurements of fasting plasma total cholesterol, triglyceride, and high-density lipoprotein cholesterol concentrations, none of which requires the use of the preparative ultracentrifuge. Comparison of this suggested procedure with the more direct procedure, in which the ultracentrifuge is used, yielded correlation coefficients of .94 to .99, depending on the patient population compared.

title: Use of Valsalva maneuver to unmask left ventricular diastolic function abnormalities by Doppler echocardiography in patients with coronary artery disease or systemic hypertension.
abstract: It has been suggested that changes in left atrial pressure may mask or mimic left ventricular diastolic function abnormalities detected by Doppler echocardiography. The effect of the Valsalva maneuver on the transmitral flow velocity profile was therefore studied in 28 patients without evidence of coronary artery disease (group 1, mean age +/- standard deviation 50 +/- 8 years) and in 94 patients with evidence of coronary artery disease or systemic hypertension (group 2, mean age 54 +/- 10 years). At baseline, group 2 patients had higher peak late diastolic filling velocity (A), lower peak early (E) to late diastolic filling velocity (E/A) ratio and longer isovolumic relaxation time than group 1, whereas heart rate, E velocity and E deceleration time were similar in both groups. During Valsalva, both groups had similar increases in heart rate and similar decreases in E velocity but E/A ratio decreased significantly only in group 2 because of a lesser decrease in A velocity. The E/A ratio was greater than or equal to 1.0 both before and during Valsalva in all but 1 patient in group 1, whereas in group 2, 32 patients had E/A greater than or equal to 1.0 at rest and during Valsalva, 33 patients had E/A greater than or equal to 1.0 at rest but less than 1.0 both at rest and during Valsalva. Using group 1 as controls, prevalence, specificity and positive predictive value of E/A less than 1.0 in group 2 were 31, 100 and 100% at rest and 66, 96 and 98% during Valsalva.(ABSTRACT TRUNCATED AT 250 WORDS)

title: Mitral annulus velocities by Doppler tissue imaging: practical implications with regard to preload alterations, sample position, and normal values.
abstract: Because it appears to be less affected by changes in preload, mitral annulus Doppler tissue imaging (DTI) has been proposed as an alternate mean of identifying pseudonormal patterns of left ventricular filling. We thus studied the practical implications of DTI in 40 patients classified according to the Canadian Consensus on Diastolic Function (9 control participants, 9 with impaired relaxation, and 22 pseudonormal participants). Using DTI, the early diastolic velocity (Ea) was the most reproducible parameter whereas the late diastolic velocity (Aa) and Ea/Aa ratio varied significantly. Nonetheless, Ea missed 23% of pseudonormal participants and its sensitivity, specificity, and positive and negative predictive values to identify diastolic dysfunction were 81%, 89%, 96%, and 57%, respectively; improving to 94%, 89%, 97%, and 80%, respectively, if used during Valsalva's maneuver. Thus, DTI is not totally preload independent and should be interpreted in light of the other Doppler parameters and the use of Valsalva's maneuver. Moreover, consistent with recent studies, these results suggest that the threshold value of Ea used to identify diastolic dysfunction should be approximately 12.5 cm/s.

title: Clinical Utility of Doppler Echocardiography and Tissue Doppler Imaging in the Estimation of Left Ventricular Filling Pressures: A Comparative Simultaneous Doppler-Catheterization Study
abstract: BackgroundNoninvasive assessment of diastolic filling by Doppler echocardiography provides important information about left ventricular (LV) status in selected subsets of patients. This study was designed to assess whether mitral annular velocities as assessed by tissue Doppler imaging are associated with invasive measures of diastolic LV performance and whether additional information is gained over traditional Doppler variables. Methods and ResultsOne hundred consecutive patients referred for cardiac catheterization underwent simultaneous Doppler interrogation. Invasive measurements of LV pressures were obtained with micromanometer-tipped catheters, and the mean LV diastolic pressure (M-LVDP) was used as a surrogate for mean left atrial pressure. Doppler signals from the mitral inflow, pulmonary venous inflow, and TDI of the mitral annulus were obtained. Isolated parameters of transmitral flow correlated with M-LVDP only when ejection fraction <50%. The ratio of mitral velocity to early diastolic velocity of the mitral annulus (E/E′) showed a better correlation with M-LVDP than did other Doppler variables for all levels of systolic function.  <8 accurately predicted normal M-LVDP, and E/E′ >15 identified increased M-LVDP. Wide variability was present in those with E/E′ of 8 to 15. A subset of those patients with E/E′ 8 to 15 could be further defined by use of other Doppler data. ConclusionsThe combination of tissue Doppler imaging of the mitral annulus and mitral inflow velocity curves provides better estimates of LV filling pressures than other methods (pulmonary vein, preload reduction). However, accurate prediction of filling pressures for an individual patient requires a stepwise approach incorporating all available data.

title: Effect of atorvastatin on exercise-induced myocardial ischemia in patients with stable angina pectoris.
abstract: To investigate whether marked and sustained lipid-lowering in subjects with stable angina pectoris and dyslipidemia reduces exercise-induced myocardial ischemia, 17 subjects were treated with dose-adjusted atorvastatin over 1 year and underwent serial evaluation of exercise electrocardiographic ischemic parameters, serum biomarkers, and brachial artery endothelial function. Endothelial function improved progressively and C-reactive protein, P-selectin, and tissue plasminogen activator inhibitor levels decreased, but there was no decrease in exercise electrocardiographic ischemia.

title: A new method for detecting anaerobic threshold by gas exchange.
abstract: Excess CO2 is generated when lactate is increased during exercise because its [H+] is buffered primarily by HCO-3 (22 ml for each meq of lactic acid). We developed a method to detect the anaerobic threshold (AT), using computerized regression analysis of the slopes of the CO2 uptake (VCO2) vs. O2 uptake (VO2) plot, which detects the beginning of the excess CO2 output generated from the buffering of [H+], termed the V-slope method. From incremental exercise tests on 10 subjects, the point of excess CO2 output (AT) predicted closely the lactate and HCO-3 thresholds. The mean gas exchange AT was found to correspond to a small increment of lactate above the mathematically defined lactate threshold [0.50 +/- 0.34 (SD) meq/l] and not to differ significantly from the estimated HCO-3 threshold. The mean VO2 at AT computed by the V-slope analysis did not differ significantly from the mean value determined by a panel of six experienced reviewers using traditional visual methods, but the AT could be more reliably determined by the V-slope method. The respiratory compensation point, detected separately by examining the minute ventilation vs. VCO2 plot, was consistently higher than the AT (2.51 +/- 0.42 vs. 1.83 +/- 0.30 l/min of VO2). This method for determining the AT has significant advantages over others that depend on regular breathing pattern and respiratory chemosensitivity.

title: Effects of exercise training on oxygen uptake kinetic responses in women with type 2 diabetes.
abstract: Women with uncomplicated type 2 diabetes have both a decreased maximal oxygen consumption (VO2max) and slowed oxygen uptake (VO2) kinetics at the onset of exercise compared with nondiabetic women. These abnormalities are seen not only at maximal workloads, but also at the onset of low-level exercise. To evaluate the hypothesis that VO2max and VO2 kinetics would improve with exercise training in untrained people with type 2 diabetes, we measured these parameters in premenopausal sedentary women before and after 3 months of supervised exercise training.



A total of 8 women with type 2 diabetes, 9 overweight nondiabetic women, and 10 lean nondiabetic women were studied. At baseline and after 3 months of exercise training, subjects underwent bicycle ergometer testing to obtain VO2max and VO2 kinetics data.



On entry, women with type 2 diabetes had the lowest VO2max and slowest VO2 kinetics of the three groups. After exercise training, the women with type 2 diabetes improved their VO2max more than the lean and overweight control women: 28 vs. 5 and 8%, respectively (P < 0.05 for the diabetic group vs. both control groups). In the group with diabetes, VO2 kinetics improved by 39 and 22% at 20 and 30 W, respectively. For the control subjects, VO2 kinetics did not improve at any workload in either group.



Despite beginning with the lowest VO2max and slowest VO2 kinetics, subjects with type 2 diabetes benefited more from an exercise training program than did control subjects. These findings suggest that in addition to its known metabolic effects, exercise training in individuals with type 2 diabetes may be an effective therapy to improve the cardiovascular response to exercise and to overcome low-level exercise impairment as reflected by improved VO2max and VO2 kinetics. If the ability to make circulatory adjustments at the beginning of exercise at low workloads is improved by an exercise training program, as suggested by the VO2 kinetics data, the clinical significance of exercise for people with type 2 diabetes is clear.

title: Serum HbA1c levels and exercise capacity in diabetic patients.
abstract: It is well known that cardiovascular morbidity and mortality are high in diabetic patients. Cardiac involvement is silent and early and these diabetic patients generally complain of chronic fatigue. This study was designed to evaluate the relation between glycemic control and exercise capacity in 330 diabetic patients who have no cardiac symptoms by sustaining dynamic exercise. After a cardiac examination, patients with coronary heart disease, ECG abnormalities, cardiac failure, valvular disease, cerebrovascular disease, peripheral artery disease, anaemia and peripheral neuropathy were excluded. Plasma HbA1c and lipid levels were obtained and a symptom limited exercise test based on "Bruce Protocol" was performed on all patients. Plasma HbA1c levels were significantly increased in smokers and in hypercholesterolemic patients (p<0.001, p=0.006). A moderate correlation between exercise capacity and HbA1c levels, and a weak correlation between duration of diabetes, age, sex, hypertension and plasma lipids were obtained. Multivariant regression analys is revealed that only HbA1c and hypercholesterolemia affected exercise capacity independently (r=-0.54 r=-0.30). In conclusion, poor glycemic control in diabetic patients causes earlier cellular involvement. Because of the high affinity of HbA1c to oxygen, the energy metabolism of the cell is affected, with a clinical correlation between chronic fatigue and worsening exercise capacity.

title: Relationship between hyperglycaemia and aerobic power in men with newly diagnosed type 2 (non insulin-dependent) diabetes.
abstract: The aim of the study described here was to evaluate aerobic function during exercise and its determinants in middle-aged men with newly diagnosed Type 2 (non insulin-dependent) diabetes. Using breath-by-breath technique, we measured O2 uptake at anaerobic (ventilatory) threshold and at peak exercise in a group of diabetic men (n = 19; fasting blood glucose 8.6 +/- 0.7 mmol l-1, mean +/- SEM) without any disease or medication that could have had an influence on exercise performance, and compared the results to those observed in non-diabetic healthy control men (n = 18). There were no differences in physical activity or smoking habits between the groups. Oxygen uptake was lower in the diabetic men than in the control men both at anaerobic threshold (15.0 +/- 0.8 vs. 18.8 +/- 1.0 ml min-1 kg-1, P < 0.01) and at peak exercise (25.3 +/- 1.5 vs. 31.1 +/- 1.4 ml min-1 kg-1, P < 0.01). In the diabetic men peak O2 uptake showed an inverse linear correlation with age (r = -0.71, P < or = 0.001), fasting blood glucose (r = -0.49, P < 0.05) and glucose response in an oral glucose tolerance test (r = -0.43, P < 0.05). In addition, long-term smoking was associated with impaired peak O2 uptake. In a stepwise multiple regression procedure 75% of the total variance of peak O2 uptake in the diabetic men was explained by age, post-load blood glucose response and smoking history. Thus, in addition to ageing and smoking, hyperglycaemia is correlated with impaired aerobic power in men with newly diagnosed Type 2 diabetes.

title: Hemodynamic adaptations to exercise.
abstract: It is not currently known whether central hemodynamic or peripheral (vascular or metabolic) factors limit maximal oxygen uptake. By measuring the blood flow and oxygen uptake of exercising muscles when only a small fraction of the total muscle mass is engaged in exercise, it has been demonstrated that the skeletal muscle of man could accommodate a blood flow of at least 200 ml/100 g min, and consume 300 ml O2/100 g min at exhaustive exercise. Thus, in whole body exercise the limiting factor is the capacity of the heart to deliver oxygen, not the muscle. It has also been observed that at high perfusion of the muscle the arteriovenous O2 difference is small (14 to 15 vol %), and that the low extraction of oxygen is related to the mean transit time (MTT) of red blood cells passing through the capillaries. It has been concluded that the primary importance of enlargement of the capillary bed with endurance training is not to accommodate flow but to maintain or elongate MTT. It has also been concluded that, in whole body exercise, the capacity of the muscles to receive a flow exceeds by a factor of 2 to 3 the capacity of the heart to supply the flow. Thus, vasoconstrictor tone must also be present in the arteries that "feed" exercising muscles.

title: Prevalence of ventricular diastolic dysfunction in asymptomatic, normotensive patients with diabetes mellitus.
abstract: To determine the prevalence of left ventricular diastolic dysfunction in asymptomatic, normotensive patients with type 2 diabetes mellitus, we studied 61 consecutive normotensive patients with type 2 diabetes using conventional Doppler echocardiography at rest (deceleration time, isovolumic relaxation time, early diastolic velocity [E]/peak atrial systolic velocity [A] ratio), and during the Valsalva maneuver. In addition, mitral annular velocity and velocity of flow propagation were assessed in all patients using tissue Doppler imaging (TDI) and color M-mode echocardiography. A standard resting echocardiogram excluded significant valvular disease and stress echocardiography excluded significant coronary artery disease in those with diastolic dysfunction. Diastolic dysfunction was found in 43 of 57 patients (75%) when all of the above echocardiographic techniques were used. TDI detected diastolic dysfunction more often (63%) than any other echocardiographic approach. Thus, the prevalence of left ventricular diastolic dysfunction in asymptomatic, normotensive patients with type 2 diabetes without significant coronary artery disease is much higher than previously suspected. TDI markedly improved the echocardiographic detection of diastolic dysfunction in asymptomatic patients with type 2 diabetes.

title: Mechanisms of diastolic dysfunction in heart failure.
abstract: Abnormalities of diastole are common to most forms of congestive heart failure (HF). Diastolic function is broadly defined as the ability of the heart to fill adequately and at normal pressure to charge the ventricular pump for each subsequent contraction. It is determined by both active and passive processes occurring at the level of the myocyte, extracellular matrix, and left ventricular chamber. Forces extrinsic to the myocardium-such as the influence of right heart filling, pericardial and extracardiac constraints, and cardiac preload and afterload also contribute. Nearly half of patients with HF have apparently preserved systolic function, and this has focused attention on diastolic dysfunction as a dominant contributor to symptoms, sparking interest for understanding and treating diastolic abnormalities. This review focuses on the mechanisms determining normal and pathologic cardiac relaxation and distensibility and highlights how these abnormalities may be therapeutically targeted to improve diastolic function in human HF.

title: The Type 2 Diabetic Heart: Its Role in Exercise Intolerance and the Challenge to Find Effective Exercise Interventions
abstract: The metabolic and microvascular benefits of regular exercise for people with diabetes are unequivocal. However, cardiovascular disease, which disproportionately affects people with diabetes, is not reduced by regular exercise, and heart disease remains the leading cause of death for people with type 2 diabetes. ‘Subclinical’ changes in the function of the diabetic left ventricle are common and reduce cardiac reserve and exercise capacity. This review describes the changes in resting and exercising left ventricular function, and the possible causes of these changes, and introduces the possibility that more vigorous exercise may be needed to improve left ventricular function and reduce rates of cardiovascular disease in people with type 2 diabetes.

title: Oxygen Uptake Kinetics in Sport, Exercise and Medicine
abstract: Part One: Introduction 1. Introduction to Oxygen Uptake Kinetics and Historical Development of the Discipline, Andrew M. Jones and David C. Poole Part Two: Theory and Practice of Measuring VO2 Kinetics 2. Measuring VO2 Kinetics: The Practicalities, Shunsaku Koga, Tomoyuki Shiojiri and Narihiko Kondo 3. The Kinetics of Oxygen Uptake: Physiological Inferences from the Parameters, Brian J. Whipp and Harry B. Rossiter 4. Effect of Exercise Modality on VO2 Kinetics, Andrew M. Jones and Mark Burnley 5. VO2 Dynamics in Different Species, Casey A. Kindig, Brad J. Behnke and David C. Poole Part Three: Mechanistic Bases of VO2 Kinetics 6. Relationship Between VO2 Responses at the Mouth and Across the Exercising Muscles, Brad J. Behnke, Thomas J. Barstow and David C. Poole 7. Intramuscular Phosphate and Pulmonary VO2 Kinetics During Exercise: Implications for Control of Skeletal Muscle Oxygen Consumption, Harry B. Rossiter, Franklyn A. Howe and Susan A. Ward 8. Limitation of VO2 On-Kinetics by O2 Delivery, Richard L. Hughson 9. Limitation of Skeletal Muscle VO2 On-kinetics by Inertia of Cellular Respiration, Bruno Grassi 10. "Priming" Exercise and VO2 Kinetics, Mark Burnley, Katrien Koppo and Andrew M. Jones 11. Influence of Muscle Fibre Type and Motor Unit Recruitment on VO2 Kinetics, Andrew M. Jones, Jamie S.M. Pringle and Helen Carter 12. Towards an Understanding of the Mechanistic Bases of VO2 Kinetics:  Raised in Chapters 2-11, David C. Poole and Andrew M. Jones Part Four: Practical Applications to the Study of VO2 Kinetics 13. VO2 Kinetics: Effects of Maturation and Ageing, Thomas J. Barstow and Barry W. Scheuermann 14. VO2 Kinetics in Different Disease States, David C. Poole, Casey A. Kindig and Brad J. Behnke 15. Effect of Training on VO2 Kinetics and Performance, Andrew M. Jones and Katrien Koppo

title: Fast-start strategy improves VO2 kinetics and high-intensity exercise performance.
abstract: The purpose of this study was to investigate the influence of pacing strategy on pulmonary VO2 kinetics and performance during high-intensity exercise.



Seven males completed 3- and 6-min bouts of cycle exercise on three occasions with the bouts initiated using an even-start (ES; constant work rate), fast-start (FS), or slow-start (SS) pacing strategy. In all conditions, subjects completed an all-out sprint over the final 60 s of the test as a measure of performance.



For the 3-min exercise bouts, the mean response time (MRT) for the VO2 kinetics over the pacing phase was shortest in FS (35 ± 6 s), longest in SS (55 ± 14 s), and intermediate in ES (41 ± 10 s) (P < 0.05 for all comparisons). For the 6-min bouts, the VO2 MRT was longer in SS (56 ± 15 s) than that in FS and ES (38 ± 7 and 42 ± 6 s, respectively, P < 0.05). The VO2 at the end of exercise was not different from the VO2max during the 6-min exercise bouts or 3-FS but was lower than VO2max for 3-ES and 3-SS (P < 0.05). The end-sprint performance was significantly enhanced in 3-FS compared with 3-ES and 3-SS (mean power = 374 ± 68 vs 348 ± 61 and 345 ± 71 W, respectively; P < 0.05). However, end-sprint performance was unaffected by pacing strategy in the 6-min bouts.



These data indicate that an FS pacing strategy significantly improves performance during 3-min bouts of high-intensity exercise by speeding VO2 kinetics and enabling the attainment of VO2max.

title: Are the parameters of VO2, heart rate and muscle deoxygenation kinetics affected by serial moderate-intensity exercise transitions in a single day?
abstract: This study compared the parameter estimates of pulmonary oxygen uptake (VO2p), heart rate (HR) and muscle deoxygenation (Δ[HHb]) kinetics when several moderate-intensity exercise transitions (MODs) were performed during a single visit versus several MODs performed during separate visits. Nine subjects (24 ± 5 years, mean ± SD) each completed two successive cycling MODs on six occasions (1-6A and 1-6B) from 20 W to a work rate corresponding to 80% estimated lactate threshold with 6 min recovery at 20 W. During one visit, subjects completed two series of three MODs (6A-F), separated by 20 min rest. VO2p time constants (τVO2p; 27 ± 10 s, 25 ± 12 s, 25 ± 11 s) were similar (p > 0.05) for MODs 1-6A, 1-6B and 6A-F, respectively. τVO2p had reproducibility 95% confidence intervals (CI95) of 8.3, 8.2, 4.7, 4.9 and 4.7 s when comparing single (1A vs. 2A), the average of two (1-2A vs. 3-4A), three (1-3A vs. 4-6A), four (1-2AB vs. 3-4AB) and six (1-3AB vs. 4-6AB) MODs, respectively. The effective Δ[HHb] response time (τ′Δ[HHb]) was unaffected across conditions (1-6A: 19 ± 2 s, 1-6B: 19 ± 3 s, 6A-F: 17 ± 4 s) with reproducibility CI95 of 5.3, 4.5, 3.1, 2.9 and 3.3 s when a single, two, three, four and six MODs were compared, respectively. τHR was reduced in MODs 6A-F compared to 1-6A and 1-6B (23 ± 5 s, 25 ± 5 s, 27 ± 6 s, respectively). This study showed that parameter estimates of VO2p, HR and Δ[HHb] kinetics are largely unaffected by data collection sequence, and the day-to-day reproducibility of τVO2p and τ′Δ[HHb] estimates, as determined by the CI95, was appreciably improved by averaging of at least three MODs.

title: Effect of physical exercise on sensitivity and responsiveness to insulin in humans.
abstract: The effect of acute physical exercise on insulin sensitivity and responsiveness of glucose uptake and hepatic glucose production was studied. Seven untrained men were subjected to four sequential euglycemic hyperinsulinemic clamps after rest (R), immediately after exercise (E), as well as 48 h after 60 min of 150 W ergometer exercise (ER). Insulin-mediated glucose uptake was higher on E and ER days compared with R days. Apparent Km decreased after exercise (52 +/- 3 R vs. 43 +/- 4 E and 40 +/- 3 ER microU/ml, means +/- SE) and Vmax increased (9.5 +/- 0.8 R vs. 10.9 +/- 0.7 E and 10.7 +/- 0.8 ER mg.min-1.kg-1). Glucose oxidation increased with the increasing insulin infusion rate, and maximal glucose oxidation rate was lower on E days compared with R days. The maximal conversion rate of glucose to glycogen was higher on E and ER days (8.0 +/- 0.3 and 7.2 +/- 0.2, respectively) than on R days (5.7 +/- 0.6 mg.min-1 kg-1). Muscle glycogen synthase I activity was higher immediately after exercise and remained higher for the next 48 h. No change in any glucoregulatory hormone or metabolite could explain the increased insulin action seen after exercise. In additional experiments (n = 3), no remaining effect existed 5 days after exercise. Both insulin and exercise suppressed the pancreatic secretion of insulin and proinsulin. The conclusions drawn are that prolonged moderate exercise increases insulin action on glucose uptake in humans by reducing apparent Km and increasing Vmax. This effect lasts 48 h but not 5 days. The increased insulin action may be related to an exercise-induced increase in glycogen synthase activity.

title: Impaired physical fitness and insulin secretion in normoglycaemic subjects with familial aggregation of type 2 diabetes mellitus.
abstract: Randomized subgroups from a health screening population were reinvestigated with oral glucose tolerance tests (OGTT) with simultaneous insulin and C-peptide measurements and submaximal exercise tests. Twenty-two normoglycaemic non-obese males with a strong family history of Type 2 diabetes were compared to 51 controls. While glucose levels tended to be somewhat higher, there was a tendency towards lower insulin and C-peptide levels in the hereditary group compared to controls, especially during the early phase of the OGTT, as reflected in a significant difference in the 40 min insulin level and the 0-40 min increment. Estimated maximal oxygen uptake was significantly lower in the hereditary group as were the sum ratios of insulin and C-peptide to glucose in the early phase of the OGTT. Insulin to C-peptide ratios did not differ. The data support both a decreased physical fitness, indicating peripheral insulin insensitivity, and a decreased insulin secretion among normoglycaemic individuals with familial aggregation of Type 2 diabetes.

title: Cardiorespiratory Fitness Is Inversely Associated With the Incidence of Metabolic Syndrome: A Prospective Study of Men and Women
abstract: Few studies have reported the relationship between cardiorespiratory fitness and metabolic syndrome incidence, particularly in women. We prospectively studied 9007 men (mean±SD age, 44±9 years; body mass index, 25±3 kg/m2) and 1491 women (age, 44±9 years; body mass index, 22±2 kg/m2) who were free of metabolic syndrome and for whom measures of waist girth, resting blood pressure, fasting lipids, and glucose were taken during baseline and follow-up examinations. Baseline cardiorespiratory fitness was quantified as duration of a maximal treadmill test. Metabolic syndrome was defined with NCEP ATP-III criteria. During a mean follow-up of 5.7 years, 1346 men and 56 women developed metabolic syndrome. Age-adjusted incidence rates were significantly lower (linear trend, P<0.001) across incremental thirds of fitness in men and women. After further adjustment for potential confounders, multivariable hazard ratios for incident metabolic syndrome among men in the low, middle, and upper thirds of fitness, were 1.0 (referent), 0.74 (95% CI, 0.65 to 0.84), and 0.47 (95% CI, 0.40 to 0.54) (linear trend P<0.001); in women, they were 1.0 (referent), 0.80 (95% CI, 0.44 to 1.46), and 0.37 (95% CI, 0.18 to 0.80) (linear trend P=0.01), respectively. Similar patterns of significant inverse associations between fitness and metabolic syndrome incidence were seen when men were stratified on categories of body mass index, age, and number of baseline metabolic risk factors, but patterns were variable in women. Low cardiorespiratory fitness is a strong and independent predictor of incident metabolic syndrome in women and men. Clinicians should consider the potential benefits of greater cardiorespiratory fitness in the primary prevention of metabolic syndrome, particularly among patients who have already begun to cluster metabolic syndrome components.

title: Insulin resistance in relatives of NIDDM patients: The role of physical fitness and muscle metabolism
abstract: SummaryFirst degree relatives of patients with non-insulin-dependent diabetes mellitus (NIDDM) are often reported to be insulin resistant. To examine the possible role of reduced physical fitness in this condition 21 first degree relatives of NIDDM patients and 22 control subjects without any history of diabetes were examined employing a 150-min hyper-insulinaemic (0.6 mU insulin kg−1 min−1) euglycaemic clamp combined with the isotope dilution technique (3-3H-glucose, Hot GINF), the forearm technique and indirect calorimetry. During hyperinsulinaemia glucose disposal (Rd) and forearm glucose extraction were significantly diminished in the relatives (p < 0.01 and p < 0.05), but glucose oxidation and the suppressive effect on hepatic glucose production were normal. Arteriovenous differences across the forearm of the gluconeogenic precursors lactate, alanine and glycerol as well as the increments in forearm blood flow during hyperinsulinaemia were similar in the two groups. Maximal oxygen uptake (VO2 max) was lower in the relatives than in the control subjects (36.8 ± 1.9 vs 42.1 ± 2.0 ml kg−1 min−1; p = 0.03). There was a highly significant correlation between Rd and VO2 max in both relatives and control subjects (r = 0.68 and 0.66, respectively; both p < 0.001). Comparison of the linear regression analyses of insulin-stimulated Rd on VO2 max in the two groups showed no significant differences between the slopes (0.10 ± 0.03 vs 0.09 ± 0.02) or the intercepts. In stepwise multiple linear regression analyses with insulinstimulated Rd as the dependent variable VO2 max significantly determined the level of Rd (p < 0.01), whereas forearm blood flow and anthropometric data did not. In conclusion, the insulin resistance in healthy first degree relatives of patients with NIDDM is associated with a diminished physical work capacity. Whether, this finding is ascribable to environmental or genetic factors (e.g. differences in muscle fibre types, capillary density etc) remains to be determined.