Regular physical activity is an evidence-based and guideline recommendation for nonpharmacological therapy in patients with coronary heart disease (CHD) and type 2 diabetes mellitus (T2DM) [1,2]. In general, aerobic exercise activity is recommended [1–4]. It was also proposed, however, that greater exercise intensities tend to yield even greater benefits in HbA1c . These common assumptions conflict with the fact that each individual has a variable glycemic response to exercise . In addition, the term ‘aerobic exercise activity’ encompasses a broad range of exercise intensities between 25% and 75% VO2peak  indicating, that the most appropriate exercise intensity for patients with CHD and T2DM seems not to be established yet.
It is well known that insulin sensitivity is improved by regular physical activity . This might be due to direct effects in the skeletal muscle, such as an improved intracellular insulin signaling and GLUT-4 glucose transporter translocation , increased blood flow and mitochondrial neobiogenesis as well as, eventually, a growing skeletal muscle mass . In addition, general effects like a loss of fat mass, improved lipid metabolism or anti-inflammatory effects might also be involved . These potential glucose-lowering mechanisms seem to be responsible for mid- to long-term effects.
The immediate response of exercise intensity on blood glucose, however, seems to be influenced more by stress hormones and sympatho-adrenal activity. It is well known that increased sympathetic nerve activity exacerbates insulin resistance , precedes hyperinsulinemia and high blood pressure . In addition, elevated exercise levels increase glucotropic hormones very rapidly [11,12] to provide sufficient glucose for the working muscles during strenuous exercise. In healthy volunteers without insulin resistance [11,12] increasing plasma glucose (PG) is transported into the muscle cells and ATP is produced by mitochondria. In deconditioned patients with T2DM, however, exhibiting insulin resistance, muscular atrophy and reduced mitochondrial density [13,14] the increasing PG might not be adequately metabolized during vigorous physical activity. Hence, it seems possible, that increased sympathetic nerve activity and elevated stress hormones during high exercise intensity neutralize the glucose-lowering effect of physical activity or even increase PG.
As to our knowledge, aerobic exercise intensity has not been investigated in this cohort of patients with CHD and T2DM. In this pilot study, we hypothesized that the individual aerobic exercise intensity to reduce blood glucose in patients with CHD and T2DM might be lower than expected and that higher exercise intensities might not reduce blood glucose in this subset. This could have an impact on the recommendations for physical activity in patients with CHD and T2DM.
Patients referred to cardiac rehabilitation after a recent acute coronary syndrome or with stable CHD were included if T2DM was newly diagnosed by standard 75 g oral glucose tolerance test (OGTT) . In all patients, CHD was diagnosed by coronary angiography and left ventricular ejection fraction (LVEF) was measured by echocardiography. Exclusion criteria were: any kind of previous hyperglycemia or diabetes dietary intervention, antidiabetic medication or insulin, surgery within 6 months, congestive heart failure, renal insufficiency (Creatinine > 115 µmol/L), peripheral arterial disease with an ankle brachial index <0.92, medication with cortisone or anti-depressant drugs, diseases of the exocrine pancreas and infections.
All patients gave their written informed consent before participating in the project that was approved by the ethics committee of the University of Lübeck (No. 15-019).
Cardiopulmonary exercise testing
Moderate (aerobic) and high (anaerobic) exercise intensities were performed during cardiopulmonary exercise testing (CPX) on an electronically braked, cycle ergometer (Ergoselect 100; Ergoline GmbH, Bitz, Germany) at constant pedal speed of 50–60 rpm and at the same time of the day for each patient . Airflow, volumes and the O2, CO2 analyzers were calibrated before each exercise session. After adaptation to the mask, parameters at rest were determined. Following a period of 2 minutes of unloaded cycling, constant workload increments were tailored to the individual patient to yield an exercise duration between 8 and 12 minutes . A 12-lead ECG was recorded continuously, blood pressure was measured at 2-minute intervals and gases were analyzed breath by breath (Cardiovit CS-200; Schiller Medizintechnik GmbH, Ottobrunn, Germany).
Anaerobic exercise (CPX-1)
CPX-1 was performed until a respiratory exchange ratio (RER) of 1.20 was reached representing metabolic acidosis at the end of maximum incremental cycle ergometer exercise in sedentary men . Maximum exercise intensity (maxIntensity, Watt) and VO2 peak (ml/min/kg) were measured at a RER of 1.20 . In case of exhaustion or other standard medical conditions , CPX-1 was stopped early and patients were excluded from statistical analysis. The recovery period of CPX-1 lasted until heart rate, blood pressure and gases had returned to resting values.
Aerobic exercise (CPX-2)
Aerobic exercise (CPX-2) was started with the same workload increments that were used in CPX-1 of the individual patient. At a RER of 0.90, this automatic workload increase was stopped and the workload was titrated manually in steps of ±1 W, thereafter, to keep the RER between 0.90 and 0.95 over a time period of 30 minutes of cycling. Thus, performing a steady-state aerobic exercise. After cessation of pedaling, RER must not exceed 1.00 during the recovery period of CPX-2, demonstrating the definite aerobic intensity of this physical activity.
Oral glucose tolerance test
T2DM was present with a 2-h-PG ≥ 11.1 mmol/l in a standardized 75 g OGTT . This screening OGTT (OGTT-0) was performed at 7 a.m. after overnight fasting. Within 3–5 days after OGTT-0, patients performed the anaerobic exercise (CPX-1) that was started at 7 a.m. after overnight fasting as well. OGTT-1 was performed immediately after the recovery phase of CPX-1 had been terminated. On the next day, aerobic exercise (CPX-2) was started at 7 a.m. after overnight fasting, and OGTT-2 was performed immediately after recovery of CPX-2. All patients performed the different tests in the same order.
Data are given as mean values ± SD. Comparisons between blood glucose values obtained during OGTT-0, -1 and -2 were made by analysis of variance test for repeated measurements. Correlation between aerobic exercise intensity (Watt) and LVEF (%) was calculated by Pearson test. P < 0.05 was considered significant.
Inclusion criteria were met by 16 consecutive patients. One patient refused participation and CPX-1 was stopped prematurely below a RER of 1.20 in five patients due to angina pectoris (n = 2), dyspnea (n = 2) and muscular fatigue (n = 1). Hence, the study protocol could be completed in 10 patients (Table 1). All patients received statins, angiotensin converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers and platelet inhibition after ST-elevation myocardial infarction (n = 7), non-ST-elevation myocardial infarction (n = 1) and with chronic CHD (n = 2).
During anaerobic exercise (CPX-1), maxIntensity averaged at 99 ± 30 W (range 50–158 W) and patients reached a mean maximum oxygen consumption (VO2peak) of 15.9 ± 2.8 ml/min/kg (range 10.6–19.6 ml/min/kg) at an average heart rate of 115 ± 13 min−1 (range 90–133 min−1). During aerobic exercise (CPX-2), it was possible to hold RER constant between 0.90 ± 0.03 and 0.96 ± 0.02 in all patients. RER did not reach 1.00 during exercise or recovery of CPX-2 and every patient was able to complete 30 minutes of aerobic exercise. In CPX-2 aerobicIntensity averaged at 29 ± 9 W (range 10–45 W). The relation between aerobicIntensity as measured in CPX-2 and parameters obtained during anaerobic exercise (CPX-1) are displayed in Table 2. aerobicIntensity (Watt) was not correlated with LVEF (%) (r = 0.534; P = 0.112).
Fasting and post-load PG are displayed in Table 3 and Fig. 1. Fasting PG was almost identical and 1-h-PG did not differ significantly between three OGTTs. After anaerobic exercise (OGTT-1), 2-h-PG showed a further increase in five patients, it remained constant in three patients and only two patients exhibited a decreasing 2-h-PG (Table 3 and Fig. 1). After aerobic exercise (OGTT-2), 2-h-PG decreased in all patients and the mean value was significantly lower as compared to 2-h-PG in the screening OGTT-0 at rest (9.4 ± 2.3 vs. 12.6 ± 2.2 mmol/l; P < 0.05). Mean values of 2-h-PG did not differ between OGTT-0 (at rest) and OGTT-1 (anaerobic).
In the study presented, 10 patients with CHD and T2DM exhibited a very low aerobic exercise intensity between 10 and 45 W (Table 2) as analyzed individually by cardiopulmonary exercise testing. In relation to parameters obtained at maximum exercise, there was a huge scattering between 10% and 44% of maximum intensity (Watt), between 47% and 76% of VO2peak and between 63% and 95% of maximum heart rate (Table 2). Considering that calculating an exercise prescription in relation to maximum exercise parameters might be erroneous per se , it seems hardly possible to derive the individual aerobic exercise intensity from one maximum exercise test in this patient cohort with CHD and T2DM.
The method presented here allowed for detection of the specific aerobic exercise intensity in every single patient being very different concerning their metabolic state. For instance, patient no. 2 (Table 1) represents an advanced diabetic state (BMI 32.2 kg/m2, waist 120 cm, HbA1c 60 mmol/mol (7.6%), Triglyceride 2.39 mmol/l) with a 2-h-PG of 12.5 mmol/l at rest and an increase to 17.9 mmol/l after anaerobic exercise. Whereas patient no. 5 was included in an earlier diabetic state (BMI 25.7 kg/m2, waist 95 cm, HbA1c 31 mmol/mol (5.0%), Triglyceride 1.15 mmol/l) with a 2-h-PG of 13.0 mmol/l at rest and a decrease to 10.7 mmol/l after anaerobic exercise. In both patients, it was possible to detect the individual aerobic exercise intensity by cardiopulmonary exercise testing (Table 2). Exercising for 30 minutes at this individually determined aerobic intensity reduced markedly the 2-h-PG in both patients (no. 2: from 12.5 to 10.9 mmol/l, no. 5: from 13.0 to 9.3 mmol/l). Using this method, 2-h-PG was significantly reduced in all patients of the cohort studied. (Table 3 and Fig. 1)
The general recommendation of greater exercise intensities to yield greater benefits in HbA1c  seems to be questionable, not only in view of our results. In 1.467 participants with normal glucose metabolism (46%), impaired glucose tolerance (22%) and not insulin-dependant diabetes mellitus (32%), the estimated energy expenditure (EEE) during physical activity was assessed by structured interviews, and insulin sensitivity was measured . Results were corrected for age, sex, dietary fat and alcohol intake, hypertension, smoking, ethnicity and clinical center. In patients with diabetes, vigorous EEE did not improve insulin sensitivity whereas nonvigorous EEE did improve insulin sensitivity significantly. In participants without diabetes, vigorous EEE increased insulin sensitivity as compared to nonvigorous EEE .
In 19 patients with the metabolic syndrome and T2DM, moderate and high exercise intensity were compared in a randomized trial . Moderate intensity was defined as exercising at 70% of the highest measured heart rate (HRmax), high-intensity exercise was performed at 90% of HRmax. After 16 weeks of training, fasting PG showed a very small (0.3 mmol/l) but significant reduction with high exercise intensity (baseline 6.9 ± 0.6 vs. 6.6 ± 0.6 mmol/l; P < 0.05) whereas moderate-intensity did not reduce fasting PG (6.1 ± 0.5 vs. 6.5 ± 0.6). The positive 2-hour post-load PG ≥11.1 mmol/l, however, was better reduced from 87.5% to 37.5% by moderate exercise intensity as compared with 72.7% to 36.4% by high exercise intensity . Considering that patients in this trial were extremely fit (VO2peak 34–36 ml/min/kg) as compared to the patients in our study (average VO2peak 15.9 ml/min/kg), an absolute reduction of fasting PG by 0.3 mmol/l and a lesser normalization rate of the 2-hour post-load PG by high intensity (36% points) as compared to moderate-intensity training (50% points), does not justify the general recommendation of greater exercise intensities to yield greater benefits in HbA1c in all patients with T2DM.
In a meta-analysis about the effects of exercise on glycemic control, Boulé et al.  did not report a relationship between exercise intensity and improvement of glucose metabolism. An other meta-analysis by the same group revealed that exercise intensity predicted the post-intervention weighted mean difference in HbA1c (r = −0.91, P = 0.002) to a larger extent than did exercise volume (r = −0.46, P = 0.26) . However, only one study included an unequivocally vigorous exercise intervention at 75% VO2peak. Most of the studies exercised the patients between 50% and 65% of VO2peak which is within the range as detected to be appropriate in our study (Table 2). Thus, Boulé et al.  concluded, that ‘high-intensity exercise might prove difficult or even hazardous for many previously sedentary people with T2DM and with lacking of individual patient data, this one study’s positive result would not be sufficient to advocate high-intensity aerobic exercise for all people with diabetes’.
In a randomized trial, continuous exercise training with moderate- and high-intensity was compared in 50 male obese T2DM patients for 6 months duration . When exercise bouts were matched for total energy expenditure, no interaction was observed between exercise intensity and the decrease in HbA1c and no correlation was found between changes in VO2peak and HbA1c . In another study, insulin sensitivity index (ISI) was measured in 60 sedentary adults with T2DM, randomly allocated to low-intensity or high-intensity continuous exercise training . Holding energy expenditure constant in both groups (240 kcal per session), ISI was increased similarly in both groups. However, only the low-intensity group maintained a significantly elevated ISI until 15 days after cessation of exercise as compared to the high-intensity group which did not .
In accordance with the literature [24,25], exercise capacity was not correlated with LVEF in this cohort with a mild to moderate reduced systolic function underscoring that cardiovascular, ventilatory and metabolic coupling as well as low muscular fitness are the determining factors for exercise capacity.
The number of patients studied (n = 10) is small. Even though being in the range of other studies , it precludes the generalization of our results. Patients were not randomized to the order of the three tests (at rest, after anaerobic and aerobic exercise). Fasting PG, however, was almost identical at the start of each OGTT (Table 3 and Fig. 1), exhibiting a very similar metabolic state during the different settings. Performing an OGTT directly after exercise is an unusual protocol. The aim of the presented study was, however, to describe direct effects of exercise on postprandial glucose metabolism. The OGTT represents a highly standardized test that allows a best possible comparison of the individual results. Since the performance of an OGTT requires an overnight fasting, aerobic and anaerobic exercise tests had to be performed under these certain conditions. A nonfasting state or even a postprandial state might have changed our results. So far, we do not know, whether our test correctly reflects the metabolic state. In addition, there were only acute measurements of the metabolic effect in this study, and the long-term response to different exercise intensities might be different. These questions should be investigated in further studies.
There seems to be no general recommendation for exercise intensity being appropriate for all patients with different metabolic disorders. In particular, there is no study so far, evaluating the optimal exercise intensity in patients with cardiovascular disease and T2DM. A very low (to at most moderate) exercise intensity might be appropriate in this deconditioned cohort with T2DM and CHD, as shown in this study. High-intensity exercise might be adequate to prevent the metabolic syndrome in healthy elderly people  and to reduce fasting glucose in younger and very fit patients with T2DM . As only a strict aerobic exercise intensity was able to reduce post-load hyperglycemia in this cohort, it is crucial to tailor exercise prescriptions to the specific needs of the individual patient.
Long-term response to different exercise intensities should be investigated without disregarding personal preferences for a specific type of exercise in order to increase the adherence to sustainable lifestyle changes in patients with T2DM. Aerobic exercise intensity to reduce blood glucose in patients with T2DM, however, seems to be much lower than anticipated so far.
There was no financial support and no grants for this work and it has not been presented before.
Conflicts of interest
There are no conflicts of interest.
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