Inflammation, Vascular Repair, Injury After Exercise in T1D
This study aimed to examine cEPCs, cECs and TNF-α at rest, and in response to acute submaximal exercise, in physically fit males with and without Type 1 diabetes. This study is the first of this kind and we have shown that resting cEPCs and cECs were similar between groups, despite patients demonstrating ~4 fold greater TNF-α concentrations. However, the increase in cEPCs was blunted in the patients, with the change from rest to the morning following exercise being ~112 % lower in Type 1 diabetes, when compared to control participants. Furthermore, our data showed that this blunted response within the Type 1 diabetes group appeared to be predicted by HbA1c and TNF-α concentrations.
Our finding that resting cEPCs and cECs were similar between groups is in agreement with Fadini et al., but also contrasts with other literature in the area. In comparison with Sibal et al., the Type 1 diabetes patients of this study were of comparable age and had similar duration of diabetes and also shared a raised inflammatory state. The difference in the findings are potentially explained by the high cardio-respiratory fitness and excellent glycemic control of our patients (HbA1c ~7 %, 53 mmol/mol vs. ~8.5 %, 69.4 mmol/mol). Indeed, the participants in the study of Fadini et al. also had good HbA1c (~7.7 %). Whilst the relationship between glycemic control and cEPCs is established in Type 2 diabetes and acute myocardial infarction, there are few studies in Type 1 diabetes. Most recently it has been shown that in children with Type 1 diabetes, cEPCs count was inversely related with HbA1c. In our study, it should be reassuring to both patients and clinicians that after achieving good glycemic control cEPCs were comparable to healthy controls. However, since our patients were also very fit, it would be interesting to investigate the change in HbA1c and cardio-respiratory fitness both independently, and concomitantly (e.g. via an exercise training programme), to provide further insight into the normalised cEPCs we show.
This is the first study to examine acute exercise and cEPCs regulation in Type 1 diabetes and our findings suggest that regulation of cEPCs release in response to an exercise stimulus may be abnormal despite eliciting normal resting cEPCs and excellent glycemic control. Research examining the bone marrow biology of both animals and patients with diabetes confirms that bone marrow function is impaired which may reduce cEPCs mobilisation. Recent research has shown that the mobilisation of cEPCs in response to administration of recombinant granulocyte colony-stimulating factor is impaired in diabetes patients. Speculatively, bone marrow function may also have contributed to the blunted cEPCs response to exercise demonstrated in the Type 1 diabetes patients.
It is well established that resting cEPCs are normal or high in active individuals, thus it is of interest that both groups of participants in our current study had a cardio-respiratory fitness (VO2max 50 ml.kg.min) which would categorise them as excellent, or above average (average VO2max for males aged ~27 being ~ 42 ml.kg.min). Earlier research has described ~4 fold higher cEPCs in trained marathon runners when compared to sedentary control participants, and there is evidence that regular aerobic-exercise training is an effective intervention to raise cEPCs in both healthy and patient populations. Potentially, the regular aerobic exercise engaged in by the participants in this study, evidenced by high cardio-respiratory fitness, may additionally explain the comparable resting cEPCs shown.
Our study provides another interesting finding that the comparable cEPCs and cECs between groups were concomitant with ~4 fold higher TNF-α concentrations seen in our Type 1 diabetes patients. The raised inflammation is in agreement with our previous data of Sibal et al.. There is evidence, in advanced cardiovascular disease patients, that cEPCs are reduced potentially due to the myelosuppressive effects of TNF-α. Furthermore, three months of TNF-α inhibitory drug treatment has been shown to significantly raise cEPCs in rheumatoid arthritis patients. Further research is required to investigate the interaction between the anti-inflammatory effects of regular exercise in populations which experience chronic inflammation, such as Type 1 diabetes.
We show for the first time that despite the excellent glycemic control and high physical fitness of the Type 1 diabetes patients there was a blunting of the rise in cEPCs elicited after exercise. Shear stress, increased nitric oxide (NO) production, through increased activity of endothelial nitric oxide synthase, and hypoxia are suggested to be key stimuli that contribute to the mobilisation of cEPCs with exercise. However, in some instances oxidative stress can reduce NO availability, which could, speculatively, attenuate the signal for cEPCs mobilisation. Recent research has shown that well controlled Type 1 diabetes patients demonstrate increased oxidative stress during aerobic exercise, in comparison with non-diabetic control participants. Furthermore, there may also be a role for the myelosuppressive effect of TNF-α in these responses. Future research should examine the role of both oxidative stress and inflammatory signalling in the acute cEPCs response to exercise.
Although this study is limited by a relatively small sample size, it is important to consider the homogenous group that were observed, with patients all male, aged 19–34 years, HbA1c range of 6–7.9 %, and all physically fit; as such, the importance of these data should not be underestimated. Future research should explore how improving HbA1c independently of improving physical fitness influences markers of vascular repair at rest and in response to exercise. Conversely, it would be of interest to explore if improving physical fitness can rescue the deleterious effect of poor glycaemic control on cEPCs regulation. Furthermore, the role of the insulin species patients are treated with could be an additional factor to consider when examining the impact of exercise on cEPCs in this population.
Discussion
This study aimed to examine cEPCs, cECs and TNF-α at rest, and in response to acute submaximal exercise, in physically fit males with and without Type 1 diabetes. This study is the first of this kind and we have shown that resting cEPCs and cECs were similar between groups, despite patients demonstrating ~4 fold greater TNF-α concentrations. However, the increase in cEPCs was blunted in the patients, with the change from rest to the morning following exercise being ~112 % lower in Type 1 diabetes, when compared to control participants. Furthermore, our data showed that this blunted response within the Type 1 diabetes group appeared to be predicted by HbA1c and TNF-α concentrations.
Resting cEPCs and cECs
Our finding that resting cEPCs and cECs were similar between groups is in agreement with Fadini et al., but also contrasts with other literature in the area. In comparison with Sibal et al., the Type 1 diabetes patients of this study were of comparable age and had similar duration of diabetes and also shared a raised inflammatory state. The difference in the findings are potentially explained by the high cardio-respiratory fitness and excellent glycemic control of our patients (HbA1c ~7 %, 53 mmol/mol vs. ~8.5 %, 69.4 mmol/mol). Indeed, the participants in the study of Fadini et al. also had good HbA1c (~7.7 %). Whilst the relationship between glycemic control and cEPCs is established in Type 2 diabetes and acute myocardial infarction, there are few studies in Type 1 diabetes. Most recently it has been shown that in children with Type 1 diabetes, cEPCs count was inversely related with HbA1c. In our study, it should be reassuring to both patients and clinicians that after achieving good glycemic control cEPCs were comparable to healthy controls. However, since our patients were also very fit, it would be interesting to investigate the change in HbA1c and cardio-respiratory fitness both independently, and concomitantly (e.g. via an exercise training programme), to provide further insight into the normalised cEPCs we show.
cEPCs Response to Exercise
This is the first study to examine acute exercise and cEPCs regulation in Type 1 diabetes and our findings suggest that regulation of cEPCs release in response to an exercise stimulus may be abnormal despite eliciting normal resting cEPCs and excellent glycemic control. Research examining the bone marrow biology of both animals and patients with diabetes confirms that bone marrow function is impaired which may reduce cEPCs mobilisation. Recent research has shown that the mobilisation of cEPCs in response to administration of recombinant granulocyte colony-stimulating factor is impaired in diabetes patients. Speculatively, bone marrow function may also have contributed to the blunted cEPCs response to exercise demonstrated in the Type 1 diabetes patients.
It is well established that resting cEPCs are normal or high in active individuals, thus it is of interest that both groups of participants in our current study had a cardio-respiratory fitness (VO2max 50 ml.kg.min) which would categorise them as excellent, or above average (average VO2max for males aged ~27 being ~ 42 ml.kg.min). Earlier research has described ~4 fold higher cEPCs in trained marathon runners when compared to sedentary control participants, and there is evidence that regular aerobic-exercise training is an effective intervention to raise cEPCs in both healthy and patient populations. Potentially, the regular aerobic exercise engaged in by the participants in this study, evidenced by high cardio-respiratory fitness, may additionally explain the comparable resting cEPCs shown.
Inflammation and cEPCs
Our study provides another interesting finding that the comparable cEPCs and cECs between groups were concomitant with ~4 fold higher TNF-α concentrations seen in our Type 1 diabetes patients. The raised inflammation is in agreement with our previous data of Sibal et al.. There is evidence, in advanced cardiovascular disease patients, that cEPCs are reduced potentially due to the myelosuppressive effects of TNF-α. Furthermore, three months of TNF-α inhibitory drug treatment has been shown to significantly raise cEPCs in rheumatoid arthritis patients. Further research is required to investigate the interaction between the anti-inflammatory effects of regular exercise in populations which experience chronic inflammation, such as Type 1 diabetes.
We show for the first time that despite the excellent glycemic control and high physical fitness of the Type 1 diabetes patients there was a blunting of the rise in cEPCs elicited after exercise. Shear stress, increased nitric oxide (NO) production, through increased activity of endothelial nitric oxide synthase, and hypoxia are suggested to be key stimuli that contribute to the mobilisation of cEPCs with exercise. However, in some instances oxidative stress can reduce NO availability, which could, speculatively, attenuate the signal for cEPCs mobilisation. Recent research has shown that well controlled Type 1 diabetes patients demonstrate increased oxidative stress during aerobic exercise, in comparison with non-diabetic control participants. Furthermore, there may also be a role for the myelosuppressive effect of TNF-α in these responses. Future research should examine the role of both oxidative stress and inflammatory signalling in the acute cEPCs response to exercise.
Although this study is limited by a relatively small sample size, it is important to consider the homogenous group that were observed, with patients all male, aged 19–34 years, HbA1c range of 6–7.9 %, and all physically fit; as such, the importance of these data should not be underestimated. Future research should explore how improving HbA1c independently of improving physical fitness influences markers of vascular repair at rest and in response to exercise. Conversely, it would be of interest to explore if improving physical fitness can rescue the deleterious effect of poor glycaemic control on cEPCs regulation. Furthermore, the role of the insulin species patients are treated with could be an additional factor to consider when examining the impact of exercise on cEPCs in this population.